text:
Equine Drugs, Medications, and Performance Altering Substances: Their Performance Effects, Detection, and Regulation
Dr. Thomas Tobin, Dr. Julio Gutierrez, Emily Schwartz,
Dr. Fernanda Camargo, and Charlie Hughes
Equine Pharmacology, Therapeutics and Toxicology Laboratory
The Maxwell H. Gluck Equine Research Center
Dr. Rodney Eisenberg
Frontier Biopharm
6013 Atwood Drive, Suite 300
e-mail: rod@frontierbiopharm.com
Dr. Andreas Lehner
Diagnostic Center for Population and Animal Health
4125 Beaumont Road
Mr. Kent Stirling
Florida Horsemen's Benevolent and Protective Association
Opa Loca, FL 33055-0808
Based on a presentation to the Equine Law section
of the Kentucky Bar Association at Keeneland,
Lexington, Kentucky, Oct 21, 2005
(webpage updated Dec 2010)
2 Background and Definitions
4 Can Drugs or Medications Influence the Outcome of a Race?
5 The Introduction of ELISA Testing (1988)
6 Mass Spectral Confirmation
7 Liquid Chromatography/Mass Spectrometry/Mass Spectrometry
(LC/MS/MS)
8 "Zero Tolerance" Testing
9 Numbers of Medication Molecules: Medication Dosing and Elimination
10 Thresholds, Including "No Effect Thresholds" (NETs)
11 Withdrawal Time Guidelines
12 Reference Standards
13 Medication Rules
14 The Current Racing Medication Testing Consortium (RMTC) &
Association of Racing Commissioners International (ARCI) Rule
16 Appendices
1. Summary
Thoroughbred Racing has been testing for drugs and medications since about 1903. Today, racehorse testing is by far the longest established, broadest in scope and most sensitive drug testing performed on earth. Racehorse testing is also performed within an extremely stringent regulatory context, and my understanding is that many of our constitutional protections as US citizens are inoperative in the racing environment. Racehorse testing is also remarkably "clean," as the incidence of deliberate use of performance affecting substances seems to be very small.
There are good reasons for all of the above. It is empirically clear that medications are highly likely to influence the performance of racing horses, although the scientific evidence for actual improved performance is much less than overwhelming.
In the mid-nineteen eighties, however, the use of high potency drugs with clear potential to affect performance was not particularly well controlled. Following a directive from the Kentucky State Racing Commission, an interdisciplinary team at the University of Kentucky worked on adapting ELISA testing to racing chemistry; this proprietary technology was at that time a major step towards solving the problem of the abuse of high potency drugs in racing horses, and these tests are now marketed worldwide out of Lexington (www.neogen.com/forensickits.htm)
One of the lessons that came out of ELISA testing is that advances in drug detection/testing are research driven. Once a medication is "called positive", that is the first "positive" is called and prosecuted, the rate of use of the substance drops dramatically, to close to zero, but not quite zero; it appears that there are always people ready to try a medication that worked for them, or for a colleague, or a rival, in the past.
Overall, the rate at which performance altering medication violations are reported in racing is extremely small. For example, from 1995–1999 there were about 3 positives for every 100,000 samples for Association of Racing Commissioners International [ARCI] Class 1 violations after trace level identifications of dietary and environmental substances are eliminated. By far, the most common identifications reported in racing are residual "traces" of well recognized and widely used therapeutic medications, so called "tail-ends" of therapeutic medications , and traces of dietary and environmental substances that also happen to be ARCI substances, for example trace level identifications of caffeine and other substances widely used by humans.
The ease with which such "traces" of therapeutic medications, dietary and environmental substances can be detected using current testing technology has now clearly led scientists and regulators away from the old "zero tolerance" approach, which many authorities now see as outdated, to defined regulatory limits or "thresholds" for therapeutic medications, endogenous, dietary and environmental substances.
This situation was driven in large part by ELISA testing, which allows highly sensitive detection of trace amounts (tail ends) of therapeutic medications, environmental and dietary substances. In the nineteen nineties, following another Kentucky Racing Commission directive, the University of Kentucky program at The Maxwell H. Gluck Equine Research Center pioneered the basic research that underpins the evolving and now in principle very well established concept concerning the use of regulatory "thresholds" in racing regulation.
More recent challenges include developing effective regulatory methods for the newer recombinant hormonal products such as the various human recombinant erythropoietin products and variants thereof and growth hormones. More recently, a high quality ELISA test has been made available for human recombinant erythropoietin and racing chemistry has scored a major scientific breakthrough by developing the first mass spectral confirmation method to detect use of recombinant human erythropoietin (rhEPO) in horses or, indeed, in any species.
2. Background and Definitions
There are at least 30 million known chemical substances and 4,000 or more prescription medications. Racing regulators in the United States , therefore, divide drugs and medications into two major groups:
The largest group of concern to regulators is the "performance-enhancing substances", whose identification in a horse is viewed with great regulatory concern. Testing for these substances usually proceeds at the highest level of sensitivity possible; so-called "zero-tolerance" testing. About 900 or so substances are classified by the Association of Racing Commissioners International (ARCI) Uniform Classification System for Foreign Substances as potentially performance enhancing in a five class system, the most complete listing of such substances available anywhere in the world (http://www.arci.com/druglisting.pdf).
The second and smaller group comprises the "therapeutic medications", recognized by the American Association of Equine Practitioners [AAEP] and the Racing Medication and Testing Consortium [RMTC]. There are approximately 50 plus of these medications used therapeutically in horses in training (Table 1). Since about the year 2000, it has come to be much more generally accepted that we must set "limitations" on the sensitivity of testing for therapeutic medications. These limitations are variously called thresholds or reporting levels, or decision levels ( California ) apparently depending on the semantic preference of the individual jurisdiction.
Table 1. Therapeutic Medications Routinely Used and Identified as Necessary by the Veterinary Advisory Committee — (Racing Medication and Testing Consortium [RMTC] draft list of therapeutic medications, 2005)
1. Acepromazine 17. Dipyrone 33. Omeprazole
2. Albuterol 18. Flunixin 34. Pentoxifylline
3. Aminocaproic Acid 19. Fluprednisolone 35. Phenylbutazone
4. Atropine 20. Fluphenazine 36. Phenytoin
5. Beclomethasone 21. Furosemide 37. Prednisolone
6. Betamethasone 22. Glycopyrrolate 38. Prednisone
7. Boldenone 23. Guaifenesin 39. Procaine Penicillin
8. Butorphanol 24. Hydroxyzine 40. Pyrilamine
9. Cimetidine 25. Isoflupredone 41. Ranitidine
10. Clenbuterol 26. Isoxsuprine 42. Reserpine
11. Cromolyn 27. Ketoprofen 43. Stanozolol
12. Dantrolene 28. Lidocaine 44. Testosterone
13. Detomidine 29. Mepivacaine 45. Triamcinolone
14. Dexamethasone 30. Methocarbamol 46. Trichlomethiazide
15. Diazepam 31. Methylprednisolone
16. DMSO 32. Nandrolone
3. History
Up to about 100 years ago there was little concern about the use of medication in racing horses, and particularly so in North America . The 1800s had seen the purification of cocaine and morphine and availability of these substances in pure form made the acute stimulant medication of racing horses a reality. Around the turn-of-the-century (1890-1910), a number of American trainers went to Europe , taking with them these new "American" medications. As a group, these trainers were so successful that they became known in European racing circles as the "Yankee Alchemists."
Figure 1. Carl Vernet depicts apparently routine
pre-race medication of horses, ca. 1810
In the early 1900s the Honorable Mr. George Lambton (Fig. 2), the sartorially correct and socially prominent leading English trainer of his time, grew tired of losing races to the "Yankee Alchemists," as he also soon grew tired of politely requesting the English Jockey Club to do "something" about the problem. He therefore purchased some of the American "medications," and publicly announced that certain horses in certain races were going to be, well, shall we say "medicated." These activities rapidly gained the Jockey Club's attention, and in 1903 the Jockey Club made the medication of a racing horse an offense against the rules of racing in England. While the record is silent as to how these medications were to be detected, the prescribed punishment was to be "ruled off the turf," a punishment still in place in parts of the English speaking world.
The Honorable George Lambton
Somewhat farther from home, an American trainer by the name of Jack Keene was also having a very good run in Russia. Mr. Keene's run, however, came to an abrupt halt one day when he was met in the paddock by a Russian racing official, followed by Russian chemist, complete with a basket of frogs. Some saliva was taken from Mr. Keene's horse, and presumably force-fed to the frog, which then reportedly behaved in a most un-frog-like way. Mr. Keene's horse was duly declared "positive," and shortly thereafter Mr. Keene left Russia and returned to Kentucky and to his family farm, Keeneland.
Classic analytical chemistry based race testing as we know it started in France , apparently before 1910. In 1935, Mr. William Woodward of Woodward Stakes fame, sent a Dr. Catlett, a veterinarian and Dr. Charles Morgan, a chemist, from Florida to France to learn the French drug testing techniques. They returned to Florida and set up the first US drug testing lab; later the New York Racing Commission opened a racing chemistry laboratory on the10th floor of a building on Chambers Street in Manhattan . In 1947 the professional association of racing chemists, the Association of Official Racing Chemists [AORC] was formed.
Figure 4. The late Mr. Robert Vessiny, Truesdail Labs, Tustin, CA, circa 2000. Robert Vessiny's professional career began in 1941 at the NY Racing Commission Laboratory on Chambers Street in Manhattan and continued until 2005, covering virtually the entire history of US racehorse testing which started about 1935 in Florida and New York under Dr. Charles Morgan.
4. Can Drugs or Medications Influence
the Outcome of a Race?
Drugs and medications can be used to influence the outcome of races in a number of ways. Acute stimulant medication is the administration of a stimulant substance to a horse shortly before post. Among the especially useful agents in this area are the opiates, which have long been used in racing horses, and also the amphetamine-like stimulants, and most especially methylphenidate (Ritalin). All of these substances have been widely used, the opiates likely for hundreds of years, and presumably particularly so when testing for these agents was not available.
Figure 6. Narcotic drug family dose response curves
As drug testing improved in sensitivity those individuals seeking an "opiate edge" began to use the more potent and thus more difficult to detect opiates. The unnamed but highly potent opiate at the far left of the above family of opiate dose response curves (Fig. 6) is etorphine, or "elephant juice." Etorphine is one of the most potent opiates known and at the time that this figure was published in "Drugs and the Performance Horse" in 1981, there was no test available that could detect it, which is the reason that this medication is unidentified in this original paper. This figure also shows, for one family of substances, the 10,000 fold range in dose/potency from the least potent opiate tested on the right, meperidine, at about a one gram/horse dose, to the very highly potent etorphine on the far left, with 50 micrograms (50 millionths of a gram) producing an equivalent pharmacological effect to one gram or more of meperidine. And, of course, etorphine was also, in round figures, about 10,000 time more difficult for the chemist to detect than the old standbys of morphine and heroin, one of whose street names was "horse." This great increase in the potency of medications being used in horses set the stage for the development of ELISA Testing, as we will discuss later.
As well as being administered stimulants to win races, horses can also be medicated to win by relaxing them and allowing the horse to run its best possible race. The widely used tranquilizer acepromazine, and any number of related or equivalent agents, have reportedly been used in this way.
Improving a horse's "wind" by opening its airways through the use of bronchodilators may also improve the performance of horse, and especially a horse that is sub-clinically broncho-constricted. In this regard, the best selling ELISA test at one time was a particularly sensitive and broad scope bronchodilator test, the availability of which test abruptly stopped the less than therapeutic use in racing horses of a bronchodilator called terbutaline.
Only triple dead heat on record
Grindstone wins the 1996
Kentucky Derby by a nose
The difficulty with trying to scientifically demonstrate performance effects of drugs in small numbers of horses is that the drug needs to produce a positive performance effect of about the same magnitude as Secretariat's win at Belmont (Fig. 9) to meet the lowest level of statistical significance acceptable in science. This is a considerable experimental challenge; another way of looking at this is that successful horse trainers make far more subtle and discriminating judgments than most scientists, of which I think there is no doubt whatsoever.
Figure 9. Secretariat wins at Belmont
Veterinarians certify horses as being sound in "wind and limb." Obviously, medications that can affect these parameters and also the "attitude" or "behavior" of a horse have the potential to affect both the presentation of a horse and also, presumably, the results of the ultimate performance analysis, the outcome of a race. By the mid-1980s the use of highly potent drugs, and most especially highly potent opiate type medications such as fentanyl (Sublimase) and etorphine, and high potency bronchodilators to improve the racing performance of horses had created considerable problems for race horse testing and also for racing.
5. The Introduction of ELISA Testing, 1988
In the mid-1980s, race testing was for all practical purposes dependent on a primary screening technique called Thin Layer Chromatography (TLC). This technology has many useful qualities, being inexpensive and fast, but it is not particularly sensitive, and in the mid-1980s some horsemen were reportedly using high potency narcotics, stimulants, bronchodilators and tranquilizers with impunity. In 1985 we were requested (directed?) by the then Kentucky State Racing Commission to "fix this problem." The solution that we developed, ELISA testing for high potency drugs and medications, is in place and widely used around the world today, and is evidenced here in Lexington by a thriving commercial concern, Neogen Corp, on Nandino Boulevard, employing 100 people and bringing in about US $50 million a year into Lexington (not all through ELISA tests – www.neogen.com/forensickits.htm).
The term ELISA is an acronym that stands for Enzyme Linked ImmunoSorbent Assay. Simply put, an ELISA test is a variant on the home pregnancy test technology. It requires a drop of urine; it can be performed relatively rapidly, it is/can be highly sensitive and can be read by eye. When ELISA testing was first introduced, the problem was to keep the technology from "putting down" too many trainers, especially in those jurisdictions that had frozen "back samples." Let me simply say that this was a turbulent time for me professionally, but matters eventually settled down and, as I indicated, ELISA testing is in many areas the backbone of drug screening worldwide today.
The term ELISA is an acronym that stands for Enyme Linked ImmunoSorbent Assay. Simply put, an ELISA test is a variant on the home pregnancy test technology. It requires a drop of urine; it can be performed relatively rapidly, it is/can be highly sensitive and can be read by eye. When ELISA testing was first introduced, the problem was to keep the technology from "putting down" too many trainers, especially in those jurisdictions that had frozen "back samples". Let me simply say that this was a turbulent time for me professionally, but matters eventually settled down and, as I indicated, ELISA testing is the backbone of drug screening worldwide today.
Figure 10. ELISA Testing
This is a 96 well ELISA plate in which the full blue color of an ELISA negative has been developed in most wells. The clear wells on the left hand side are the "positive controls" containing calibration standards. All of the other wells represent ELISA "negative" urine samples. A "track" ELISA positive would show up as a clear well in the middle of the blue samples, in laboratory jargon, a so called "whiteout," or an ELISA positive.
Figure 11. ELISA Test Results
An ELISA test will usually detect about 5 ng/ml (or 5 parts per billion) or less of drug or drug metabolite in the sample. Some tests are 10 fold more sensitive, detecting down to the high parts per trillion. To put these figures in perspective, one part per billion is one second in your life if you are 32 years old.
To put the matter of testing sensitivity into regulatory perspective, a sure prescription for regulatory friction/problems is a therapeutic medication (or a dietary or environmental substance) given at higher (gram) doses to horses, excreted efficiently in urine, and being tested for by an analyst with a highly sensitive ELISA test with no thresholds/decision levels in place. In the absence of "thresholds" or detection/decision limits in place, a sensitive ELISA test can become basically a hunting tool/license for forensic chemists. Isoxsuprine, an ARCI class 4 therapeutic medication, administered orally in gram amounts per day, and excreted very efficiently and at very high concentrations in equine urine, is a classic example.
Finally, we must always remember that an ELISA test simply binds to and "sees" one side/surface of the medication molecule. Therefore, while an ELISA "negative" is almost certainly a true negative, an ELISA test will, by definition, interact to some extent with substances other than the drug in question. As such, the rule with an ELISA "positive" is that it can always be, by definition, a so-called "false positive." Which is, of course, why chemists invariably follow ELISA screening with the much more chemically specific technique of Mass Spectral "confirmation."
And again, on the other hand, within the performance limits of the assay, an ELISA "negative" is virtually certainly a true negative.
6. Mass Spectral Confirmation
While ELISA screening/testing is fast and highly sensitive, it is, as set forth above, far from specific. The second and absolutely critical and essential step in the testing process is confirmatory testing, usually by Mass Spectroscopy. In this step, the molecule is isolated and its precise mass measured, and the molecule is also broken into a series of fragments. Both the mass and relative proportions of these fragments (the fragmentation pattern) are specific for the given drug, and are then matched with known certified reference standards run through the Mass Spectrometer in parallel with the test samples. As such, a full scan mass spectrum, with appropriate matching controls, is the "gold standard" in drug testing, and is considered definitive evidence for the presence of the substance in the sample in question. Additionally racing also almost always allows collection of an independent or "split" or "referee" sample, which the trainer can have analyzed independently [although sometimes more independently than others!] to check for the presence of the substance in question. Independent replication of the primary findings in the "split" or "referee" analysis usually neutralizes any substantial challenges in the area of the substance claimed identified and for some classes of substances, namely therapeutic medications, dietary and environmental substances, may well yield important mitigating or exculpatory information.
Figure 12.
Dr. Lehner and the LC/MS/MS
Comparison of Mass Spectra of a post-race etorphine and an authentic standard. The lower figure shows the mass spectrum of an authentic etorphine laboratory standard. Note the molecular ion at mass 483, the base peak at mass 272 and the various other ions of the standard or control spectrum. Note the very close correspondence of the standard or control mass spectrum with the mass spectrum of the derivatized material recovered from the post-race sample, indicating that the material recovered from the post race sample is indistinguishable from authentic derivatized reference standard etorphine.
7. Liquid Chromatography/Mass Spectrometry/
Mass Spectrometry (LC/MS/MS)
More recently an even higher sensitivity and specificity technology has become widely available, namely, Liquid Chromatography/Mass-Spectrometry/Mass-Spectrometry (LC/MS/MS).
Schematic of MS/MS showing the relationship between the Mass Spectrometers and the parent/precursor and product/daughter ions.
LC/MS/MS technology allows the unequivocal identification and quantification of substances down to low picogram per milliliter, that is, low part per trillion concentrations, or at times even lower concentrations. The technology is called LC because the separation technique, the liquid chromatographic (LC) "feed" into the mass spectrometer, which expands the range of substances that can be chromatographed and therefore analyzed. The actual analysis takes place in a dual stage Mass Spectrometer (MS/MS), linked by a reaction/fragmentation chamber. The first Mass Spectrometer stage is calibrated/set to identify a specific drug/molecular mass of interest, let us say clenbuterol, which has a molecular mass of 277.19. This drug molecule/mass then feeds into the reaction/fragmentation chamber, where it is fragmented, and the molecular fragments are then fed into the second Mass Spectrometer stage, where the product/daughter ion fragments are identified. Figure 16 below shows the fragmentation of clenbuterol in our hands, showing how the 277.19 mass clenbuterol molecule fragments to yield an intermediate of 259 and a final mass of 203, one of several possible fragmentation sequences as set forth in (Fig. 16).
The entire family of clenbuterol fragments, going from 277->203, 279->205, 277->259, 279->261, 277->57 and 277->57. As we indicated, since each drug molecule has a specific starting mass, and a specific fragmentation pattern and the relationship between parent and daughter ions can be clearly identified, this is a highly sensitive and highly specific analytical technique.
Finally, given the very high sensitivity and specificity of this testing procedure, it can be used to detect parts per trillion or picograms per ML of drug in relatively small sample volumes, such as a one milliliter plasma sample, as set forth in Reference 9 below.
This very high and continually increasing sensitivity of drug testing techniques and instrumentation brings with it the problem of detecting more and more minute traces of drugs, including therapeutic medications used legitimately and appropriately to protect the health and welfare of the horse, traces that are clearly pharmacologically and forensically irrelevant. As such, the extremely high sensitivity of current analytical techniques has created significant problems, and perhaps has made the so called "zero-tolerance" concept or approach to equine drug testing irrational and irrelevant when applied to therapeutic medications and dietary and environmental substances.
8. Zero Tolerance Testing
"Zero Tolerance" testing is not testing down to "Zero" molecules, which no analytical chemist can yet accomplish, but rather testing to the Limit of Detection (LOD) of the best available technology. While this may be an entirely appropriate analytical approach to the regulation of performance altering substances which have no place in racing, it is absolutely not considered appropriate for therapeutic medications. Therapeutic medications are substances used to maintain the health and welfare of horses, and to arbitrarily change the sensitivity of testing for these substances depending on either the whim of the chemist or today's availability of improved testing technologies, is entirely inappropriate, as we will see from review of the following basic mathematics of drug/medication dosing and drug elimination.
9. Numbers of Medication Molecules:
Medication Dosing and Elimination
When you administer a dose of phenylbutazone to a horse, you administer about the same number of phenylbutazone molecules as there are stars in the known universe, that is about 6 followed by 21 zeros molecules. This is a very large number of molecules indeed.
The horse will eliminate the bulk of this dose of phenylbutazone quite rapidly. If phenylbutazone in the horse has a 7.22 hour half-life, 50% of the drug will be eliminated by 7.22 hours after dosing, 75% by 14.44 hours post dosing, 87.5 by about 21 hours post dosing, and 90% by 24 hours after dosing. At the end of day 1, when 90% of the drug is eliminated, the pharmacological effect of the drug is, for all practical purposes, gone, but there is still present in the horse the not inconsiderable number of 6 followed by 20 zeros worth of phenylbutazone molecules. Every day another 90% of the drug in the body of the horse will be eliminated, and other zero drops off.
However, if the chemist really wants to look, with current technology he or she can easily find traces of the phenylbutazone or its metabolites for 14 days or more after administration, a time post-administration that even the most conservative chemists and regulators generally do not wish to pursue a medication identification. However, the question now arises of when, precisely, should the chemist stop pursuing these traces? Or at what trace concentration should racing regulators cease being concerned?
10. Thresholds, Including "No Effect Thresholds" (NETs)
The answer to this question is simple; the chemist should stop pursuing these traces precisely when he/she is instructed to stop. It is, however, slightly more complicated to determine the exact point at which chemists should be instructed to cease and desist their analytical endeavors.
We approached this question experimentally in the Maxwell H. Gluck Equine Research Center during the second half of the 1990s. Simply put, we administered decreasing doses of local anesthetics to horses until we saw no detectable local anesthetic effect, which gave us the No Effect Dose for the drug, in this case a local anesthetic. Then we measured the concentrations of the drug, actually a recovered drug metabolite fragment, in the urine, and the concentrations we came up with are, by experimental demonstration, not associated with any pharmacological effect. These concentrations then become "No Effect Thresholds" in urine for the specific therapeutic medication. These No Effect Threshold [NET] concentrations can then be written into the medication rules, and the chemist can then be advised not to test below these now scientifically defined "no effect" regulatory threshold concentrations.
Figures 19-21. Equine response to heat lamp stimuli
We presented this scenario hypothetically in 1994-95, and then started the actual research on regulatory thresholds. We were immediately vigorously attacked from conservative quarters, at first anonymously and libelously. In 1996 one of these libelous letters surfaced signed by Mrs. Donna Ewing of the Illinois Hooved Animal Humane Society. The University of Kentucky "encouraged me," shall we say, to sue, which I did. While I eventually dropped the suit, its filing had the desired effect of silencing the complaining parties, who have not been heard from since with regard to racing. More to the scientific point, we completed our ongoing thresholds research and published it in the refereed scientific literature. By the year 2000, the intellectual concept and more importantly, the actual word "thresholds" became more or less "safe" for a courageous racing administrator to allow past his (or her) lips. Indeedby today December 2010, the concept of regulation by the use of specified concentration "thresholds" in plasma or in urine is extremely well established, at least in North America .
In this regard, is of interest to note that the concept/approach of "zero tolerance" was, to some extent, officially voted out of favor and "off the regulatory island" in one of the opening papers of the 13th International Conference of Racing Analysts and Veterinarians (ICRAV 2000) in Cambridge, England. In this paper Professor Robert L. Smith addressed the concept of zero tolerance, which he considered a "fading illusion," and reviewed the events "which are increasingly undermining the suitability of this approach." In his words, "The zero tolerance approach . . . is in essence an illusion in which the magician is the racing chemist." He continued, "The zero tolerance approach is both philosophically and pragmatically unsound. . . . The goal for the future integrity of racing is to develop "reporting values" for therapeutic substances based upon rigorous analysis of their pharmacological and pharmacokinetic properties and using an appropriate model."
11. Withdrawal Time Guidelines
Let us now move from the theoretical and illusionary concept of "zero tolerance" to practical horsemen's concerns. A "regulatory threshold" or a "reporting level" is a concentration value (such as, for example 10 parts per billion in urine) that has, in the larger scheme of things, little actual reality for horsemen. This is because a horseman or, for that matter, a chemist locked out of his/her laboratory, cannot "see" 10 parts per billion of anything in horse urine. What the horseman needs are clear, transparent "withdrawal time guidelines," i.e., guidelines as to when he/she should stop administering the medication prior to post so that the blood or urine "reading" comes in below the stipulated regulatory threshold, whatever that particular threshold may be.
Establishing withdrawal time guidelines is considerably more difficult than determining threshold concentrations. The only way to answer the guidelines question is, again, by actual experimental determination, followed by field application. The specific medication product/formulation in question must be defined/specified, and the formulation, dose, route, and duration and number of administrations specified. The medication must be administered to a significant number, hopefully at least 20 or more, Thoroughbred horses in training, and the blood or urinary concentrations of the parent medication or its principal urinary metabolite/analyte followed over a period of time. The laboratory performing the analyses should be appropriately accredited (American Association of Laboratory Accreditation, A2LA), and have in place a validated quantitative analytical method for the threshold substance at concentrations down to concentrations significantly below the lowest concentration of interest in the experimental model/horses. (http://hbpa.org/resources/MedicationPolicy.pdf).
The data obtained must then be analyzed statistically, and fitted to a defined mathematical distribution. One can then use this mathematical distribution to advise horsemen that if they administer the drug following X stipulation doses/days, and stop administration at Y hours prior to post, there will be a Z probability of exceeding the regulatory threshold. One of the things that everybody must understand is that if you administer a medication to a horse at any time close to post, there is always a finite mathematical probability of exceeding the threshold; all anybody can do is estimate as accurately as possible the statistical probability of exceeding the regulatory threshold, i.e., of incurring an "overage", and make sure that the risk of an inadvertent or statistical "overage" is a risk that the horseman can live with.
This finite probability of a therapeutic medication overage is most likely the reason that regulatory authorities are almost invariably reluctant to be associated with "withdrawal time" guidelines. While a 1/1000 risk of a "positive" may be an entirely acceptable risk for an individual horseman running a small number of horses, if the authority approves a given "withdrawal time," it immediately assumes responsibility for all 10-20,000 or more samples tested in the jurisdiction, which increases the probability of a statistical overage 10-20,000 fold, or more if the authority tests more than 20,000 samples per year.
The first formal scientific approach to this question of determining a regulatory threshold linked to a specific withdrawal time was undertaken at the request of the Kentucky Horsemen's Benevolent and Protective Association [KY HBPA] in the early 1980s. Responding to a request from President Ed Flint of the Kentucky HBPA, we defined the population distribution characteristics of furosemide in equine plasma after its administration to 49 horses [Chay et al, Ref 11]. This work was soon published, and then picked up by a number of racing states, starting with Oklahoma in about 1986. Since then, the regulatory threshold for furosemide, adjusted upwards to 100 ng/mL to allow for "field" variability and linked to a 1.010 urinary specific gravity value, has become the scientific basis for the widely applied four hour furosemide rule in the United States, as set forth in the ARCI medication thresholds/rules.
At the personal level, given the current state of knowledge, it is at best extremely challenging to provide useful "withdrawal time information" advice. The number of factors which affect the withdrawal time is very large indeed, and in the absence of a defined threshold ("Zero Tolerance" testing) it may be little more that a guessing game. Whenever I get a "withdrawal time" estimate request, I try to make these uncertainties clear, and to also clearly communicate that any estimates offered are nothing more that my best professional opinion, and my opinion is always qualified with the statement that "there are no guarantees in life, and this caveat most certainly includes "withdrawal time" estimates."
The various factors that can affect "withdrawal times" are set forth in some detail in Appendix #1, Thomas Tobin and Kent H. Stirling (2009) Equine Drug Testing & Therapeutic Medication Regulation; 2009 Policy of the National Horsemen's Benevolent and Protective Association, Inc. Wind Publications, 600 Overbrook Dr, Nicholasville, KY 40356, USA pp 170
12. Reference Standards
When we administer a medication to a horse [or a human] what the chemist finds in the urine is generally not the drug itself, but a chemically modified [metabolized] form of the drug linked to a sugar molecule, glucuronic acid. Figure 23 below sets forth this process for lidocaine which is first hydroxylated by the horse to give rise to 3-hydroxylidocaine. The hydroxylated lidocaine is then linked to glucuronic acid to give the final metabolite, 3-hydroxylidocaine glucuronide. When this resultant highly water-soluble glucuronide metabolite of lidocaine enters the urine, it cannot be re-absorbed by the horse, and the end result is a high urinary concentration of this glucuronide conjugated metabolite of lidocaine, which is removed from the body of the horse the next time the horse urinates.
And as an aside, where the metabolized drug goes after urination can be a matter of some regulatory significance. If the dose of drug administration to horses large, and the drug/metabolite is excreted at high concentrations in the horse's urine, the horse will contaminate his stall environment. It has been shown that a "clean" horse put into the environmentally contaminated stall can immediately go "positive" for the medication in question, creating an interesting regulatory circumstance, and demonstrating another compelling argument in favor of regulatory thresholds for therapeutic medications.
Lidocaine is first hydroxylated by the horse to give rise to 3-hydroxylidocaine; this hydroxylated lidocaine is then linked to glucuronic acid to give the final highly water soluble metabolite, 3-hydroxylidocaine glucuronide. Analyzing this sample, the chemist first hydrolyses off the glucuronic acid, and then recovers the 3-hydroxylidocaine metabolite fragment from the urine sample and quantifies it. To correctly perform this analysis requires a certified reference standard for 3-hydroxylidocaine and a deuterated internal standard in which 10 of the hydrogen atoms in 3-hydroxylidocaine have been replaced with 10 deuterium atoms, as set forth in Appendix II
To quantify the amount of this 3-hydroxylidocaine glucuronide metabolite in a urine sample, the chemist needs a certified reference standard for 3-hydroxylidocaine, and also what is called a deuterated version of 3-hydroxylidocaine, which serves as an internal or "loss check" reference standard throughout the analytical procedure. At the time that we started this work there was no source for these reference standards and internal standards, so we began creating a line of certified reference standards and internal standards for equine therapeutic medications. Creation of these standards is not a trivial process, and the synthetic scheme set forth below is that generated by our colleagues Dr. Rodney Eisenberg and Dr. Julio Gutierrez for the synthesis of the required 3-hydroxylidocaine certified reference standard and internal standard, as set forth in APPENDIX III.
13. Medication Rules
More than forty years ago, when the Kentucky medication rule was first being formulated (even before I came to Lexington) there were no thresholds or regulatory limits anywhere. Indeed, there were very few, if any, quantitative analytical methods applied to racing. Under these circumstances the Kentucky medication rule was clear, simple, effective and highly practical. You could not run your horse on stimulants, depressants, local anesthetics, tranquilizers or narcotic analgesics, the classic performance altering substances. However, the use of substances that were perceived as therapeutic was permitted, with the goal of protecting the health and welfare of the horse. This Kentucky rule was well fitted to the regulatory technology then available, and indeed is, I understand, close to the rule currently applied in human athletics. At that time, this very practical rule had been in place in Kentucky for at least 30 years and, to the best of my knowledge, served the horses and horsemen of Kentucky well.
14. The Current Racing Medication Testing
Consortium (RMTC) & Association of Racing
Commissioners International (ARCI) Rule
As of December 2010 the following is a summary of the RMTC/ARCI model rules referring to thresholds for therapeutic medications. Additionally, one must keep in mind that at any given time individual states may have in place thresholds that at times differ from and/or extend the RMTC/ARCI model rules. Many of these individual state thresholds are presented in the National HBPA booklet, Appendix #1, but given the rate of change of medication rules, for definitive information with respect to any individual state, the most up to date version of the individual state' medication rules should always be consulted.
The current Association of Racing Commissioners International model rule includes the thresholds presented below (Table 2.). Again, for definitive information the Association of Racing Commissioners International should be consulted. See the ARCI website http://www.arci.com.
NONSTEROIDAL ANTI-INFLAMMATORY MEDICATIONS:
Phenylbutazone - 2 micrograms per milliliter;
Flunixin - 20 nanograms per milliliter;
Ketoprofen - 10 nanograms per milliliter.
Phenylbutazone [subthreshold] - 0.5 micrograms per milliliter;
FUROSEMIDE:
Furosemide - 100 nanograms per milliliter, urinary specific gravity < 1,010
ANTI-ULCER MEDICATIONS
Cimetidine - up to 24 hours before post
Omeprazole - up to 24 hours before post
Ranitidine - up to 24 hours before post
ENVIRONMENTAL SUBSTANCES
Caffeine - 100 ng of caffeine per ml in plasma or serum
ANDROGENIC-ANABOLIC STEROIDS:
a) 16β-hydroxystanozolol (metabolite of stanozolol (Winstrol)) - 1 ng/ml in urine for all horses regardless of sex;
(b) Boldenone (Equipoise® is the undecylenate ester of boldenone) in male horses other than geldings - 15 ng/ml in urine. No boldenone shall be permitted in geldings or female horses.
(c) Nandrolone (Durabolin® is the phenylpropionate ester and Deca-Durabolin® is the decanoate ester)
(A) In geldings - 1 ng/ml in urine
(B) In fillies and mares - 1 ng/ml in urine
(d) Testosterone
(A) In geldings - 20 ng/ml in urine
(B) In fillies and mares - 55 ng/ml in urine
ALKALINIZING SUBSTANCES
The threshold for TCO2 is 37.0 millimoles per liter of plasma/serum or a base excess level of 10.0 millimoles, and;
The decision level to be used for the regulation of TCO2 is 37.0 millimoles per liter of plasma/serum plus the measurement uncertainty of the laboratory analyzing the sample, or a base excess level of 10.4 millimoles per liter of plasma/serum.
Table 2. RMTC/ARCI model threshold rules
Finally, as of this writing, the RMTC appears committed to developing regulatory thresholds in plasma for all of the therapeutic medications listed in Table 1. This is a significant regulatory advance based on recent technological and regulatory developments set forth in this medication regulation overview.
13. Further Reading
1/ www.thomastobin.com
2/ Thomas Tobin. Drugs and the Performance Horse by Thomas Tobin, 463 pages, Charles C. Thomas, Springfield, Illinois, 1981.
3/ Thomas Tobin and Kent H. Stirling. Equine Drug Testing & Therapeutic Medication Regulation:
2009 Policy of the National Horsemen's Benevolent and Protective Association, Inc., Wind Publications, Nicholasville, Kentucky, 2009, 170 pages.
4/ Tobin T, Mundy GD, Stanley SD, Sams RA, Crone D (eds): Testing for Therapeutic Medications, Environmental and Dietary Substances in Racing Horses, Proceedings of Workshop, Lexington, KY, 220 pages, 1995. [KY Ag Exp Sta #95-14-058]
5/ The Association of Racing Commissioners International (ARCI) Uniform Classification System for Foreign Substances: http://www.arci.com/druglisting.pdf
6/ Tobin T, Harkins JD, Sams RA: Testing for therapeutic medications: Analytical/ pharmacological relationships and the need for "limitations" on the sensitivity of testing for certain agents. J Vet Pharm Therap, 22:220-233. 1999. [KY Ag Exp Sta #98-14-134].
7/ Smith R.L "The zero tolerance approach to doping control in horse racing: a fading illusion." Proceedings of the 13th International Conference of Racing Analysts and Veterinarians (ICRAV) Cambridge , United Kingdom , p 9-14, 2000.
8/ Tobin T, Watt DS, Kwiatkowski S, Tai HH, Blake JW, McDonald J, Prange CA, Wie S. Non-isotopic immunoassay drug tests in racing horses: a review of their application to pre- and post-race testing, drug quantitation, and human drug testing. Res Commun Chem Pathol Pharmacol. 1988 Dec;62(3):371-95.
9/ Neogen ELISA tests: www.neogen.com/forensickits.htm
10/ Lehner A.F.; Harkins J.D.; Karpiesiuk W.; Woods W.E.; Robinson N.E.; Dirikolu L.; Fisher M.; Tobin T; .Clenbuterol in the Horse: Confirmation and Quantitation of Serum Clenbuterol by LC/MS/MS after Oral and Intratracheal Administration; Journal of Analytical Toxicology, Volume 25, Number 4, May/June 2001 , pp. 280-287(8)
11/ Chay S, Woods WE, Rowse K, Nugent TE, Blake JW, Tobin T. 1983The pharmacology of furosemide in the horse. V. Pharmacokinetics and blood levels of furosemide after intravenous administration Drug Metab Dispos. May-Jun;11(3):226-31.
12/ Thomas Tobin, et al. Furosemide in the Horse. Wind Publications, Nicholasville, Kentucky, 2000.
Appendix #1
Table of Contents from Equine Drug Testing & Therapeutic Medication Regulation:
2009 Policy of the National Horsemen's Benevolent and Protective Association, Inc.
by Thomas Tobin and Kent H. Stirling
Wind Publications, Nicholasville, KY 40356 , USA pp 170
SYNTHESIS OF 3-HYDROXYLIDOCAINE & DEUTERATED 3-HYDROXYLIDOCAINE
The synthesis of 3-hydroxylidocaine started with commercially available 2,6-dimethylaniline 1, which required 4 steps to produce 3-hydroxylidocaine.
Scheme 1: Synthesis of 3-hydroxylidocaine.
Synthesis of 3-hydroxylidocaine-d10 starts with the same starting material 1, above, and then follows steps similar to those used to produce 3-hydroxylidocaine..
Scheme 2: Synthesis of 3-hydroxylidocaine-d10.
EQUINE MEDICATION AND METABOLITE REFERENCE
STANDARDS AND STABLE ISOTOPE STANDARDS
Julio Gutierrez, Wojtek Karpiesiuk, Gabrielle Herrensmith, Elizabeth Armstrong,
Charlie Hughes, Job Tharappel, and Thomas Tobin.
The Maxwell H. Gluck Equine Research Center ,
Department of Veterinary Science,
University of Kentucky , Lexington , KY 40546
Rodney Eisenberg.
Frontier Biopharm, P.O. Box 614 , Richmond , KY 40476
Brent Mayer and Emilie Stanley.
Neogen Corp., Nandino Boulevard , Lexington , KY 40511
The equine medication metabolite standards and stable isotope reference standards listed here are being synthesized by a team of scientists, starting with Dr. Wojciech Karpiesiuk in the Gluck Equine Research Center, more recently in cooperation with Dr. Rodney Eisenberg and more recently again with Dr. Julio Gutierrez and Ms. Gabrielle Herrensmith, whose synthetic methods have been guided by the analytical skills of Dr. Andreas Lehner, Dr. Job Tharappel and Mr. Charlie Hughes. These syntheses have been an ongoing project, starting in the mid-nineties with the need to synthesize reference standards for unique equine drug metabolites and metabolite fragments. More recently, there has been an increasing need for high-quality certified reference standards and stable isotope internal standards for use in quantitative equine medication regulation, or more simply, to allow the regulatory application of thresholds for therapeutic medications.
The University of Kentucky and Frontier Biopharm, in cooperation with Neogen Corp., are working to provide the horse race testing community with certified quantitative analytical reference standards for equine therapeutic medications that will satisfy the ISO-17025 and ISO-34 requirements for quantitative measurements, and related reference materials which are increasingly required for equine forensic testing. These reference standards will meet industry requirements for chemical identity, spectroscopic and chemical purity, and the levels of residual volatile solvents, water and inorganic, in accordance with accepted ISO analytical standards.
Synthesis of these standards has been made possible by ongoing research support from a large number of Horsemen's Benevolent and Protective Association's, starting with the Florida HBPA in the mid-90s, and since then including the National Horsemen's Benevolent and Protective Association and the Alabama, Arizona, Arkansas, Canada, Charles Town West Virginia, Florida, Iowa, Indiana, Kentucky, Louisiana, Michigan, Minnesota, Nebraska, Ohio, Oklahoma, Ontario Canada, Oregon, Pennsylvania, Tampa Bay Downs Florida, Texas, Washington State, and West Virginia Horsemen's Benevolent and Protective Associations, the Kentucky Equine Drug Research Council, and the Kentucky Racing Commission, the Kentucky Horse Racing Authority and the Kentucky Science and Engineering Foundation, Grant agreement KSEF 148-502-05-160 with the Kentucky Science and Technology Corporation, and this support is gratefully acknowledged, along with the ongoing support of the Director and Faculty of the Maxwell H. Gluck Equine Research Center and the University of Kentucky College of Agriculture.
Standards Available or in Synthesis
Parent Medication
Regulatory Analyte or
Deuterated Internal Standard
Acepromazine
2-(1-hydroxyethyl) promazine sulfoxide (D4)
(deuterated metabolite)
2-(1-hydroxyethyl) promazine sulfoxide
(metabolite)
Bupivacaine
3-Hydroxybupivacaine
Clenbuterol (D9 )
(deuterated standard)
Detomidine
Carboxydetomidine
Carboxydetomidine (D4)
Hydroxydetomidine
Hydroxydetomidine (D4)
Furosemide (D5)
Flunixin
Flunixin (D3)
Guafenesin
Guafenesin (D4)
(deuterated standard )
Ketoprofen
Ketoprofen (D3)
3-Hydroxylidocaine
Mazindol
2-(2-Aminoethyl)-3-(4-Chlorophenyl3-Hydroxy-2,3-dihydro-isoindol-1-one
Mepivacaine
3-Hydroxymepivacaine
Methocarbamol
Methocarbamol (D4)
Modafinil acid
Phenylbutazone (D9 )
Procaine
Procaine (D10)
Promazine
3-Hydroxypromazine
Promethazine sulfoxide
4-Hydroxypropanolol
Click here to see Certificates of Analysis as a PDF document.
Metabolites are filed under the name of the parent medication. zA thru M z N thru Z
Wait a moment for PDF to load after clicking.
If you do not have the Acrobat PDF Reader you may download Acrobat here.
Also Synthesized or Synthesis in Progress
Acepromazine Sulfoxide
Amitraz
N-2,4-Dimethylphenyl-N'-methyl-formamidine (D6)
Chlorpromazine
7-Hydroxychlorpromazine
1-(4-Amino-3,5-Dichlorophenyl)ethane-1,2-diol
(metabolite )
2-(2-)4-Amino-3,5- dicholorophenyl)-2-hydroxyethylamino)-2-methyl-propan-1-ol
Colterol and Bitolterol
3-0-Methoxycolterol
7-Hydroxyfluphenazine
Guanabenz
Hydroxyguanabenz
3-hydroxylidocaine (D10)
2-(2-Aminoethyl)-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydro-isoindol-1-one
3-Hydroxymepivacaine (D3)
Propiomazine
2-(1-Hydroxypropyl)promethazinesulfoxide
Propionylpromazine
2-(1-Hydroxypropyl)promazine sulfoxide
Pyrilamine
Pyrilamine (D4)
Ropivacaine
3-Hydroxyropivacaine
Desmethylselegiline
Desmethyltramadol
Association of Racing Commissioners International "Drug Positives"
ARCI Drug Postive Rulings From 8/1/2004 Thru 8/1/2005
4 ACEPROMAZINE
1 ACETYLSALICYLIC ACID (ASPIRIN)
10 ALBUTEROL
4 AMINOREX
4 AMPHETAMINE
1 BENZOCAINE
9 BENZOYLECGONINE
1 BETAMETHASONE
1 BOLDENONE
1 BUMETANIDE
1 BUSPIRONE
1 BUTORPHANOL
16 CAFFEINE
3 CAFFEINE, THEOPHYLLINE
1 CAFFEINE, THEOBROMINE, THEOPHYLLINE
1 CARPROFEN
1 CELECOXIB
3 CIMETIDINE
26 CLENBUTEROL
6 CROMOLYN
1 DANTROLENE
1 DESMETHYLPYRILAMINE
1 DESMETHYLPYRLAMINE
1 DETOMIDINE
45 DEXAMETHASONE
1 DEXTRORPHAN
14 DICLOFENAC
20 DIMETHYLSULFOXIDE
1 DIPHENHYDRAMINE
1 DIPRENOPHINE
3 DORMOSEDAN
2 EPHEDRINE
1 ERGONOVINE
3 EXCESS TCO2
1 FEXOFENADINE
1 FLUMETHASONE
85 FLUNIXIN
4 FLUNIXIN/PHENYLBUTAZONE
1 FLUPHENAZINE
25 FUROSEMIDE
3 GUAIFENESIN
6 GUANABENZ
1 HALOPERIDOL
2 HYDROCORTISONE AND MEVIPICAINE
1 HYDROMORPHONE
1 HYDROXYDANTROLENE
2 HYDROXYDETOMIDINE
2 HYDROXYETHYL PROMAZINE SULFOXIDE
1 HYDROXYLIDOCAINE
1 HYDROXYMEPIVACAINE
1 IPRATROPIUM
4 IPRATROPIUM BROMIDE
1 ISOFLUPREDONE
2 ISOXSUPRINE
6 KETOPROFEN
18 KETOROLAC
10 LASIX
2 LIDOCAINE
3 MEPIVACAINE
7 METHAMPHETAMINE
24 METHOCARBAMOL
16 METHYLPREDNISOLONE
2 MORPHINE
9 NAPROXEN
1 NAPROXEN POSITIVE
2 NAPROXENTHE
1 NAQUASONE
1 NORPSEUDOEPHEDRINE DESMETHYLPYRILAMINE
1 O-DESMETHYLPYRILAMINE AND NORPSEUDOEPHEDRINE
2 PENTAZOCINE
2 PENTOXYFYLLINE
1 PERINDOPRIL
1 PHENYLBUTAZONE
4 PHENYOXYPHEN
1 PIRBUTEROL
3 POLYETHYLENEGLYCOL
15 PROCAINE
2 PROPANTHELINE
1 PROPRANOLOL
1 PSEUDOEPHEDRINE
1 PSEUDOEPHEDRINE And NORPSEUDOEPHEDRINE
1 PSEUDOEPHEDRINE AND NORPSEUDOEPHEDRINE AND DESMETHYLPYRILAMI
2 PYRILAMINE
8 RANITIDINE
1 SALICYLIC ACID
4 SALIX
1 TERBUTALINE POSTV
5 THEOPHYLLINE
47 TOTAL CARBON DIOXIDE (TCO2)
3 TRIAMCINOLONE
4 TRICHLORMETHIAZIDE
4 TRIMETHOPRIM
4 TRIPELENNAMINE
23 UNKNOWN
1 VENTIPULMIN SYRUP
DETAILS OF THE FIELD AND MEDICATION REGULATION
National Horsemen's Benevolent and Protective Association, Inc. Proposed National Policy on Drug Testing and Therapeutic Medication. J Eq Vet Sci 23(1): 4-5, 18-40, 2003. http://hbpa.org/resources/MedicationPolicy.pdf
Published as Kentucky Agricultural Experiment Station Article #_____ with the approval of the Dean and Director, College of Agriculture and the Kentucky Agriculture Experiment Station.
Publication #359 From the Equine Pharmacology, Therapeutics and Toxicology Program of the Maxwell H. Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546-0099.
Supported by the National, Alabama, Arizona, Arkansas, Charles Town WV, Florida, Iowa, Kentucky, Louisiana, Michigan, Minnesota, Nebraska, Ohio, Oklahoma, Oregon, Pennsylvania, Tampa Bay Downs, Texas, Washington State, West Virginia, Ontario, and Canada Horsemen's Benevolent and Protective Associations.


text:
CommentaryDrug Discovery
A Call for Sharing: Adapting Pharmaceutical Research to New Realities
Bernard H. Munos* and
William W. Chin
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
*Corresponding author. E-mail: b.munos{at}lilly.com
Science Translational Medicine 02 Dec 2009:
Vol. 1, Issue 9, pp. 9cm8
DOI: 10.1126/scitranslmed.3000155
Bernard H. Munos
For correspondence: b.munos@lilly.com
From the dawn of time, the sharing of knowledge has been one of the main forces driving science and innovation. Yet in recent decades, a proprietary culture, which wrongly posits that all intellectual property must be restricted, has spread across the pharmaceutical industry and threatens to stall the engine that has given us so many valuable treatments. This paper argues that pharmaceutical companies, together with universities and government agencies, stand to gain much from reversing that trend and engaging in widespread collaboration early in the research process to expand foundational knowledge and create a shared infrastructure to tap it.
Citation: B. H. Munos and W. W. Chin, A call for sharing: Adapting pharmaceutical research to new realities. Sci. Transl. Med. 1, 9cm8 (2009).
Copyright © 2009, American Association for the Advancement of Science
Vol 1, Issue 9
Thank you for your interest in spreading the word about Science Translational Medicine.
You are going to email the following A Call for Sharing: Adapting Pharmaceutical Research to New Realities
Message Subject (Your Name) has forwarded a page to you from Science Translational Medicine
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By Bernard H. Munos, William W. Chin
Science Translational Medicine 02 Dec 2009 : 9cm8
In recent decades, a proprietary culture, which wrongly posits that all intellectual property must be restricted, has spread across the pharmaceutical industry and threatens to stall the engine that has yielded many valuable treatments.
Stay Connected to Science Translational Medicine

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: Mysior's example of not completely Hausdorff space https://www.ams.org/journals/proc/1981-081-04/S0002-9939-1981-0601748-4/S0002-9939-1981-0601748-4.pdf
In this link, there is the example of regular space, that is not completely regular. This space is also completely Hausdorff (Is Mysior's example completely Hausdorff?). But in the article, the second page is remark, where is written, that if we add one point b to the space, with its local neighborhoods, that the space is also regular and not completely regular, but also not completely Hausdorff, because there is not the continuous function f, for which f(a)=f(b). I am interested in, how to prove that (that this space is not completely Hausdorff).

redpajama_set_name: RedPajamaStackExchange


text:
By Douglas Soltys Canadian Startup News May 25, 2020
Black Swan #9 – Calgary and Toronto look to stop the bleeding
It's been two weeks since our last episode, and there's a reason for that.
Black Swan was launched shortly after the pandemic hit, as a rapid-response to the emergency Canadian tech found itself in. More than two months later, the emergency has evolved into reality.
"How do we not lose the last decade of investment into the ecosystem?"
Despite nascent attempts at 're-opening' across Canada (and we'll see how long they last), the impact of COVID-19 on Canadian tech and innovation won't be subsiding any time soon. That requires a different approach to storytelling. One a little less reactive, and more proactive. Exploratory.
Like today's episode, where we look at how different tech ecosystems across Canada are working to keep their ecosystem together.
Our first guest is Terry Rock, President and CEO of Platform Calgary, which is a member of the Alberta Innovation Corridor.
Like the rest of Canada, tech companies within the Corridor have been hit hard. But also at a weird time – Alberta was just beginning to set the roots of its ecosystem, culminating in the opening of its own Hub, the Platform Innovation Centre, in 2021. Other Corridor members like Innovate Edmonton have been rocked with executive departures while the city's government decides it needs a different innovation entity.
We talk to Rock about all of this, and why he still believes Platform will be the hub Alberta tech needs a year from now.
The City of Toronto is hoping to sustain the investments it has made in the local tech ecosystem over the last decade. To do that, Toronto has tapped Chris Ricket, Director of Municipal and Stakeholder Relations at MPAC, but also the Director of COVID-19 Business Mitigation and Recovery, a role he was seconded to following his departure from the City last year.
In Toronto circles, Rickett is known as the guy tech companies go to if they want to work with the City. We ask him about exactly what role a municipal government can play in mitigating the economic bleeding, and the major recent departures of OneEleven and Sidewalk Labs.
BetaKit · Black Swan #9 – Calgary and Toronto look to stop the bleeding
Subscribe via: RSS, iTunes, Spotify Stitcher, Google Play
Hosted by Douglas Soltys & Rob Kenedi. Edited by Kattie Laur. Produced with support from TWG.
calgaryCOVID-19toronto
Douglas Soltys
Douglas Soltys is the Editor-in-Chief of BetaKit and founder of BetaKit Incorporated. He has worked for a few failed companies and written about many more. He spends too much time on the Internet.
Director-general of World Health Organization to speak at Collision from Home
AbCellera partners with American pharmaceutical company on multi-year antibody discovery project
Report: 53 percent of customers abandon purchases when there's payment friction
A new report by Payments Canada has revealed that over half of Canadians (53 percent) abandon a purchase when checking out at a retailer…


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Trains from Newcastle upon Tyne to Sheffield
Train from Newcastle upon Tyne to Sheffield
Newcastle upon Tyne to Sheffield train information
Arrival Sheffield, England
Departure Newcastle upon Tyne, England
Lowest train price from £73.10
Average train price £74.00
The trains between Newcastle upon Tyne (North East England) to Sheffield (Yorkshire and the Humber England) are operated by Cross Country. The services on board may change depending on the train operator.
Travelling by train is a quick and easy option to go to Sheffield from Newcastle upon Tyne. The average travel time from Newcastle upon Tyne to Sheffield is 2h03m to cover the 111 miles.
What is the price of a train ticket for this journey?
The cheapest fare we've found for the next 180 days is £73.10 one way.
Best prices for Newcastle upon Tyne to Sheffield train tickets
Newcastle upon Tyne - Sheffield prices calendar
Find the cheapest tickets to travel from Newcastle upon Tyne to Sheffield by train, bus, ride sharing and plane.
Megabus£16
FlixBus--
Newcastle upon Tyne - Sheffield: the best time to book cheap trains
The Prices for train tickets Newcastle upon Tyne to Sheffield tend to increase the closer you get to your departure day. Based on our data, if you purchase your ticket 1 month in advance, the price of the ticket starts at £17 whereas when booking on the day you're travelling, you will need to spend at least £34 for your trip. Thus, you will save 53% on the price of your ticket by buying your ticket 1 month in advance as opposed to on the day you're travelling.
The data are based on the best fares found over the past 6 months when buying in advance versus at the last minute.
Best prices for Newcastle upon Tyne to Sheffield trains
We compare train ticket for all major companies to travel between Newcastle upon Tyne and Sheffield by train and find the best prices for the coming days. Take a look at the prices of train tickets Sheffield to Newcastle upon Tyne and find the best deal for your outbound journey.
Newcastle Sheffield
£73.10 28/03/2022 10:35 Cross Country 28 days ago
Discount Newcastle upon Tyne - Sheffield train tickets
The easiest way to pay less on your Newcastle upon Tyne Sheffield train ticket is probably to buy a railcard. While regional railcards are available in some areas, National railcards enable you to spend less on most rail fares across the UK. Everyone is eligible to at least a certain railcard, even non-UK residents. National railcards available: 16-25 discount card, Senior railcard, Two together discount card, Family and Friends railcard and Disabled persons discount card.
You will need to purchase at least £88 of train tickets throughout the duration of the railcard's validity for the railcard to pay for itsfel. It corresponds to the price of the card, thirty pounds, divided by the saving, thirty four percent. On every train that you buy after that, you will save money.
For instance, train tickets from Newcastle upon Tyne to Sheffield cost on average £73.95 (1). If you're dividing £88 by £73.95 (£88/£73.95 = 1.19), it turns out that after only 2 one way trips from Sheffield to Newcastle upon Tyne, the card will have paid for itself.
What is the cost of a railcard?
All railcards cost £30 except the Disabled persons railcard for which you will pay £20. Railcards give you 34% off most rail fares, thus you will save 1/3 on most train fares.
Newcastle upon Tyne to Sheffield train £73.95 £49.30 £24.65 1.19
Train tickets from Newcastle upon Tyne
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bus from Newcastle upon Tyne to Sheffield


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Q: Two entities without collections I have following issue. One entity with name "user" have an many to many relationship to entity "address". I would like to create a form "UserType". In this form i will show exactly to address entities. One address for privat address informations and one address for business adress informations.
I realized this with collection, i can add and remove many adress collections.
http://symfony.com/doc/current/cookbook/form/form_collections.html
But how can i exactly show two address entity on creating or editing a user without collections?

A: There are several approaches to it.  One is to add get/set privateAddress and businessAddress methods to you user entity then make sure you initialize the collections.  Something like:
$user = new User();
$user->addAddress(new Address('Private'));
$user->addAddress(new Address('Business'));

$builder = $this->createFormBuilder($user);
$builder
    ->add('privateAddress',  new AddressFormType())
    ->add('businessAddress', new AddressFormType())
;

I often use a second approach when creating an object with multiple children.  In this approach, you feed the form multiple independent objects in an array and then stitch things together after the form is posted.
$data = array(
    'user' => new User(),
    'privateAddress'  => new Address('Private'),
    'businessAddress' => new Address('Business'),
);
$builder = $this->createFormBuilder($data);
$builder
    ->add('user', new UserFormType())
    ->add('privateAddress',  new AddressFormType())
    ->add('businessAddress', new AddressFormType())
;
...
if ($form->isValid())
    // Stitch your object together then persist

Either method works.  The second one is a bit more flexible and avoids the need to add additional methods to the user object.  Of course, you will probably want those methods anyways.


text:
'DIVORCE COURT' JUST GOT A LOT DIRTIER
By Michele Greppi
August 31, 1999 | 4:00am
"Divorce Court" Weekdays at 10 a.m. on WNYW/Ch.5
YOU might think the third resurrection of "Divorce Court" would just be a matter of bringing the increasingly popular court-show genre back to its roots.
But "Divorce" is clearly digging deeper for dirt than it did in its first two incarnations, which predated the mud-slinging that has become de rigueur in the wake of the amazing success of the name-calling and chair-tossing on "The Jerry Springer Show."
The smell of success in syndication now is not sweet. It is bitter.
And the bitterer the better, judging from the first two cases offered up by the new "Divorce Court," presided over by Mablean Ephriam, who has been a family-law attorney and arbitrator in real life but who now plays a judge on TV.
No matter in whose favor "Judge" Ephriam rules, there are no winners here.
Only losers.
First case: Elizabeth Scott, who looked like a bleached Monica Lewinsky, vs. Charles Scott, who looked like a man for whom phone sex is a godsend.
In less than two years of marriage, hastily entered into just months after she'd been raped by two men, Charles had run up several thousand dollars worth of phone-sex credit-card bills.
He may also have given her gonorrhea several months into her pregnancy. Charles blamed the disease on her rapists.
"Oh, my God, you filthy trailer-trash loser, you," Elizabeth screamed tearfully. "I can't believe you have the broken diseased manhood to bring this up in court."
Elizabeth wanted Charles to pay for his phone play.
She was also seeking public payback for him having demanded unspecified (a small blessing for which we give endless thanks) sex acts from her in her pregnant and still traumatized condition, sometimes after she'd fallen asleep, often before he'd even bathed.
"Legally, I don't know if she's right or wrong, so I have to agree with [Ephriam]," Elizabeth blubbered before shouting to Charles that "I will personally see you burn in hell."
"Tough," responded Charles, now involved with their former babysitter – who jeered in "court" that Charles no longer needs telegratification.
TV TICKER


Prensoland will be exhibiting at Concreteshow 2013, from August 28th to 30th at Booth # 650, at the fairgrounds Immigrants in Sao Paulo, Brazil.
Our company will showcase its high-tech block making machines and all its machinery and equipment for the production of prestressed beams and hollow core slabs.
Concreteshow South America is an international meeting point of business and technology, exclusive for concrete supply chain and its users.
Concreteshow brings together more than 20 different segments of the concrete production chain and as a shop window, it reflects the growth of the economy, pushing the sector forward and is strongly representative of Brazil. In its 6th edition, it is recognized by the worldwide market as the most important meeting point of the concrete production chain with the Latin American civil construction industry. In recent years, it has been the ideal platform for the launch of new products, sales and networking.


text:
Band Aid II - Do They Know It's Christmas? (1989)
Genre(s): Christmas
"Do They Know It's Christmas?" is a song written in 1984 by Bob Geldof and Midge Ure in reaction to television reports of the ...
"Do They Know It's Christmas?" is a song written in 1984 by Bob Geldof and Midge Ure in reaction to television reports of the 1983–1985 famine in Ethiopia.
A second version of "Do They Know It's Christmas?" was recorded under the name of Band Aid II in 1989, overseen by the most successful British production team of the late 1980s, Stock Aitken Waterman. Geldof had telephoned Pete Waterman to ask him to produce a new version of the song to aid the ongoing situation in Ethiopia, and within 24 hours the recording session had been arranged at Stock Aitken Waterman's studios on London's South Bank. The recording took place over the weekend of 2 and 3 December, and featured several artists who had already been produced by SAW, including Kylie Minogue, Jason Donovan, Bananarama, Sonia, and Cliff Richard, as well as other artists who had big hits in 1989, such as Lisa Stansfield, Jimmy Somerville, Wet Wet Wet and Bros. Bananarama's Sara Dallin and Keren Woodward became the only artists to appear on both the 1984 and 1989 versions of the record. Siobhan Fahey, who had been part of Bananarama's line-up at the time the first recording of the song was released, had left the group in 1988.
The lyrics were rearranged for a more traditional 'verse and chorus' structure, with the opening verse being split in two with a short repeat of the ending chorus being played at the end of both, followed by the "here's to you" section and a final lengthened version of the closing chorus (with commentary by Michael Buerk played over the outro in the music video).
Released on 11 December 1989, the Band Aid II version spent three weeks at number one in the UK, becoming the Christmas number one single and the last number one single of the 1980s, and ended the year as the ninth biggest selling single of 1989.
Bananarama, Big Fun, Bros, Cathy Dennis, D Mob, Jason Donovan, Kevin Godley, Glen Goldsmith, Kylie Minogue, The Pasadenas, Chris Rea, Cliff Richard, Jimmy Somerville, Sonia, Lisa Stansfield, Technotronic and Wet Wet Wet.
Wham! - Last Christmas (1984)
Chris Rea - Driving Home For Christmas (1986)
Band Aid - Do they know it's christmas (1984)
Bryan Adams - Christmas Time (1985)
Annie Lennox & Al Green - Put A Little Love In Your Heart (1988)
Billy Ocean - Tear Down These Walls (1988)
Eurythmics - It's Alright (Baby's Coming Back) (1985)
Whitney Houston - Greatest Love Of All (1986)
Eddie Money - The Big Crash (1983)
Michael Jackson - She's Out of My Life (1980)
A-ha - Train Of Thought (1986)
Madonna - Angel (1985)
LL Cool J - I'm Bad (1987)
Def Leppard - Armageddon It (1988)
U2 - Another Day (1980)
Dionne & Friends - That's What Friends Are For (1985)
Level 42 - Heaven In My Hands (1988)


Weekly diet is a fast response to the long-tormenting question! Seven days is the most popular length of time for experiments with losing weight. On the one hand, it is a short term, on the other it is psychologically significant and allows us to count on some visible results. However, do not prepare yourself for the semi-starvation. Along with monotonous diets, there are diet plans that allow losing weight in a week, adhering perfectly wholesome varied menu.
For those who are willing to spend seven days on weight loss, there is a great variety and diversity of the weekly diets that allow to get rid of surpluses of different sizes – from 3 to 10 kg. The key to success is the right choice of the diet,comfortable for you that does not require the impossible voluntary feat or fundamental review of lifestyles.
Urgent Weight Loss in a Week – at What Cost?
In order for weight loss in a week to make sense, you need to choose a diet effective for you, and the measure of effect in this case is not only the amount of lost weight, but also the possibility to save the results with no harm to the health and quality of life.
In the context of time restrictions slimming completely "lays on the shoulders" of the daily diet. Any other good intentions (changing daily routine, increase of physical activity, positive attitude) just do not have time to express themselves in such a short period of time.
by chemical processes (primarily protein diets, making adjustments in metabolism. They are famous for the longest preservation of the result due to the relative decrease in the risk of loss of muscle mass, typical of express diets).
You can assume that the more monotonous and poor your nutrition is, the more success you can achieve in the field of losing weight. However, this is not quite so: seven days is a sufficiently long period for nutrition with noticeable restrictions. Moreover, the consequences will be serious for the health, and the risk of failure increases many times. In addition, there is a tendency for strict diets: the kick-start loss of excess weight in the first two days stops because the body turns on the emergency mode and "freezes" the power consumption. This means not only failure in losing weight, but also lethargic feeling and fatigue.
Therefore, even with a strong motivation to lose weight as soon as possible, try to choose the lesser evil of the existing and evaluate the limits of your willpower and the risks. A short productive diet, allowing losing weight in a week, can be a good impetus for the follow-up activities to reduce weight, but do not forget that all the "hungry" diets fraught with rapid return of the lost weight. It is therefore essential, surviving a weekly diet, to refrain from overeating after the difficult seven days of fasting for the sake of beauty and harmony.
It is also important to assess your health sensibly. Do not lose weight on your own if your excess weight exceeds 30 kg or 65 lbs. – in this case, you require multidisciplinary medical support. Moreover, be sure to consult with your doctor before significantly reducing daily energy value of your menu or switcing to increased use of a single product (or similar products).
1. Kefir diet for 7 days allows you to lose weight by 3-5 kg or 5-10 lbs. for the entire period, eating yogurt (kefir) and – very limited – a few other approved products.
2. Japanese weekly diet – "truncated" version of one of the most popular diets for quick weight loss, the famous "Japanese" one. You lose an average of 4 kg or 8 lbs. for 7 days. This is a carbohydrate-free diet, all meals of which have limits in grams and time.
3. Buckwheat diet promises a record – about 1 kg or 2.5 lbs. of lost weight per day. Russians favorite cereal for this eating plan should not be boiled, but cooked in a special way – perhaps this ritual distracts from the treacherous thoughts of a full meal?
4. Juicing or juice monodiet – a favorite emergency means of the photo models, loved for its reliability, but it is terribly unhealthy. Juicedietfor a week – the extreme option, which should be treated as a last resort. You should be ready to interrupt your Drinking Slimming Marathon, barely noticing the signs of dissatisfaction of the body. (Do you like fruit? Try a more balanced grapefruit diet).
5. Unloading diet by Korolyova – the best-selling invention of the famous Russian nutritionist Marguerite Korolyova. Using the meal plan that allows to drink one liter of nonfat yogurt and 2.5 liters of plain water, eat a potato, 100 grams of cottage cheese, 2 cucumber and ¼ chicken a day at regular intervals, you can lose 2-3 kg or 4-6 lbs.
To lose weight by 10 lbs per week will allow the diet known as Estonian (to find out the origin of the name is not possible). This is anintricate meal plan, which is a series of mono-diets. Throughout the duration of this week's diet sauces, spices, sugar, and salt are banned. It is also advised to abstain from tea and coffee, but you should drink still water at least 1.5 liters daily.
Day one: boiled eggs 6 pieces.
Day Two: fat cottage cheese – 1 kg.
Day three: boiled or steamed chicken – 300 g.
Day Four: rice – 100 g of dry cereal to boil in 1 liter of water.
Day Five: jacket potatoes – 6 pieces.
Day six: apples – 1 kg.
Day Seven: 1.5 liters of yogurt.
Egg diet helps lose weight in a week by 3-10 kg or 6-20 lbs (depending on the original weight and features of metabolism). When discussing the effect of this diet they use the thesis about the benefits of vitamin H (biotin). Biotin accelerates carbohydrate and lipid metabolism, as well as blood sugar levels in the blood, so the substance is especially important in the diet for those who suffer from diabetic and pre-diabetic states.
If you want to lose weight quickly, the egg diet is a reasonable choice also because of the high satiating power of chicken eggs – because they are digested slowly, starving suffering is not as painful. Adding grapefruit to the menu also makes its useful contribution – enzyme naringinin,which is contained in the bitter citrus fruit, regulates insulin secretion, allowing you to control your appetite.
For the entire period of the diet it is necessary to give up sugar, salt, sauces and other food additives, bread, sodas and juices. Do not forget to drink water – at least 1.5 liters per day.
Breakfast: 2 eggs, grapefruit, coffee without sugar and milk.
Lunch: 2 eggs, tomato, herbal tea.
Dinner: 2 eggs, no butter vinaigrette (carrots, beets, potatoes), grapefruit, tea.
Breakfast: 2 eggs, grapefruit, black coffee without sugar.
Dinner: 2 eggs or lean meat (150g, boiled or grilled), a portion of green salad.
Breakfast: 2 eggs, grapefruit and coffee without milk and sugar.
Lunch: 2 eggs, spinach and tea.
Dinner: 2 eggs, salad without oil (see. Day 1), 100 g of cottage cheese, herbal tea.
Breakfast: 2 eggs, grapefruit and black coffee.
Lunch: 2 eggs, a portion of spinach, black coffee with no additives.
Dinner: 2 eggs or 150 grams of sea fish, salad without oil, tea.
Breakfast: 2 eggs, grapefruit and coffee without sugar.
Lunch: 2 eggs, a portion of spinach, black coffee.
Dinner: 150 g of sea fish, cabbage salad, black coffee or tea without sugar.
Breakfast: 2 eggs, grapefruit and black coffee without sugar.
Lunch: salad of any fruit.
Dinner: 2 eggs or 150 grams of lean meat, salad (tomato, cucumber, celery), herbal tea.
Lunch: 2 boiled eggs or cold chicken, tomato and grapefruit.
Dinner: 2 boiled eggs or cold chicken (150 g), salad (carrots, cabbage, tomato) and black coffee without sugar.
During egg diet it is recommended to drink alkaline mineral water to neutralize the grapefruit acid.
This type of menu is known as the "chemical": the name of the low-carbohydrate diet with high-protein diet was fixed thanks to Osama Hamdy. When losing weight on a diet like protein the reserves of the body are not exhausted, and due to lower revenue of carbohydrates the body faces a shortage of available "fuel" for the energy of the body and quite quickly begins to consume the fat reserves.
If the egg diet for 7 days seems too strict to you, use a gentler, but no less effective analogue – egg diet for 4 weeks.
Seven Days of Patience – Five Pounds Off!
A diet that lets you lose weight 5 lbs in a week is based on the rules of a healthy diet, but with one cunning feature – it is forbidden to have dinner. The last meal should be no later than 16.00. However, it is possible to see a positive thing in the sad fact – it is a good motive to go to bed early, not sitting up in front of the TV or computer.
It is not recommended to break the order of days; also you need to adhere to the daily list of products and do not make your own adjustments. An important rule of this week's diet is the exclusion of salt, sugar, and alcohol from the diet. The fruit given the menu are eaten the not in the main meal, but half an hour before meals or half an hour after them. Every day you need to drink plenty of plain carbonated water.
Breakfast: Steamed fish – 50g, lettuce with a few drops of olive oil, yogurt 1% fat 250 ml.
Lunch: boiled egg, whole meal bread, 2 slices of meat turkey or chicken – 90 g.
Breakfast: celery without limitation, boiled veal 80 grams, one boiled potato(plus one),steamed carrots, green tea without sugar.
Dinner: 1 cup low-fat yogurt, 100 grams of fat-free yogurt, oatmeal on the water, five dates.
Breakfast: unsalted chicken broth – 250 ml, 3 pcs bread, steamed chicken breast – 50g.
Lunch: rye bread – 2 slices, boiled beef – 50 g, spinach without limitation, an apple and an orange.
Breakfast: boiled buckwheat, yogurt 1% fat – 250 ml of tomato salad with olive oil.
Lunch: boiled rice, fresh juice from citrus fruit – 250 ml, cottage cheese with plums – 100 grams, grapefruit and kiwi.
Breakfast: boiled beef – 60g, one egg plus one two cucumber and bell peppers.
Lunch: steamed chicken breast, boiled potato, apple and orange, 2 walnuts, dried apricots – 3pc.
Breakfast: Chicken broth without salt – 100 ml, steamed red fish – 100 gr with green peas (3 tbsp. L.), Rye bread – 1 slice, green tea with 1 tsp honey.
Lunch: boiled brown rice, lettuce, tomatoes, seasoned with lemon juice with sesame seeds; for dessert, one hour after the meal: a glass of skim milk, kiwi and banana.
Breakfast: chicken breast – 60 gr, a plate of buckwheat, one bell pepper + nonfat cottage cheese (2st. L)., Black tea with a spoonful of honey, a handful of raisins for dessert.
Lunch: boiled lentils, boiled beef – 100 g, low-fat plain yogurt (1 cup 125 g), almonds (30 g).
"6 petals"diet – the original series of mono-diets with additional motivating tools in the form of a flower with 6 petals, that should be torn away with a sense of accomplishment after another day.
Nourishing and easy to comply pumpkin diet for 12 days is particularly relevant in the fall, when there is a new crop.
The famous and efficient chicken diet exists as a standard seven-day version, and the option for those who love it quickly, for three days.
Cottage cheese diet – a proven way to lose a few pounds in the format of a double fasting day.


Goodman Games Isle of Dread - Is Mine!
Hey all just received my preorder of isle of dread. It looks fantastic.
Introductions are pages 5-15, reprints are pages 16-91, 5e conversion and all the new stuff is pages 92-322!
Inside front and back end pages feature the color front and back covers, version 1 on the front and 2 on the back.
The 5e version even has its own key to the continental map of the Known World (Mystara) with sadly no development, just the same one page or so overview as in the originals.
More as I go through it all.
Re: Goodman Games Isle of Dread - Is Mine!
I know the 5e conversion author added some details to the Isle encounters, but I was wondering if he touched on the main continent of the Known World. You've answered that question for many of us, so thanks for that!
That doesn't make me unhappy. If I were to run a KW campaign, it would be pre "Mystara" naming. heheh. I'd use all the gazetteers I have (nearly all of them in deadtree or pdf) and make up much as the players explored. That is still a LOT of world to explore!
But to kick all of this off, the Isle of Dread would come first!
Of course, I'd have to throw in the Princess Ark series eventually, because I always liked the flying ships.
The 5e version even has its own key to the continental map of the Known World (Mystara) ...the same one page or so overview as in the originals.
What would you have liked to see? Expanded material that didn't appear in the original? Or were there points in the original that didn't align to the map given? I wonder how fans would react to a map with new material, especially given that this is from Goodman Games and not WotC.
It is interesting to hear about this book. I will be getting a copy when I find time to order one. What is contained in the "new stuff" section of the book? Just conversions of the original encounters and monsters or something else?
From what I read at Goodman Games website interview with the author who converted the material, he updated the island encounters and added some stuff that should be really exciting. The only clue I recall reading about was one of the side islands around the reef and a reference to "shark week".
Oh, and I suspect lots and lots of dinosaurs!
Thanks for the info, Mal. I wasn't aware of this book, just the first one they did for B1 & B2.
I got a copy of this as well, and I am pleased to report that in addition to preserving all of the Known World information from the reproduction of the original blue X1 and orange X1, they do write the new 5E adventure with the Known World and Mystara in mind. So you get three copies of the Known World map and three copies of the pronunciation guide and Known World nation descriptions...the blue X1 version, the orange X1 version and the 5E version. The 5E map is based off the orange X1 map which has Threshold and Kelvin marked in Karameikos.
The default 5E setting for the Isle of Dread, which places it in the Elemental Plane of Water, is dealt with in an appendix.
So this really is a Known World/Mystara adventure first and foremost.
I have to wait for some money (as I live of 125euro's monthly now). Even my birthday(03-01) didn't bring much, yet I will collect and eventually optain a copy for myself...at least that is the intention.
I don't suppose any of the maps fold out?
No inserts or fold out maps, everything is printed on the pages of the hardback.
Bringing up the hex maps reminds me...this latest work perpetuates the error that goes all the way back to the original X1. The Known World map portrays the Isle of Dread on 24 mile hexes as being about 150 miles from north to south, but the 6 mile hex close up map of the island portrays it as being about 250 miles north to south. I prefer the latter myself, and just requires the Isle of Dread to stretch out bigger in the sea on the Known World map.
The new monster section from this and KOTB I use in other games. I'm putting the Giant Ant, Soldier Ant, Living Iron Statue, Living Rock Statue, Spitting Cobra, Skeletal Snake and Swarm of Sandlings in my 5e B4 game. The Coffer Corpse and Osquip made it in from the KOTB. Good Stuff.
I hope to find PDFs of these someday, so I can print out just the sections (new monsters & items appendices, and the 5e adventures themselves) I need for the table-top, rather than clunking the whole book out at every game!
I'm not too worried about the map not being fold-out. I'll most likely make a large scale blank interior copy of it for the players to start with and have them fill in the interior spaces as they explore.
Bringing up the hex maps reminds me...this latest work perpetuates the error that goes all the way back to the original X1.
Did they correct the missing secret door in the temple that cropped up in the orange cover X1 map? (northwest corner of the Chamber of the Great One; area 39 on the orange cover module, area 2 on the blue cover).
No, the replica of the orange version of X1 does not have the secret door. The 5E version does have the secret door though.


text:
Dairy farming not just jobs for the boys
Dairy farming is far from being a job for the boys on the Sherborne family farm in the southern highlands, south of Sydney.
Grant and Jane Sherborne want to dispel the myth that dairy farming is just a job of last resort for strong lads, and their farm at Burrawang proves that's no longer the reality.
Eldest child Georgia, 19, now works with her parents and the farm's roster of casual employees is almost exclusively female.
The Sherbornes never set out to prove a point by hiring female workers; it's just evolved that way.
"Girls seem to be the only applicants we have at the moment," Grant said.
The female workers have ranged from international backpackers to university students and they consistently help the Sherbornes to maintain their high standards for quality milk production and environmentally efficient farming.
"Maybe if you go back years ago, farm work was thought of as a basic labouring job," Grant said. "But one of the reasons I employ girls is that they don't have to be physically strong to do this today; they just have to be smart and want to do it."
Grant believes the job market would improve if dairy was seen in the positive light it deserves.
"The perception of dairy needs to be lifted," he said. "The student we have here loves what she's doing but she doesn't know how to tell everyone that she's gone to uni and is not using that degree. It's got to have more appeal to their peers. If you say you work in a dairy they might think that you can't do anything else."
That's why Grant and Jane are strong supporters of Dairy Australia's Cows Create Careers program that introduces school students to the many jobs available in the dairy industry, and the Legendairy initiative that aims to improve the profile and reputation of dairy farming.
"There's a terrific amount involved in dairy," he said. "We had a policeman work here for a while and he found it was a bit beyond him with all that's involved in animal health and working with cattle – he said police work was far easier."
One of the great things about dairy farming is family involvement.
In addition to Georgia, son William is finishing Year 11 at school and will follow in his sister's footsteps on the farm. Youngest Samuel, 14, is still at school as well but already has his eyes on entering the farm business through calf rearing.
"Georgia's been on the farm for the past 12 months," Grant said. "She could have gone to uni but she wasn't keen. She said the farm is what she'd like to do and she seems to be more interested in it as time goes on."
The Sherbornes are doing their part to change negative perceptions. Their involvement in Cows Creates Careers takes them into local and Canberra schools to help students raise calves and learn about the importance of, and opportunities in, the dairy industry.
"We're trying to get kids out of the idea that 'if I can't get into anything else I might be able to get a job on a farm'. We show them how much is involved in dairy farming," Grant said. "It's working quite well," he added.
A career dairy farmer, Grant sees a bright future for the industry.
"If you can get everything right on-farm there's a good future. There are a lot of farms out there who are spot on and they'll do well," he said.
The Sherbornes maintain high standards to ensure they produce top quality milk while caring for their animals and land.
"I do have high standards," Grant says. "If someone gets a bit slack I say: 'no, it's got to be done this way'. We want top quality production and top quality milk."
This has always been the successful philosophy behind the Sherborne farm.
When Grant was 13 his father, a potato and dairy farmer, was killed in a tractor accident. His mother was able to carry on the dairy until Grant left school to help.
"I could have gone further than Year 10 but I had more interest in coming home and doing stuff on the farm than going to school.
"Teachers used to say I should go on and do engineering or something like that but farming's an engineering thing as well. If you're interested in it, it's amazing how much you can learn.
"When I left school I had more interest in growing pasture and the machinery than the cow side of it. I'd help, but my mother was still running the dairy."
Grant was particularly interested in irrigation and at 17 he became the first dairy farmer in the district to have a travelling irrigator.
"A lot were saying: 'he's a young kid, he'll go broke spending all this money', but it worked out all right. Every dairy around here has irrigation now."
Grant still likes to innovate, especially when it comes to farming to maintain the land for future generations. The farm has introduced a mirror-image feedpad to more efficiently feed the cows after milking, a slurry tanker to pump out sludge and recycle it to paddocks, a new large dam and expanded irrigation system, and more recently a mobile phone app that is used for taking milk cell counts and detecting bacteria.
Grant has converted some of his extensive experience into an Advanced Diploma in Agriculture, and he's also joined the Board of the Dairy Farmers Milk Co-operative to give something back to the industry.
His innovation and quality work pays off with the mainly Holstein herd producing about five per cent more this year.
"I think it's looking good into the future. The top farms will continue to do well," Grant said.
Tamworth farming veteran to speak at Australian Dairy Conference
Moss Vale farming veteran to speak at Australian Dairy Conference
Natasha builds resilience in tough dairy season
Irish backpacker flourishes in Australian dairy industry
Blighty farmer sets a good example for farm safety
Australian Dairy Conference gives Forbes farmer big boost
Studious teenager becomes successful dairy farmer
A vision for good dairy farming land
Farm Visit program to bridge city-country divide
The next generation of LEGENDAIRY
Enjoying life on the farm
NSW young farmers unite to improve proficiency
Sam's mission to bring young people to dairy
Mount Annan students perfect their heifer-raising skills
Student heifer-raising champ to be decided at Camden Show
Travis Thompson
Grant and Jane Sherborne
Ian Hindmarsh
Luke Micallef
Marie Farley
John Fairley
Dianna Ferguson
Tim & Clare Boone


Better You are an innovative natural health company specialising in the supplementation of the growing number of key nutrients lost through modern diet & lifestyle.
They commissioned Motiv to produce a series of animations to explain a range of their products. We created the animations with 2D and 3D elements, helping to explain the way the nutrients are absorbed into the body.
BetterYou enjoyed the production process and we're very happy with the final videos. We are currently working on a new batch for new products.


Welcome to one of the Shawnee Wine Trail's best offerings!
Cave Creek Cabins, premier cabin rentals on Shawnee Wine Trail. Custom built in 2017 with artisan crafted wood features and furnishings made from 100 year old reclaimed lumber, our beautiful rental cabins are a must see for your next visit. You can relax on one of the covered decks while enjoying a local wine, and let the trickling sounds of Cave Creek take your cares away.
Approximately one mile north of Alto Pass, our cabins are both quiet and convenient. And just beyond our wooded property, we are surrounded by Rendleman Orchard farmland. Enjoy the beautiful orchard blooms on a springtime drive or the flavors of a bountiful harvest from the nearby farm store during peak season. The cabins are only minutes away from many of the Shawnee Trail wineries, a growing number of craft breweries, a variety of restaurants, an abundance of outdoor activities, parks and scenic trails.
Cave Creek Cabins offer the perfect accommodations for a wedding weekend, pre-wedding event, family gathering, or just a relaxing getaway with friends. Be among the first to take advantage of this new rental offering and plan your next stay with us.
Call today for a quote on our winter rates!
The location of the cabins is in a perfect area to enjoy the wine trail, the Bald knob Cross and have access to good restaurants and food within a short drive. The cabins are beautiful and truly have everything you need! There is a large selection of utensils and cookware if you want to cook. The layout of the cabin is perfect for couples or two families and is very secluded. The sounds of the creek and the breeze through the trees make sitting on the large deck such a relaxing experience. No better place to have your morning coffee! This is glamping at it's best!


text:
Eric Lopez
Member, Board of Directors
Eric Lopez graduated from New Mexico State University in 1992 with a degree in Journalism/Mass Communications with an emphasis in Advertising Design. Eric spent 1992 to 1996 working as a graphic artist at multiple offset printing companies as well as a freelance graphic artist for many commercial companies.
In 1996 Eric became a trainer at New Horizons Computer Learning Center of Albuquerque, NM teaching graphic design software courses such as CorelDRAW!, Adobe Photoshop , Adobe Illustrator and Adobe In-Design. Eric also taught the Microsoft Office Suite through the advanced level.
From 1996 to 2008 Eric worked at several New Horizons CLC franchises including those in Santa Cruz, CA, Tucson, AZ, El Paso, TX and finally back to Albuquerque, NM. During this tenure, Eric worked at a Trainer, Training Manager, Operations Manger, Sales, Manager, Senior Sales Manager, General Manager and finally co-owner at New Horizons CLC of El Paso and New Horizons CLC of New Mexico.
In 2008 Eric took his vast training center experience to EC-Council North America where he developed and launched the iClass training division whose charter is to offer EC-Council certification courses in live, online, and streaming video online training formats to clients who don't have access to an EC-Council Authorized Training center in their local area. EC-Council Authorized Training Centers also utilize the iClass platform to deliver online training to their students.
Eric continues to run the iClass training division and has also become the Executive Director of the EC-Council Foundation, which delivers IT Security conferences all over the world. The EC-Council Foundation, under Eric's leadership, also runs the Global Cyberlympics hacking competition with world finals held in locations around the world.
Lastly, Eric is a member of the EC-Council Executive Management team and the EC-Council Product Council. Eric and his team are responsible for the Certified Chief Information Security Officer (CCISO) certification program including its training program, body of knowledge, and exam.


(CNN Money) — One of America's biggest mass shootings happened recently at a country music festival but organizers at the Country Music Association don't want the tragedy to overshadow the genre's biggest night.
"The 51st Annual CMA Awards" will be held Wednesday, November 8 at Bridgestone Arena in Nashville, Tennessee, and it will be broadcast live on ABC.
In its media guidelines CMA is asking journalists to avoid discussing several politically charged topics including the mass shooting at the Route 91 Harvest Festival in Las Vegas last month, which left 58 people dead and more than 500 injured.
The CMA Awards draw some of the music genres' biggest names and for the tenth straight year, it will be hosted by country superstars Carrie Underwood and Brad Paisley.
The guidelines also includes a warning to those who don't heed them, including potentially missing out on covering country music's premiere event.
The tragedy has stirred a great deal of discussion in the country music community among fans and performers alike, given the genre's association with gun culture.