text:
41-Methoxy isotope labeled rapamycin 42-ester
41-methoxy-labeled rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) compounds are provided, along with methods for the synthesis and use thereof.
Gu, Jianxin (River Edge, NJ, US)
Ruppen, Mark (Garnerville, NY, US)
Wyeth (Madison, NJ, US)
540/456, 534/11
A61K51/00; A61K31/4745; C07D491/14
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KIFLE, BRUCK
Attn: Cathy Kodroff (Blue Bell, PA, US)
1. A 41-methoxy-isotope-labeled compound of a rapamycin 42-ester.
2. The 41-methoxy-isotope-labeled compound according to claim 1, wherein the rapamycin 42-ester is rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779).
3. The compound according to claim 1, which is 41-[13C]methoxyl rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (41-[13C]methoxyl CCI-779).
5. The compound according to claim 1, which is 41-[2H3]methoxyl rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (41-[2H3]methoxyl CCI-779).
7. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. A process for preparing a 41-methoxy-labeled rapamycin 42-ester comprising the steps of: (a) acylating 41-desmethylrapamycin with an activated ester side chain in the presence of a suitable lipase to provide an 42-ester derivative of 41-desmethylrapamycin; (b) treating the compound of step (a) with a silylating agent to form a 31,41-bis-O-silyl ether derivative; (c) selectively removing the 41-O-silyl group from the compound of step (b) with an acid; (d) treating the compound of step (c) with a labeled methanol alkylating agent; and (e) removing the protecting group with an acid.
9. The process according to claim 8, wherein the activated ester derivative in step (a) is isopropylidene ketal protected 2,2-bis(hydroxymethyl)propionic acid vinyl ester.
10. The process according to claim 8, wherein the lipase in step (a) is a microbial lipase.
11. The process according to claim 10, wherein the microbial lipase is an immobilized lipase.
12. The process according to claim 11, wherein the immobilized lipase is lipase PS-C "Amano" II™.
13. The process according to claim 11, wherein the immobilized lipase is lipase PS-D "Amano" I™.
14. The process according to claim 8, wherein the reaction in step (a) is carried out in anhydrous tert-butyl methyl ether.
15. The process according to claim 8, wherein the reaction in step (a) is carried out at 20-55° C.
16. The process according to claim 8 wherein the silylating agent in step (b) is a trialkylsilyl halide.
17. The process according to claim 16, wherein the trialkylsilyl halide is chlorotrimethylsilane.
18. The process according to claim 8, wherein the acid in steps (c) and (e) is sulfuric acid.
19. The process according to claim 8, wherein the isotope-labeled methanol alkylating agent in step (d) is Methyl-13C trifluoromethanesulfonate.
21. The process according to claim 8, wherein the isotope-labeled methanol alkylating agent in step (d) is Methyl-d3 trifluoromethanesulfonate.
22. The process according to claim 8, wherein the isotope-labeled methanol alkylating agent (d) is Methyl-t3 trifluoromethanesulfonate.
23. A method for monitoring the pharmacokinetic properties of a rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) comprising assaying a sample from a subject to which CCI-779 has been administered using the 41-methoxy isotope-labeled CCI-779 according to claim 1.
24. A method for the treatment of a disease selected from the group consisting of: renal cancer, soft tissue sarcoma, breast cancer, neuroendocrine tumor of the lung, cervical cancer, uterine cancer, head and neck cancer, glioma, non-small cell lung cancer, prostate cancer, pancreatic cancer, lymphoma, melanoma, small cell lung cancer, ovarian cancer, colon cancer, esophageal cancer, gastric cancer, leukemia, colorectal cancer, and unknown primary cancer; comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.
25. A compound of the structure wherein R1 is a linear, cyclic, or aromatic, saturated or unsaturated hydrocarbon which optionally contains hydroxyl, boron, nitrogen, halogen and/or thio; and R′, R″ and R′″ are the same or differently selected from alkyl of 1-6 carbon atoms, phenyl and benzyl
26. The compound of claim 25, wherein said compound is of the structure wherein R′, R″ and R′″ are the same or differently selected from alkyl of 1-6 carbon atoms, phenyl and benzyl.
27. The compound of claim 26 which is rapamycin 31-O-trimethyl silyl ether, 42-ester with 2,2,5-trimethyl[1,3-dioxane]-5-carboxylic acid having the structure
This application claims the benefit under 35 USC 119(e) of U.S. Provisional Patent Application No. 60/733,563, filed Nov. 4, 2005.
This invention relates to isotope-labeled compounds of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779).
CCI-779 is a derivative of rapamycin, which is a macrocyclic triene antibiotic produced naturally by Streptomyces hygroscopicus. The preparation and use of CCI-779 is described in U.S. Pat. No. 5,362,718. Regioselective syntheses of CCI-779 are described in U.S. Pat. No. 6,277,983 and US Patent Publication No. 2005/0033046 A1.
Rapamycin has been found useful in an array of applications based on its antitumoral and immunosuppressive effects. Such uses include preventing, inhibiting, or treating transplant rejection, graft vs. host disease, autoimmune diseases including systemic lupus erythematosis, inflammatory diseases including pulmonary and ocular inflammation, adult T cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders, including smooth muscle cell proliferation and intimal thickening following vascular surgery. Rapamycin and rapamycin derivatives, including CCI-779, continue to be studied for treatment of these and other conditions.
Both radio- and stable-isotope-labeled CCI-779 are required for drug absorption, distribution, metabolism and excretion (ADME) studies and as standard for quantitative mass spectrometry (MS) bio-analytical studies. Clinically useful isotope-labeled CCI-779, either stable-isotope-labeled (e.g., deuterium, 13C) or radioactive-isotope-labeled (e.g., tritium, 14C), has been made through labeling its 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid side chain. However, this ester-linked side chain has been found unsuitable for labeling due to metabolic instability. Similarly, the 7-methoxy moiety in the rapamycin skeleton is unsuitable for labeling (US Patent Publication No. 2004/0198762 A1).
Accordingly, what is needed are CCI-779 compounds isotope-labeled in metabolically resistant sites having increased metabolic stability and processes for their preparation.
In one aspect, compounds of isotope-labeled rapamycin 42-ester which are isotope labeled in the rapamycin skeleton, i.e., in a metabolically resistant 41-methoxyl position (41-isotope-labeled compounds of rapamycin 42-esters), are provided. In a further aspect, 41-isotope-labeled compounds of a rapamycin 42-ester bearing carbon isotopes are provided. In one embodiment, the compound is 41-[13C]methoxyl CCI-779 (shown below). In another embodiment, the compound is 41-[14C]methoxyl CCI-779 (shown below). In a further aspect, 41-isotope-labeled compounds of a rapamycin 42-ester bearing hydrogen isotopes are provided. In one embodiment, the compound is 41-[2H3]methoxyl CCI-779 (shown below). In another embodiment, the compound is [3H3]methoxyl CCI-779 (shown below).
In another aspect, the processes for the preparation of compounds of the invention from 41-desmethylrapamycin are provided.
In still another aspect, the use of the above compounds in pharmaceutical compositions is provided. In one embodiment, the use of compounds of the invention or compositions containing compounds of the invention in determining pharmacokinetic properties of unlabeled parent compound and for evaluation of ADME data is provided. In another embodiment, the use of compounds of the invention or compositions containing compounds of the invention in bio-analytical study is provided. In still other embodiments, the use of the above compounds and compositions containing the above compounds in the treatment or prevention of, or in the preparation of a medicament useful in the treatment or prevention of, diseases and disorders including transplant rejection, graft vs. host disease, autoimmune diseases including systemic lupus erythematosis, inflammatory diseases including pulmonary and ocular inflammation, adult T cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders, is provided.
Other aspects and advantages will be apparent from the following detailed description of the invention.
Isotope-labeled compounds of present invention are rapamycin 42-esters labeled at the 41-methoxyl position in the rapamycin skeleton by reaction of an isotope-labeled methanol alkylating agent with a 41-desmethylrapamycin 42-ester intermediate. In one embodiment, the 41-desmethylrapamycin 42-ester intermediate is a 41-desmethylrapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid.
As used herein, the term "metabolically resistant" refers to an isotope-labeled compound that is labeled at a site resistant to degradation in metabolic reaction, i.e., is sustainable toward metabolic reactions such as hydrolysis, hydroxylation, demethylation, oxidation, etc., under physiological conditions. Compared with compounds having isotopes incorporated at the site of metabolism, e.g., in the acid side chain or at the 7-methoxyl position, these "metabolically resistant" compounds can provide more accurate information due to their longer in vivo half-life.
An isotopic label is made of an element or group which has a plurality of stable isotopes of at least one element constituting the element or group, wherein at least one stable isotope of the constituent element is so controlled that it is present in an amount higher than the natural isotopic abundance ratio (although both are same structurally, the content ratio of the stable isotope of the element is so controlled as to be not lower than the natural isotopic abundance ratio).
Labeling in metabolically resistant sites, e.g., the 41-methoxy site in the CCI-779 skeleton, is useful in obtaining compounds having multiple labeling and compounds having improved metabolic stability. Such compounds are more useful for the evaluation of ADME data.
As used herein, the terms "provide", "providing", and variants thereof, mean administering one or more compounds or compositions described herein to a mammal in need thereof.
As used herein, the terms "prevent", "preventing", and variants thereof, mean providing one or more compounds or compositions described herein to a mammal susceptible to one or more diseases or conditions. As used herein, the terms "inhibit", "inhibiting", and variants thereof, mean providing one or more compounds or compositions described herein to a mammal having one or more diseases or conditions so as to stop or reduce the progress thereof. As used herein, the terms "treatment", "treating", and variants thereof, mean providing one or more of the described compounds or compositions to a mammal having one or more diseases or conditions so as to prevent, inhibit, palliate, or eradicate the disease(s) or condition(s), or to reduce the symptoms thereof.
Throughout the specification, the words "comprising," "including," and "having" and variations thereof are intended to be inclusive and mean that there may be additional elements other than the listed elements.
I. Synthesis
The compounds described are prepared according to the following general synthetic scheme:
R is 13CH3, 14CH3, C2H3, or C3H3.
R1 is a linear, cyclic, aromatic, saturated or unsaturated hydrocarbon which optionally contains hydroxyl, boron, nitrogen, halogen and/or thio.
R′ is selected from H, Me.
The first step in the synthesis of 41-methoxy isotope-labeled rapamycin 42-ester compounds of the invention is the attachment of an ester side chain onto position 42 of 41-desmethylrapamycin. Unlike rapamycin which contains two secondary hydroxyl groups at position 31 and 42, its preparation of 42-esters can be performed either by non-regioselective chemical reacting rapamycin with various acylating agents or by lipase-catalyzed regiospecific esterification method (US patent application 2005/0234234A1). 41-desmethylrapamycin, on the other hand, is much more complicated, in addition to a secondary hydroxyl group at C-31, it contains two very similar 41,42-bishydroxyl group, this makes the selective 42-esterification much more difficult. The invention provides a lipase-catalyzed process for the introduction of 42-ester side chain into 41-desmethylrapamycin molecule. The remarkable features of this simple process are regiospecificity and excellent yield under mild conditions. In one embodiment, this lipase-based process of the invention is illustrated by the installation of an isopropylidene ketal protected (acetonide protected) 2,2-bis(hydroxymethyl)propionic acid side chain to position 42 of 41-desmethylrapamycin, which is useful for preparation of CCI-779 analogs. However, it will be readily understood that other ester side chains can be readily introduced using the method described above. Examples of such ester side chains can be selected from, including, e.g., alkyl esters (U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803); fluorinated esters (U.S. Pat. No. 5,100,883); amide esters (U.S. Pat. No. 5,118,677); carbamate esters (U.S. Pat. No. 5,118,678); aminoesters (U.S. Pat. No. 5,130,307); acetals (U.S. Pat. No. 5,51,413); aminodiesters (U.S. Pat. No. 5,162,333); alkoxyesters (U.S. Pat. No. 5,233,036); hydroxyesters (U.S. Pat. No. 5,362,718); hindered esters (U.S. Pat. No. 5,385,908); heterocyclic esters (U.S. Pat. No. 5,385,909); gem-disubstituted esters (U.S. Pat. No. 5,385,910); amino alkanoic esters (U.S. Pat. No. 5,389,639); carbamate esters (U.S. Pat. No. 5,411,967); carbamate esters (U.S. Pat. No. 5,434,260); amidino carbamate esters (U.S. Pat. No. 5,463,048); carbamate esters (U.S. Pat. No. 5,480,988); carbamate esters (U.S. Pat. No. 5,480,989); carbamate esters (U.S. Pat. No. 5,489,680); hindered N-oxide esters (U.S. Pat. No. 5,491,231); biotin esters (U.S. Pat. No. 5,504,091); 5,665,772); and PEG esters of rapamycin (U.S. Pat. No. 5,780,462). The preparation of these esters and ethers is described in the patents listed above.
Production of desmethylrapamycins (also known in the art as O-desmethylrapamycins) has been described. See, e.g., U.S. Pat. No. 6,358,969 (29-desmethylrapamycin) and U.S. Pat. No. 6,670,168 (17-desmethylrapamycin), both of which are hereby incorporated by reference. The numbering convention for rapamycin has been changed. Therefore, according to Chemical Abstracts nomenclature, the compounds described above would be at 32- and 8-positions. In one embodiment, 41-desmethylrapamycin may be obtained via biotransformation either by Streptomyces sp. ATCC 39471 (Nishida, H. et al, The Journal of Antibiotics, 48(7), 1995, 657-666) or by Streptomyces rimosus ATCC 28893 (Kuhnt M., et al, Enzyme and Microbial Technology, 21, 1997, 405-412).
The installation of 42-ester side chain (e.g., isopropylidene ketal protected 42-ester 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid) in the first step, as shown in Scheme 1 above, is accomplished via a lipase-catalyzed acylation of 41-desmethylrapamycin with an activated ester, e.g., vinyl esters, isopropenyl esters and anhydrides. In one embodiment, the activated ester derivative is vinyl ester of the 2,2-bis(hydroxymethyl)propionic acid (1). However, other ester side chains are readily selected by one of skill in the art, in one embodiment, the activated ester side chain is selected from among esters of the formula CH2═CH—O—COR1, where R1 is linear, cyclic, aromatic, saturated, or unsaturated hydrocarbon chain, which optionally contains hydroxyl, boron, nitrogen, halogen and/or thio, in another embodiment, such activated ester side chains are isopropenyl esters having the structure CH2═C(CH3)—O—COR1, wherein R1 is defined above.
The acylation reaction may be carried out using a catalytic effective amount of any suitable lipase in a suitable solvent. In one embodiment, the lipase used is a microbial lipase. As used herein, "microbial lipases", i.e., lipases with microbial origin, include enzymes which were originally isolated from a non-eukaryotic source, such as, Aspergillus niger, Candida antarctica, Candida rugosa, Mucor miehei, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar. However, the enzyme selected for use need not be directly isolated and purified from the original source, but can be prepared synthetically, recombinantly, or through other suitable means. A variety of these enzymes are available from commercial sources. Further, these enzyme preparations can be used as crude, partially purified, purified or immobilized form from different microbial origin under different trade names by various suppliers. In one embodiment, the lipase is lipase PS from Pseudomonas cepacia. In another embodiment, the lipase is an immobilized lipase PS from Pseudomonas cepacia. In a further embodiment, the lipase is lipase PS-C "Amano" II™ (Amano Enzymes, Inc.). In yet another embodiment, the lipase is lipase PS-D "Amano" I™ (Amano Enzymes, Inc.).
The reaction is typically carried out in an organic solvent. Suitable solvents include, but are not limited to, toluene, tert-butyl methyl ether (TBME), ethyl ether, THF (tetrahydrofuran), MeCN, CH2Cl2, CHCl3, iPr2O, hexane, dioxane, or mixtures including these solvents. In one embodiment, TBME (tert-butyl methyl ether) is used. It will be appreciated by those skilled in the art that the solvent is used in an amount which can effectively dissolve all or part of starting 41-desmethylrapamycin at the beginning and allows the reaction to proceed at a reasonable rate. For example, a solvent, such as TBME, can be used in an amount of at least 4 wt volume (i.e., a volume that is in an excess of 4 times (4×) the amount of 41-desmethylrapamycin to about 10 wt volume), with about 5 to 8 wt volumes being preferred.
TBME (tert-butyl methyl ether) may contain residual water (e.g., about 0.05%) which could decompose the rapamycin compound. In order to minimize this side-reaction, a low amount of moisture is maintained in the reaction system. In one desirable embodiment, anhydrous TBME is used with a standard commercial preparation of the lipase catalyst. In another embodiment, moisture can be controlled through adjusting the amount of water present in the lipase solution by adding a drying agent. In yet another embodiment, a molecular sieve can be used to control the moisture. Since a molecular sieve will slow the reaction down, more enzyme may be added to compensate, or a longer reaction time can be used. In one embodiment, a 5 Å molecular sieve is used. However, other sieve sizes including, but not limited to, 4 Å and 3 Å, can be readily utilized. Suitable molecular sieves are available from a variety of commercial sources. In still another embodiment, drying agents such as MgSO4, Na2SO4, among others, can be used to control the moisture content.
Other lipases, solvents (including solvent mixtures), are known to those of skill in the art and are encompassed herein.
The acylation reaction is conducted at a temperature low enough to reduce the formation of unwanted by-products, but not so low as to require an unreasonably long reaction time. In one embodiment, the acylation is carried out at from about 20 to about 55° C. In other embodiments, the acylation reaction is carried out at about 25 to 50° C., about 35 to 50° C., about 40 to 50° C., or other ranges therein. For example, in one embodiment, the acylation reaction is carried out at about 40 to 45° C.
In one embodiment, the acylation is carried out as follows. 41-desmethylrapamycin, the protected side chain vinyl ester (1) (e.g., isopropylidene ketal protected 2,2-bis(hydroxymethyl)propionic acid vinyl ester), and lipase PS-C "Amano" II are combined in anhydrous TBME. The mixture is heated under nitrogen at 40-45° C. for about 24 hours or until 41-desmethylrapamycin starting material disappears as monitored by TLC or HPLC. After removing enzyme by filtration, 41-desmethyl intermediate A was obtained in nearly quantitative yield.
In the next step, intermediate A is treated with a silylating agent to form a 31,41-bis-O-silyl ether derivative B. In one embodiment, the silating agent has the formula LV-SiR′R″R′″, wherein R′, R″, and R′″ are the same or different and are independently selected from an alkyl of 1, 2, 3, 4, 5 or 6 carbon atoms, phenyl and benzyl, and LV is a leaving group. In one embodiment, the LV is a halide (e.g., Cl, Br, or I). Desirably, silylating agents that can be used for this transformation are readily selected from among trialkylsilyl halides, many of which are commercially available, e.g., chloroalkylsilanes, such as chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane or chlorotriisopropylsilane. In one embodiment, the silylating agent is chlorotrimethylsilane. The bulkier the trialkylsilane, the more time is needed to remove it in acid media in the following step to free the 41-hydroxyl group. One of skill in the art will recognize that reduced reaction time generally results in reduced formation of unwanted by-products.
The silylation reaction is carried out in a suitable organic solvent in the presence of a suitable base, which can be readily selected from among those known in the art, e.g., imidazole, 1-methyl imidazole, trialkylamines and N,N-diisopropylethylamine. In one embodiment, imidazole is used as the reaction can be completed in less than 1 hour. A number of organic solvents can be selected for silylation including, e.g., DMF. In one embodiment, ethyl acetate is the solvent. The reaction may be carried out at ambient temperature, e.g., room temperature, or lower, e.g., 0° C., or about 0-5° C. In one embodiment, intermediate A is treated with excess chlorotrimethylsilane in ethyl acetate at 0-5° C. in the presence of imidazole for 120 minutes to form 31,41-bis-O-trimethylsilyl (TMS) ether B.
Following silylation, without separation and purification, crude B in EtOAc solution is treated with a dilute organic or inorganic acid to selectively remove the less hindered 41-O-silyl group, while retaining the silyl group at the more hindered C-31 position, to provide compound C. In one embodiment, the acid is an inorganic acid such as sulfuric, hydrochloric or phosphoric acid. In a further embodiment, the acid is aqueous sulfuric acid having a concentration less than 2.5 N. In still a further embodiment, about 0.1-1 N, or about 0.5 N aqueous sulfuric acid is used. In one embodiment, the reaction can be completed within 1-3 hours. However, longer reaction times may be used where less reactive silyl protecting groups such as triethylsilyl or tripropylsilyl are employed. In one embodiment, the reaction is carried out at a temperature of about 25° C. or below, from about +10° C. to −5° C., or from about 0° C. to 5° C. In one embodiment, when silylation with chlorotrimethylsilane/imidazole is completed as confirmed by TLC or HPLC, 0.5 N aqueous H2SO4 is added to the reaction mixture, the reaction mixture is stirred for about 2 hours or monitored by TLC while maintaining the temperature at 0-5° C. Regular workup and purification via silica gel chromatography or recrystallization provides compound C. These and other purification means are known to those of skill in the art and are contemplated by the invention.
An important feature is that various isotope atoms are introduced from a common intermediate at a relatively late stage of synthesis. This strategy offers great flexibility for the synthesis of a variety of 41-methoxylabeled rapamycin 42-esters. The late stage option is also desirable, particularly for radioactive isotope labels, because it minimizes handling of radioactive materials and waste disposal and thus is beneficial for personnel and environmental safety.
Compound C is methylated at the C-41 position in the rapamycin skeleton with an isotope-labeled methanol equivalent (also referred to herein as a methanol alkylating agent or a methylating agent) or comprising one leaving group (LG). Examples of leaving groups include, but are not limited to, sulfonates such as methanesulfonate (mesylate, MsO), p-toluenesulfonate (tosylate, TsO), fluoromethanesulfonate, difluoromethanesulfonate, trifluoromethanesulfonate (triflate, TfO), and halogens (e.g. I, Br, Cl). In one embodiment, the leaving group is triflate. Thus, in one embodiment, the methylating agent is Methyl-13C trifluoromethanesulfonate (13CH3OTf). In another embodiment, the methylating agent is Methyl-14C trifluoromethanesulfonate (14CH3OTf). In yet another embodiment, the methylating agent is methyl-d3 trifluoromethanesulfonate (CD3OTf), where d is understood to represent deuterium (2H). In still another embodiment, the methylating agent is methyl-t3 trifluoromethanesulfonate (CT3OTf), where t is understood to represent tritium (3H).
A number of hindered, non-nucleophilic bases can be used for such methylation. Examples of such bases include, but not limited to, 2,6-lutidine, 2,6-di-tert-butylpyridine, 2,6-di-tert-butyl-4-methylpyridine, N,N-dimethylaminopyridine, diisopropylethylamine. In one embodiment, the base is 2,6-di-tert-butyl-4-methylpyridine. In one embodiment, the solvent is toluene, benzene, 1,2-dichloroethane, methylene chloride, or chloroform. However, other suitable solvents may be readily selected by those of skill in the art. In a further embodiment, compound C is treated with an excess amount of labeled methyl triflate in methylene chloride at ambient temperature in the presence of 2,6-di-tert-butyl-4-methylpyridine, followed by purification of the product, compound D, by silica gel chromatography. Modifications in the reaction temperatures and times may be adjusted by one of ordinary skill in the art based on the leaving group utilized and other reaction conditions.
Removal of isopropylidene ketal and 31-silyl protecting groups in compound D to furnish 41-labeled rapamycin ester (e.g., 41-labeled CCI-779) is accomplished by using organic or inorganic acid. In one embodiment, the acid is an inorganic acid such as sulfuric, hydrochloric or phosphoric acid. In a further embodiment, the acid is aqueous sulfuric acid having a concentration less than 4 N. In a further embodiment, about 1-3 N or about 2N aqueous sulfuric acid is used. The reaction is carried out in a water-miscible solvent. In one embodiment, the solvent is acetone. In another embodiment, the solvent is tetrahydrofuran (THF). In one embodiment, the reaction is carried out at a temperature of about 25° C. or below, from about −5° C. to about 10° C., or from about 0° C. to about 5° C. In one embodiment, compound D is dissolved in THF at 0-5° C. and is treated with 2N aqueous sulfuric acid. The progress of the reaction may be monitored by TLC or HPLC. Isotope-labeled CCI-779 was then isolated and purified by silica gel chromatography. This and other purification means are known to those of skill in the art and are contemplated by the invention.
II. Uses and Kits
Currently, the preferred method for following the fate of a drug in vivo is to administer a radiolabelled form of the compound, typically one that incorporates 14C or 3H into the structural core. A radiolabel can easily be detected and quantified, making it particularly well suited for use as a tracer. Radioactivity is the gold standard for tracing and measuring the ADME properties of a drug candidate (Dalvie, D., 2000, "Recent advances in the applications of radioisotope in drug metabolism, toxicology and pharmacokinetics", Curr. Pharm. Des., 6, 1009-1028). Hence, Radioisotope-labeled rapamycin 42-ester (e.g., 41-[14C]methoxy-CCI-779, and 41-[3H3]methoxy-CCI-779) is required for drug absorption, distribution, metabolism and excretion (ADME) studies. LC/MS is used extensively to identify drug metabolites, but it is not used quantitatively unless authentic standards of the metabolites are available (Clarke, N. J., et al, 2001, "Systematic LC/MS metabolite identification in drug discovery", Anal. Chem., 73, 430A-439A) and such standards require the incorporation of stable isotope, typically 13C and 2H into the core of the molecule. Hence, stable isotope-labelled rapamycin 42-ester (e.g. 41-[13C]methoxy-CCI-779, and 41-[2 H3]methoxy-CCI-779) are useful as internal standard of quantitative mass spectrometry (MS) for bio-analytical studies. Moreover, isotopically altered drugs have shown widely divergent pharmacological effects. Petersen et al, found increased anti-cancer effect with deuterated 5,6-benzylidene-dl-L-ascorbic acid (Zilascorb) (Anticancer Res., 1992, 12, 33), and recently, some deuterated rapamycin as therapeutical agents has been incorporated into medical devices (US2003/0130206). Due to the nature of the isotope-labeled rapamycin 42-ester compounds of this invention, i.e., isotope-labeled in a metabolically resistant 41-methoxyl position, they are particularly useful in studying and/or monitoring the pharmacokinetic properties of the rapamycin 42-ester, including the metabolic fate of CCI-779 in the cell/tissue.
Determination of pharmacokinetic properties using radiolabeled rapamycin 42-ester (e.g., CCI-779) as described herein may be accomplished using standard chemical and biological assays and mathematical modeling techniques known to those of skill in the art. For example, the compounds of the invention can be used in the assays such as those described in the following [J. M. Peralba, et al, Clin. Cancer Res, 9:2887-2892 (2003); B Coiffier et al, Blood, 92(6):1927-1932 (Sep. 15, 1998)].
In one embodiment, the invention provides kits for use in detection of particular metabolites of a selected rapamycin 42-ester comprising the counterpart radiolabeled rapamycin 42-ester compound as described herein. In a further embodiment, kits of the invention may also contain additional components, such as, e.g., a positive control (e.g., radiolabeled CCI-779 or a radiolabel-containing metabolite thereof), a negative control, reagents (e.g., buffer, lysozyme, nuclease), vials, tubes, and instructions for performing the method of the invention.
The isotope-labeled rapamycin 42-ester compounds described herein are also useful in the prevention, inhibition, or treatment of transplant rejection, graft vs. host disease, autoimmune diseases including systemic lupus erythematosis, inflammatory diseases including pulmonary and ocular inflammation, adult T cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders, including smooth muscle cell proliferation and intimal thickening following vascular surgery, and other conditions for which rapamycin and its derivatives, including rapamycin 42-ester (CCI-779), has been described. The isotope-labeled compounds described herein are also useful in preparing medicaments useful in the treatment of these diseases and disorders.
In a further embodiment, pharmaceutically effective amounts of the isotope-labeled rapamycin 42-ester compounds described herein are used in the treatment of a disease selected from renal cancer, soft tissue sarcoma, breast cancer, neuroendocrine tumor of the lung, cervical cancer, uterine cancer, head and neck cancer, glioma, non-small cell lung cancer, prostate cancer, pancreatic cancer, lymphoma, melanoma, small cell lung cancer, ovarian cancer, colon cancer, esophageal cancer, gastric cancer, leukemia, colorectal cancer, and unknown primary cancer. The isotope-labeled rapamycin 42-ester compounds described herein are also useful in preparing medicaments useful in the treatment of these diseases.
III. Compositions
The isotope-labeled compounds prepared as described above are useful in pharmaceutical compositions. Such compositions can be formulated by any suitable method described in the art for rapamycin or derivatives thereof.
Oral formulations containing the active compounds as described herein may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. In one embodiment, surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or a fruit juice, which contains appropriate solubilizers or emulsifiers as needed.
In one embodiment, oral formulations for isotope-labeled CCI-779 of the invention are described in US Patent Publication No. US 2004/0077677 A1, which is hereby incorporated by reference. Other isotope-labeled rapamycin 42-esters may be used in a similar manner. Such an oral formulation contains a granulation prepared using a wet granulation process.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
In one embodiment, injectable formulations for isotope-labeled rapamycin 42-ester are described in US Patent Publication No. US 2004/0167152 A1, which is hereby incorporated by reference.
In another embodiment, a useful injectable formulation provides an isotope-labeled-rapamycin 42-ester cosolvent concentrate containing a parenterally acceptable solvent and an antioxidant as described above and a parenteral formulation containing an isotope-labeled rapamycin 42-ester described herein, a parenterally acceptable cosolvent, an antioxidant, a diluent solvent, and a surfactant. Any given formulation may contain multiple ingredients of each class of component. In one embodiment, a parenterally acceptable solvent can include a non-alcoholic solvent, an alcoholic solvent, or mixtures thereof. Examples of suitable non-alcoholic solvents include, e.g., dimethylacetamide, dimethylsulfoxide or acetonitrile, or mixtures thereof. "An alcoholic solvent" may contain one or more alcohols as the alcoholic solvent component of the formulation. Examples of solvents useful in the formulations invention include, without limitation, ethanol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, or mixtures thereof. These cosolvents are particularly desirable because degradation via oxidation and lactone cleavage occurs to a lower extent for these cosolvents. Furthermore, ethanol and propylene glycol can be combined to produce a less flammable product, but larger amounts of ethanol in the mixture generally result in better chemical stability. In one embodiment, the mixture contains an ethanol concentration of 30 to 100% v/v.
In another embodiment, the stability of an isotope-labeled-rapamycin 42-ester of the invention in parenterally acceptable alcoholic cosolvents is enhanced by addition of an antioxidant to the formulation. Acceptable antioxidants include, but are not limited to, citric acid, d,l-α-tocopherol, BHA, BHT, monothioglycerol, ascorbic acid, propyl gallate, and mixtures thereof. Generally, the parenteral formulations useful in this embodiment of the invention will contain an antioxidant component(s) in a concentration ranging from 0.001% to 1% w/v, or 0.01% to 0.5% w/v, of the cosolvent concentrate, although lower or higher concentrations may be desired. In one embodiment, d,l-α-tocopherol is used at a concentration of 0.01 to 0.1% w/v, or 0.075% w/v, of the cosolvent concentrate.
In other embodiments, the antioxidant component of the formulation of the invention also exhibits chelating activity. Examples of such chelating agents include, e.g., citric acid, acetic acid, and ascorbic acid (which may function as both a classic antioxidant and a chelating agent in the present formulations). Other chelating agents include such materials as are capable of binding metal ions in solution, such as ethylene diamine tetra acetic acid (EDTA), its salts, or amino acids such as glycine that are capable of enhancing the stability of a rapamycin 42-ester. In still other embodiments, components with chelating activity are included in the formulations as the sole "antioxidant component". In one embodiment, such metal-binding components, when acting as chelating agents, are used in the lower end of the range of concentrations for the antioxidant component provided herein. Additionally, such chelating agents may be used in combination with other antioxidants as part of the antioxidant component of the invention. For example, an acceptable formulation may contain both citric acid and d,l-α-tocopherol. Optimal concentrations for the selected antioxidant(s) can be readily determined by one of skill in the art, based upon the information provided herein.
Advantageously, in certain embodiments of the parenteral formulations, precipitation of an isotope-labeled rapamycin 42-ester upon dilution with aqueous infusion solutions or blood is prevented through the use of a surfactant contained in the diluent solution. The most important component of the diluent is a parenterally acceptable surfactant. In one embodiment, the surfactant is polysorbate 20 or polysorbate 80. However, one of skill in the art may readily select other suitable surfactants from among salts of bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.) which are optionally combined with lecithin. Alternatively, ethoxylated vegetable oils, such as a pegylated castor oil [e.g., such as PEG-35 castor oil which is sold, e.g., under the name Cremophor EL, BASF], vitamin E tocopherol propylene glycol succinate (Vitamin E TGPS), and polyoxyethylene-polyoxypropylene block copolymers can be used in the diluent as a surfactant, as well as other members of the polysorbate family such as polysorbate 20 or 60 Other components of the diluent may include water, ethanol, polyethylene glycol 300, polyethylene 400, polyethylene 600, polyethylene 1000, or blends containing one or more of these polyethylene glycols, propylene glycol and other parenterally acceptable cosolvents or agents to adjust solution osmolarity such as sodium chloride, lactose, mannitol or other parenterally acceptable sugars, polyols and electrolytes. It is expected that the surfactant will comprise 2 to 100% w/v of the diluent solution, 5 to 80% w/v, 10 to 75% w/v, 15 to 60% w/v, or at least 5% w/v, or at least 10% w/v, of the diluent solution.
A useful parenteral formulation can be prepared as a single solution. In another embodiment, a parenteral formulation useful in the invention can be prepared as a cosolvent concentrate containing a isotope-labeled rapamycin 42-ester described herein, an alcoholic solvent, and an antioxidant, which is subsequently combined with a diluent that contains a diluent solvent and suitable surfactant. Prior to use, the cosolvent concentrate is mixed with the diluent. When an isotope-labeled CCI-779 described herein is prepared as a cosolvent concentrate, the concentrate can contain concentrations of an isotope-labeled CCI-779 from 0.05 mg/mL, from 2.5 mg/mL, from 5 mg/mL, from 10 mg/mL, or from 25 mg/mL up to approximately 50 mg/ml. The concentrate can be mixed with the diluent up to approximately 1 part concentrate to 1 part diluent, to give parenteral formulations having concentrations of an isotope-labeled CCI-779 from 1 mg/mL, from 5 mg/mL, from 10 mg/mL, from 20 mg/mL, up to approximately 25 mg/ml. For example, the concentration of an isotope-labeled CCI-779 in the parenteral formulation may be from about 2.5 to 10 mg/mL. Also provided is the use of formulations having lesser concentrations of an isotope-labeled CCI-779 of the invention in the cosolvent concentrate, and formulations in which one part of the concentrate is mixed with greater than 1 part of the diluent, e.g., concentrate:diluent in a ratio of about 1:1.5, 1:2, 1:3, 1:4, 1:5, or 1:9 v/v and so on, to parenteral formulations having a isotope-labeled CCI-779 concentration down to the lowest levels of detection.
In one embodiment, the antioxidant may comprise from about 0.0005 to 0.5% w/v of the formulation, the surfactant may comprise from about 0.5% to about 10% w/v of the formulation, and the alcoholic solvent may comprise from about 10% to about 90% w/v of the formulation.
The parenteral formulations can be used to produce a dosage form that is suitable for administration by either direct injection or by addition to sterile infusion fluids for intravenous infusion.
For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Transdermal administration may be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
Further provided are packaging and kits containing an isotope-labeled CCI-779 as described herein formulated for administration by a suitable delivery method. A variety of suitable containers, including bottles, vials, blister packs, and the like are known to those of skill in the art. Such packaging and kits may further contain other components, including, e.g., instructions for use, syringes, applicators, and the like.
The following examples are illustrative of the preparation of isotope-labeled rapamycin 42-ester compounds. It will be readily understood by one of ordinary skill in the art from a reading of this application that these examples do not serve to limit the scope of the invention.
A. Synthesis of 41-[13C]methoxyl CCI-779 from 41-desmethylrapamycin
The synthesis described herein for 41-[13C]methoxyl CCI-779 may be used to generate 41-[14C]methoxyl CCI-779, except that the former was accomplished using 13CH3OTf and the latter is accomplished using 14CH3OTf. The synthetic scheme is summarized as follows.
Synthesis of A
A mixture of 41-desmethylrapamycin (770 mg),
(1) (500 mg) and lipase PS-C "Amano" II (2.0 g) in anhydrous tert-butyl methyl ether (TBME, 6 mL) was heated under N2 at 40-45° C. for 24 hours. Following the acylation, the enzyme was removed by filtration and washed with TBME. The crude mixture was concentrated to dryness under reduced pressure, crude A was obtained as white form, MS (ESI) m/e 1055 (M−).
Synthesis of C
Crude A was dissolved in EtOAc (15 mL) and the mixture was cooled to 0-5° C. with an ice-bath and imidazole (238 mg) was added. To this cold solution chlorotrimethylsilane (324 mg) was added dropwise and the mixture was stirred for 120 minutes. Thin layer chromatography (TLC) indicated all of A was converted to B (31,41-bis-O-trimethylsilyl ether). Diluted aqueous H2SO4 (2.5 mL, 0.5 N) was then added dropwise to above solution. The mixture was stirred for an additional 3 hours at 0-5° C. and diluted with ethyl acetate (EtOAc) (25 mL)/H2O (10 mL). The aqueous layer was then separated and extracted with EtOAc. Following extraction, the combined organic layer was washed successively with brine, 5% NaHCO3 and brine, and then dried and concentrated under reduced pressure. Silica gel column purification gave C (650 mg) as white foam, MS (ESI) m/e 1127 (M−).
Synthesis of D-1
A solution of C (68 mg) and 2,6-di-tert-butyl-4-methylpyridine (148 mg) in CH2Cl2 (0.5 mL) was cooled to 0-5° C. To this solution, methyl-13C triflate (13CH3OTf) (99 mg) was added dropwise. The mixture was then allowed to warm to room temperature over 1 hour and was stirred for 48 hours. Silica gel column purification of reaction mixture furnished D-1 (42 mg) as white foam [MS (ESI) m/e 1142 (M−)].
Synthesis of 1a
A solution of D-1 (20 mg) in tetrahydrofuran (THF) (1 mL) was cooled to 0-5° C. and was treated with aqueous 2N H2SO4 (0.5 mL). The mixture was then stirred for 24 hours at 0-5° C. The reaction mixture was then diluted with EtOAc (20 mL) and washed successively with brine (5 mL), 5% NaHCO3 (5 mL), and brine (5 mL). The organic layer was dried and concentrated under reduced pressure. The crude product was purified on a silica gel column to give 41-[13C]methoxyl CCI-779 (1a) (15 mg) as white foam [MS (ESI) m/e 1075 (M+HCOO−)].
B. Synthesis of 41-[2H3]methoxyl CCI-779 from 41-desmethylrapamycin
The synthesis described herein for 41-[2H3]methoxyl CCI-779 is the same as that used to generate 41-[3H3]methoxyl CCI-779, except that the former was accomplished using CD3OTf and the latter is accomplished using CT3OTf. The synthetic scheme is summarized as follows.
A solution of C (34 mg) and 2,6-di-tert-butyl-4-methylpyridine (74 mg) in CH2Cl2 (0.25 mL) was cooled to 0-5° C. Methyl-d3 triflate (CD3OTf) (50 mg) was added dropwise. The mixture was then allowed to warm to room temperature over 1 hour and was stirred for 48 hours. Silica gel column purification of reaction mixture furnished 6 (23 mg) as white foam [MS (ESI) m/e 1145 (M−)].
Synthesis of 1b
A solution of D-2 (17 mg) in THF (1 mL) was cooled to 0-5° C. and was treated with aqueous 2N H2SO4 (0.5 mL). The mixture was stirred for 24 hours at 0-5° C. The reaction mixture was diluted with EtOAc (20 mL) and washed successively with brine (5 mL), 5% NaHCO3 (5 mL), and brine (5 mL). The organic layer was then dried and concentrated under reduced pressure. The crude product was purified on a silica gel column to give 41-[2H3]methyl CCI-779 (1b) (13 mg) as white foam [MS (ESI) m/e 1077 (M+HCOO−)].
All documents identified herein are incorporated by reference. One of skill in the art will recognize that minor modifications to the conditions and techniques described in the specific embodiments described herein can be varied without departing from the invention. Such minor modifications and variants are within the scope of the invention described herein and as defined by the following claims.
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Massimo Vitali was born in Como, Italy, in 1944. He moved to London after high school, where he studied Photography at the London College of Printing.
In the early Sixties he started working as a photojournalist, collaborating with many magazines and agencies in Italy and in Europe. It was during this time that he met Simon Guttmann, the founder of the agency Report, who was to become fundamental in Massimo's growth as a "Concerned Photographer".
At the beginning of the Eighties a growing mistrust in the belief that photography had an absolute capacity to reproduce the subtleties of reality led to a change in his career path. He began working as a cinematographer for television and cinema. However, his relationship with the still camera never ceased, and he eventually turned his attention back to "photography as a means for artistic research".
His series of Italian beach panoramas began in the light of drastic political changes in Italy. Massimo started to observe his fellow countrymen very carefully. He depicted a "sanitized, complacent view of Italian normalities", at the same time revealing "the inner conditions and disturbances of normality: its cosmetic fakery, sexual innuendo, commodified leisure, deluded sense of affluence, and rigid conformism".
Over the past 12 years he has developed a new approach to portraying the world, illuminating the apotheosis of the Herd, expressing and commenting through the most intriguing, palpable forms of contemporary art – Photography. In 1995 he commenced the Beach Series. He lives and works in Lucca, Italy, and in Berlin, Germany.
Website: massimovitali.com
Selected photographs by Massimo Vitali
© Massimo Vitali
1944Contemporary PhotographyDocumentaryItalyLandscapeMassimo VitaliPeople
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Make a potpourri out of things you already have at home (read on for suggestions!) Do a quick wipe-down with a great-smelling household cleaner. Even if you don't have time to clean your entire home, you can give guests that impression.... Make it easy to get the laundry to the laundry room. Laundry chutes are low tech but require careful planning to locate them well. Bathrooms or halls near bedrooms are both great spots, making it easy for everyone in the family to send dirty clothes straight to the laundry room.
Make it a Race Becky, a mom and cleaning expert who blogs at Clean Mama, recommends that you: "Time yourself and try to beat last week's time." If you're the ultra-competitive type (even with yourself), this can be a great way to get motivated. Challenge your kids to see who can make a bed the fastest and give a prize to the winner -- maybe they get to pick the next flick for movie night. how to add signature in outlook 2010 This key move can instantly make an untidy room look much neater. Conversely, even if the rest of your room is clean, an unmade bed can make the whole thing feel messy.
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ORIGINAL INVESTIGATION Restless Legs Syndrome Prevalence and Impact REST General Population Study Richard P. Allen, PhD; Arthur S. Walters, MD; Jacqu...
Author: Kory Pearson
Restless Legs Syndrome in 2004
Movement Disorders Restless Legs Syndrome
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Restless legs syndrome (RLS) is characterized by an
ORIGINAL INVESTIGATION. Restless Legs Syndrome Symptoms in Primary Care
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Restless legs syndrome (RLS) is a common sleep disorder DOES VALERIAN IMPROVE SLEEPINESS AND SYMPTOM SEVERITY IN PEOPLE WITH RESTLESS LEGS SYNDROME?
Restless-legs-Syndrom: Wege zur Diagnose
RESTLESS LEGS SYNDROME. Selim R. Benbadis, M.D. Associate Professor Departments of Neurology & Neurosurgery Epilepsy & Sleep Disorders
Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1
RESTLESS LEGS SYNDROME NOCTURNAL LEG CRAMPS SULFONAMIDES. Issue 49 December Strong opioids in palliative care
Restless Legs Syndrome and Risk of Incident Cardiovascular Disease in Women and Men: Prospective Cohort Study
UNTERSUCHUNG DES RESTLESS LEGS SYNDROMS MITTELS DER TRANSKRANIELLEN MAGNETSTIMULATION
ORIGINAL INVESTIGATION
Restless Legs Syndrome Prevalence and Impact REST General Population Study Richard P. Allen, PhD; Arthur S. Walters, MD; Jacques Montplaisir, MD, PhD; Wayne Hening, MD, PhD; Andrew Myers, PhD; Timothy J. Bell, PhD; Luigi Ferini-Strambi, MD
Background: Restless legs syndrome (RLS), a com-
mon sensorimotor disorder, has a wide range of severity from merely annoying to affecting sleep and quality of life severely enough to warrant medical treatment. Previous epidemiological studies, however, have failed to determine the prevalence of those with clinically significant RLS symptoms and to examine the life effects and medical experiences of this group. Methods: A total of 16 202 adults (aged ⱖ18 years) were
interviewed using validated diagnostic questions to determine the presence, frequency, and severity of RLS symptoms; respondents reporting RLS symptoms were asked about medical diagnoses and the impact of the disorder and completed the Short Form-36 Health Survey (SF-36). Criteria determined by RLS experts for medically significant RLS (frequency at least twice a week, distress at least moderate) defined "RLS sufferers" as a group most likely to warrant medical treatment.
Author Affiliations are listed at the end of this article. Financial Disclosure: Dr Walters received financing from GlaxoSmithKline to attend an author meeting, and Drs Allen, Hening, and Myers have served as paid consultants to GlaxoSmithKline.
Results: In all, 15 391 fully completed questionnaires were obtained; in the past year, RLS symptoms of any frequency were reported by 1114 (7.2%). Symptoms occurred at least weekly for 773 respondents (5.0%); they occurred at least 2 times per week and were reported as moderately or severely distressing by 416 (2.7%). Of those 416 (termed RLS sufferers), 337 (81.0%) reported discussing their symptoms with a primary care physician, and only 21 (6.2%) were given a diagnosis of RLS. The SF-36 scores for RLS sufferers were significantly below population norms, matching those of patients with other chronic medical conditions. Conclusion: Clinically significant RLS is common (preva-
lence, 2.7%), is underdiagnosed, and significantly affects sleep and quality of life. Arch Intern Med. 2005;165:1286-1292
ESTLESS LEGS SYNDROME
(RLS) is a neurological sensorimotor disorder1 characterized by the following 4 diagnostic criteria: an urge to move that is usually associated with abnormal sensations in the legs, and symptoms that are engendered or worsened by rest, relieved by movement, and most severe at night.2,3 Although the condition was probably first described in the 17th century,4 the pioneering clinical studies were carried out in the 1940s by Ekbom,5 who recognized the adverse effects of RLS on sleep and daytime functioning. (Restless legs syndrome is sometimes referred to as Ekbom syndrome.) More recently, research has shown that RLS negatively affects sleep,6 cognitive function,7 and quality of life.8 Population-based studies using the full standard diagnostic criteria2 for RLS report a prevalence of 5% to 10%9-11 in western industrial countries, but a lower prevalence in Asian populations.12,13 Restless legs syndrome has a wide range of severity, from minimally annoying and somewhat infrequent to severely disrup-
(REPRINTED) ARCH INTERN MED/ VOL 165, JUNE 13, 2005 1286
tive of life.2 The aims of the RLS Epidemiology, Symptoms, and Treatment (REST) program were to characterize the epidemiology of RLS in a general population, both for any significant degree and for a clinically significant degree of the disorder that,
CME course available at www.archinternmed.com in the opinion of RLS experts, is frequent and distressing enough to warrant consideration for treatment. We present herein the first data from a large, multinational general population in which current diagnostic criteria for RLS were used. To our knowledge, this is the first report to characterize those with what experts judge to be a clinically significant degree of the disorder. Our results characterize patients whose RLS symptoms probably require medical attention and provide some indication of the current response by physicians (in terms of diagnosis and treatment) to their patients' report of symptoms. A companion study, the REST primary care study,14 has assessed the fre-
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quency, symptoms, and treatment of RLS in a multinational primary care population.
Table 1. Summary of the REST General Population Questionnaire Questionnaire Parts
METHODS The REST general population study was conducted in the United States and 5 European countries (France, Germany, Italy, Spain, and the United Kingdom). In the United States, quotas matching the overall population were placed on the 4 US Census regions (Northeast, Midwest, South, and West) and sorted by male and female, generating 8 quota groups (half male and half female in each region). Trained telephone interviewers then carried out the population survey for the US sample; each telephone number was selected by means of random-digit dialing. The sample called provided the same proportion of numbers for each state and matched the distribution of the national population. In Europe, face-to-face interviews were undertaken by experienced interviewers using a computer-assisted personal interviewing omnibus. Interviews of persons 18 years or older were undertaken in a number of randomly selected locations to achieve a national spread within each of the 5 European countries. Respondents were then randomly selected from postal address files, telephone directories, or voting registers, but with quotas set for age, sex, and working/social status to ensure that the sample was nationally representative. Respondents were asked to complete a questionnaire consisting of 3 parts (Table 1). Part 1 collected background information on recent medical consultations and current diagnoses. Part 2 comprised the 4 diagnostic questions for RLS, which were were based on standard diagnostic criteria,2,3 and collected information about the frequency of RLS symptoms and the degree of associated distress. Part 3 was administered only to those who responded positively to part 2 and was designed to collect more detailed information on the frequency, nature, and impact of RLS symptoms, consultation rates, diagnosis, and treatment. Responses were analyzed to produce an estimate of the prevalence of RLS symptoms of any frequency and of specific frequencies. A subpopulation of "RLS sufferers" was defined whose symptoms occurred at least twice weekly during the past 12 months and were reported to be moderately or extremely distressing. This definition was chosen to focus on those judged by a panel of 5 RLS experts as having clinically significant symptoms that were likely to warrant treatment. The analysis focused primarily on descriptive statistics and ␹2 statistics to identify significant relationships (a significant result being P⬍.05). Answers to the Short Form-36 Health Survey (SF-36)15 were obtained from the subpopulation of RLS sufferers by the same methods used for obtaining the answers to the other survey questions (face-to-face vs telephone reading of the questions with verbal replies). The SF-36 was developed for the Medical Outcomes Study and has been extensively tested and validated. The questionnaire assesses the following 8 dimensions of healthrelated quality of life: physical functioning, physical limitations on normal role activities, bodily pain, general health, energy and vitality, social functioning, emotional limitations on normal role activities, and mental health. The SF-36 data were analyzed separately for each country. The number of RLS sufferers who completed the SF-36 was inadequate for comparison with their country norms except for the sample from the United States (n=158). The mean SF-36 scores of US RLS sufferers were compared statistically with age- and sex-adjusted US population norms using the t test, with the level for statistical significance set at P⬍.05. Scores for US patients with RLS symptoms were also compared with scores obtained from patients with other chronic medical conditions.
(1) Introductory questions (2) Screening questions
(3) Postscreening questions*
Questions No. of times consulted PCP, specialist in past 3 mo Symptoms currently experienced (from a list of 22) Diagnostic questions Do you have, or have you sometimes experienced, recurrent, uncomfortable feelings or sensations in your legs while sitting or lying down? Do you have, or have you sometimes experienced, a recurrent need or urge to move your legs while sitting or lying down? Do these uncomfortable feelings or sensations in your legs, or the need or urge to move, disappear/improve when you are active or moving around? Are these uncomfortable feelings, or this urge to move, worse in the evening or at night compared with the morning? Frequency of symptoms Degree of distress Time of day symptoms experienced Type of symptoms experienced (from a list of 14, indicating most troublesome) Severity of symptoms Effect of symptoms Experience of recurrent episodes Rate of consultation Diagnosis Treatment
Abbreviations: PCP, primary care physician; REST, RLS (restless legs syndrome) Epidemiology, Symptoms, and Treatment. *Asked of those who answered positively to questions in part 2.
SURVEY POPULATION A total of 16 202 people were approached to be interviewed (10 188 in Europe and 6014 in the United States); 98.2% agreed to the interview and 15 391 (95.0%) fully completed questionnaires were obtained from respondents who were 18 years or older. Sample sizes by country are presented in Table 2. The survey population as a whole did not differ markedly from international and country norms (derived from the Mattson Jack Epidemiology Database [http://www .mattsonjack.com]) for sex distribution (␹2 =3.36, P⬎.05). For age distribution, the survey population was closely matched to international norms for most age groups (Figure 1A), but individuals 80 years and older were underrepresented and those aged 20 to 29 years were slightly overrepresented compared with the norms. This resulted in a statistically significant difference between the 2 populations (␹2 =116.18, P⬍.001). The flow of respondents through the survey is summarized in Figure 2. EPIDEMIOLOGY Of the 15 391 respondents, 1114 (7.2%) reported all 4 diagnostic symptoms of RLS at any frequency and 773 (5.0%) experienced symptoms at least weekly. Four hun-
Table 2. Prevalence of RLS Symptoms by Country and Degree of Severity Prevalence of RLS Symptoms, No. (%)†
Country France Germany Italy Spain United Kingdom United States Total
Questionnaires Distributed, No.
Fully Completed Questionnaires, No. (%)*
Any Frequency
ⱖOnce/wk
ⱖTwice/wk
ⱖTwice/wk and of Moderate or Extreme Distress
2010 2040 2036 2020 2082 6014 16 202
1884 (93.7) 1929 (94.6) 1768 (86.8) 1896 (93.9) 1950 (93.7) 5964 (99.2) 15 391
203/1884 (10.8) 79/1929 (4.1) 119/1768 (6.7) 92/1896 (4.9) 167/1950 (8.6) 454/5964 (7.6) 1114/15 391 (7.2)
125/1884 (6.6) 53/1929 (2.7) 74/1768 (4.2) 66/1896 (3.5) 109/1950 (5.6) 346/5964 (5.8) 773/15 391 (5.0)
103/1884 (5.5) 38/1929 (2.0) 55/1768 (3.1) 58/1896 (3.1) 95/1950 (4.9) 289/5964 (4.8) 638/15 391 (4.1)
79/1884 (4.2) 25/1929 (1.3) 43/1768 (2.4) 37/1896 (2.0) 45/1950 (2.3) 187/5964 (3.1) 416/15 391 (2.7)
Abbreviation: RLS, restless legs syndrome. *Excludes those from respondents younger than 18 years. †Prevalence indicates respondents who met all 4 diagnostic criteria for RLS.
dred sixteen respondents (2.7%) met the criteria for RLS sufferers, ie, they reported that moderately or severely distressing symptoms consistent with RLS occurred at least twice weekly. The proportion of RLS sufferers in the survey population ranged from 1.3% in Germany to 4.2% in France (Table 2). The overall differences between countries for the prevalence of RLS was not statistically significant (F=0.72, P = .40) The prevalence of RLS was generally approximately twice as high for women as it was for men (9.0% vs 5.4% for any frequency of symptoms, 6.2% vs 2.8% for symptoms ⱖ1/wk, and 3.7% vs 1.7% for women vs men in the subpopulation of RLS sufferers). The prevalence of RLS sufferers was higher for women in all age groups (Figure 1B). Women experiencing RLS symptoms at any frequency were asked about pregnancy status; 12 reported being pregnant and 6 (50%) of these met the criteria for RLS sufferers. This was somewhat larger than the 40.1% of all women with RLS who were classified as being RLS sufferers. For men with any RLS symptoms, 31.7% met the criteria for an RLS sufferer. The prevalence of RLS sufferers increased with age up age 79 years and then declined (Figure 1B). A comparison of the age profile of the groups with and without RLS symptoms showed that RLS sufferers were older (Figure 1C). However, 150 (36.1%) of the 416 RLS sufferers were 49 years or younger. SYMPTOMS In response to more detailed questioning, RLS sufferers reported the symptoms they experienced most often, choosing from a list of 14 symptoms in 5 categories (Table 3). The percentage of RLS sufferers reporting symptoms for each category was 88.0% for sensory symptoms, 75.5% for sleep-related symptoms, 55.5% for disturbance of daytime functioning, 37.0% for symptoms affecting movement, and 26.2% for mood disturbance; 59.4% reported pain associated with their RLS symptoms. When asked which symptom was most troublesome, 45.7%of the RLS sufferers mentioned one of the sensory symptoms (including 19.0% who mentioned pain), 37.8% mentioned a sleep-related symptom, and
6.9% mentioned symptoms disturbing daytime functioning. IMPACT ON DAYTIME FUNCTIONING AND QUALITY OF LIFE Questionnaire Responses to Impact of Symptoms The RLS sufferers were asked which, if any, of 9 aspects of daytime functioning were affected when they had symptoms (Table 4). Most (85%) reported that their RLS symptoms disturbed 1 or more of these specific daytime symptoms. The items most commonly reported to be affected were negative influence on mood (50.5%), lack of energy (47.6%), and disturbance of normal daily activities (40.1%). SF-36 Survey Responses Responses to the SF-36 were obtained from 384 RLS sufferers, of whom 375 answered every domain. In general, RLS sufferers had lower quality-of-life scores than the general population, as measured by the SF-36. A comparison between the mean SF-36 scores of RLS sufferers and age- and sex-adjusted US population norms is presented in Figure 3. An examination of results from the European countries compared the results from each country with the population norms for that country and showed that the values were lower than population norms in all domains, but the sample sizes were too small to permit statistical analyses. A comparison of RLS data with results for other chronic medical conditions in US populations15 indicated that RLS sufferers had SF-36 scores similar to those of patients with other medical conditions, such as type 2 diabetes mellitus, depression, and osteoarthritis with hypertension (Figure 4). CONSULTATION RATES A large proportion (n=416)of RLS sufferers had discussed their symptoms with a primary care physician (PCP); 61.3% reported doing so in the past 12 months and 81.0% had done so at any time. In the past 3 months,
International REST Population (N = 15 391) International Population Norms
Proportion of Participants, %
16 202 Questionnaires Distributed
15 391 Fully Completed Surveys (Respondents Aged ≥18 y)
15 Prevalence of RLS Symptoms 1114 (7.2%) With Symptoms of Any Frequency 773 (5.0%) With ≥1 Symptom/wk 416 (2.7%) With ≥2 Symptoms/wk and Causing ≥Moderate Distress ("RLS Patients")
PCP Consultation Rates (Among 416 RLS Patients) 255 (61.3%) Within Past Year 82 (19.7%) >1 y Ago 337 (81.0%) Total
Age Group, y B 8
Prevalence, %
Diagnosis Rates∗ Any Diagnosis for Symptoms 193/255 (75.7%) Within Past Year 59/82 (72.0%) >1 y Ago 252/337 (74.8%) Total
RLS Patients (n = 416) All Men Women
4 21/337 (6.2%) Received Diagnosis of RLS∗ 2
Age Group, y
252 (74.8%) recalled receiving a diagnosis for their symptoms. The most common diagnosis was "poor circulation" (18.3% of those receiving a diagnosis), followed by arthritis (14.3%), and back/spinal injury or problem (12.7%). Varicose veins (7.5%), depression/anxiety (6.3%), and trapped nerve (5.6%) were also commonly diagnosed in RLS sufferers. Only 21 sufferers (6.2%) indicated that they were given a diagnosis of RLS.
Figure 2. Flow of patients with restless legs syndrome (RLS) through the study. PCP indicates primary care physician. Asterisk indicates those consulting a PCP.
10 RLS Patients (n = 416) Other Participants (n = 14 975)
Figure 1. Age distribution and prevalence of patients with restless legs syndrome ("RLS sufferers"). A, Age distribution of the survey population compared with international norms. (International population norms were derived from the Mattson Jack Epidemiology Database [http: www.mattsonjack.com].) B, Prevalence of RLS sufferers by age and sex. C, Age distribution of the group of RLS sufferers compared with the remainder of the survey population.
75.5% of the RLS sufferers had consulted a PCP for any reason and 46.6% had consulted a specialist, compared with 54.3% and 33.7%, respectively, for an age- and sexmatched set drawn from the survey population who were not considered RLS patients (P⬍.001, ␹2 test). Specialists consulted (in the order of frequency) included neurologists, cardiologists, rheumatologists, phlebologists or vascular surgeons, psychiatrists, diabetologists or endocrinologists, sleep specialists, and geriatricians. DIAGNOSIS RATES Of the 416 RLS sufferers, 337 (81.0%) reported discussing their symptoms with a physician (Figure 2). Of these,
To our knowledge, REST is the first large-scale, multinational, population-based profile study of RLS that uses the full standard diagnostic criteria,2 and it is the only large study of RLS that has systematically investigated quality of life. This study, like the associated primary care study,14 is structured to identify those individuals considered likely to warrant treatment (RLS sufferers). The results clearly demonstrate the significant negative impact of RLS on sleep, subsequent daytime performance, and quality of life for these RLS sufferers. PREVALENCE Our survey population covers a wide geographic area. A rigorous sampling method was designed to ensure that the sample being interviewed provided a demographic balance—for age, gender, working/social status, and region—to achieve nationally representative samples. The results, therefore, give a picture of RLS that can be generalized to more than 400 million people in western industrial countries. It is true that we have classified patients as suffering from characteristic symptoms of RLS on the basis of their self-report. However, the diagnostic questions in our sur-
Table 3. Specific Symptoms Reported by Restless Legs Syndrome (RLS) Sufferers % of RLS Sufferers Category, Symptom* Sensory Inability to get comfortable Pain Uncomfortable feelings Inability to stay still/urge to move Sleep Inability to fall asleep Inability to stay asleep Disturbed sleep/interrupted sleep Insufficient sleep Disturbance of daytime functioning Exhaustion/fatigue Daytime sleepiness Difficulty in concentrating next afternoon Difficulty in concentrating next evening Abnormal movements Twitching/jerky movements Mood Tendency to become depressed/"low"
Reporting ⱖ1 Item in Each Category
Reporting Symptom
Reporting Symptom as Most Troublesome
Reporting ⱖ1 Category Item as Most Troublesome 45.7
13.5 7.2 14.7 2.4 55.5
*Of patients with RLS responding, 2.4% did not list specific symptoms and 3.4% did not give a most troublesome symptom.
Table 4. Reported Effects of Restless Legs Syndrome (RLS) Symptoms on Those Classified as RLS Sufferers % Reporting Effect
Effect of Symptoms These symptoms have a negative influence on my mood I lack energy when I suffer from these symptoms My daily activities are disturbed (eg, home, family, social, or work-life) My social life is affected These symptoms can distract me from doing my job I get a feeling of desperation when I have these symptoms My partner is kept awake by me when I am suffering from these symptoms My personal relationships are affected I have to miss work due to feelings of tiredness No answer given
vey were based on the current diagnostic standards2 and have been validated in a study in primary care,16 showing a diagnostic sensitivity of 82.3% and a specificity of 89.9%. Previous smaller studies indicated an RLS prevalence of 5% to 10% in the general population that increases with age until at least the eighth decade of life and is higher in women than in men.9-11 We had a comparable prevalence estimate of 7.2% for RLS symptoms of any frequency. In our study, the RLS sufferers, who reported symptoms at least twice weekly combined with moderate or severe distress, also showed the same pattern of prevalence being greater in women and increasing with age. Pregnancy among women with RLS symptoms was uncommon, occurring in only 12 subjects and thus having no significant impact on the analyses. Nonetheless, for subjects with RLS, the risk
of being in the group of RLS sufferers was increased by being pregnant and decreased by being male. Although the prevalence of RLS sufferers increases with age (Figure 1B), we found RLS sufferers among people of all ages. Indeed, 36.1% of the RLS sufferers were 49 years or younger (Figure 1C). Thus, RLS should not be classified as a condition that exclusively or primarily affects the elderly. Despite the use of different survey techniques, we did not find any differences in prevalence between the United States and Europe. The refusal rate was low (1.8%) and had no measurable impact on our results. There is no indication that the differences in survey techniques significantly biased the results. The one significant difference for individual countries was the somewhat higher prevalence of RLS sufferers in France. This may have resulted by chance or it may represent a founder effect. A similar difference was reported in Canada,17 with a higher prevalence among persons of French vs English descent. IMPACT ON QUALITY OF LIFE Our results identify the marked negative impact of RLS symptoms on sleep. More than 75% of the RLS sufferers reported at least 1 sleep-related symptom. Disrupted sleep, an inability to fall asleep, and insufficient hours of sleep are expected consequences of the sensorimotor abnormalities of RLS, which are worse at night and while at rest. Many RLS sufferers reported performance-related effects, presumably resulting from RLS-related sleep disruption, such as daytime sleepiness and difficulty in concentrating the following day. Sleep disruption has also been associated with negative effects on cognitive function in patients with RLS.7 Thus, RLS should be consid-
RLS Patients Age- and Sex-Adjusted Norms for the US General Population (n = 2474)
Mean Score
∗ ∗
Role Physical
Bodily Pain
Social Functioning
Role Emotional
Physical Functioning
Energy/ Vitality
SF-36 Health Survey Domain
Figure 3. Comparison of mean Short Form 36 Health Survey (SF-36) scores of patients with restless legs syndrome ("RLS sufferers") with age- and sex-adjusted US population norms. Asterisks indicate that the scores of the RLS sufferer group were significantly below the norms for all 8 dimensions.
RLS Patients (n = 158) Patients in the US General Population With Type 2 Diabetes Mellitus (n = 541) Osteoarthritis With Hypertension (n = 175) Depression (n = 502)
Figure 4. Comparison of mean Short Form 36 Health Survey (SF-36) scores of US patients with restless legs syndrome ("RLS sufferers") with those of US patients with common chronic medical conditions.
ered within the differential diagnosis when a patient complains of sleep abnormalities, such as an inability to fall asleep and frequent wakefulness during the night. Restless legs syndrome sufferers had a reduced quality of life compared with adjusted population norms (as measured by the SF-36 for the US sample). The reduced quality of life for RLS sufferers appears comparable with that experienced by those with other serious chronic medical conditions, such as type 2 diabetes mellitus and clinical depression. The results herein are also supported by another, smaller study of RLS in a clinical population that compared their data with population
norms.8 These data from 2 different studies strongly support the need to ensure that RLS is recognized and treated appropriately. RLS SUFFERERS' EXPERIENCE WITH MEDICAL CONSULTATION The fact that 81% of our respondents categorized as RLS sufferers had discussed their symptoms with a physician indicatesthatpatientswiththisdegreeofRLSsymptomsarelikely to seek medical attention. Moreover, those with RLS symptoms had significantly higher consultation rates with both
PCPs and specialists compared with a matched set drawn from the remainder of the sample. Thus, the RLS sufferers characterized by the REST study correspond to those RLS patients most likely to be encountered in clinical practice. However,despiteseekingmedicalhelp,only6.2%reported having received a diagnosis of RLS. The low rate of diagnosis given to those presenting with RLS symptoms reflects the current lack of understanding of the disorder. Because RLS is not generally recognized as a medically significant disorder, there may be a tendency to account for these RLS symptoms as an expression of better recognized medical conditions, such as pain syndromes associated with a back injury, peripheral neuropathy, or arthritis. The failure to diagnose and treat RLS leaves the patient with unnecessary suffering for 2 reasons. First, the patient fails to receive effective treatments such as dopamine agonists.18 Second, focusing medical attention on the other conditions mistakenly identified with the RLS may lead to unnecessary treatments that incurextracostandadverseeffects.Theclinicianneedstoknow that RLS is not generally caused by the common pain syndromes (eg, peripheral neuropathy,19 diabetes,20 and osteoarthritis21,22). Education about RLS should emphasize both the defining features and the differential diagnosis with other conditions that produce leg problems. A companion study14 has indeed shown that this failure to diagnose RLS extends to a failure to prescribe appropriate medications. IMPLICATIONS FOR MEDICAL CARE The presence or absence of the key diagnostic criteria for RLS can be easily determined by asking 4 diagnostic questions. Thus, if clinicians, particularly PCPs, were aware of the profile and impact of RLS, diagnosis rates would likely improve and inappropriate treatments would be reduced. In addition, if current guidelines for diagnosis2 and treatment23 were more widely disseminated to PCPs, misdiagnoses and unnecessary referrals could be reduced. In conclusion, the results of the REST general population study provide an important initial step in the understanding of RLS as encountered in clinical practice. The symptoms of RLS, particularly sleep-related symptoms, are sufficiently distressing and debilitating such that many sufferers seek medical treatment. Hence, improved diagnosis of RLS should not result in an increase in physicians' workloads. On the contrary, increased diagnosis resulting from increased understanding and awareness of the condition is essential for providing effective treatment. These results deserve careful consideration by all clinicians responsible for the diagnosis and management of those with RLS. Accepted for Publication: January 6, 2005. Author Affiliations: Department of Neurology, The Johns Hopkins University, Baltimore, Md (Dr Allen); New Jersey Neuroscience Institute at JFK Medical Center, Edison, and School of Graduate Medical Education, Seton Hall University, South Orange, NJ (Dr Walters); Departments of Psychiatry and Neurosciences, Université de Montréal, Montreal, Quebec (Dr Montplaisir); Department of Neurology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick (Dr Hening); Premark Services Ltd, Crawley Down, West Sussex,
England (Dr Myers); Health Solutions, Research Triangle Institute, Research Triangle Park, NC (Dr Bell); and Department of Neurosciences, Università Vita–Salute San Raffaele, Milan, Italy (Dr Ferini-Strambi). Dr Bell is now with the Gastrointestinal Research and Development Group of GlaxoSmithKline, Research Triangle Park. Correspondence: Richard P. Allen, PhD, Department of Neurology, The Johns Hopkins University, Baltimore, MD 21224 ([email protected]). Previous Presentation: This study was presented at the European Federation of Neurological Societies; August 30–September 2, 2003; Helsinki, Finland. REFERENCES 1. Hening WA. Restless legs syndrome: a sensorimotor disorder of sleep/wake motor regulation. Curr Neurol Neurosci Rep. 2002;2:186-196. 2. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J; Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology: a report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119. 3. Walters AS; International Restless Legs Syndrome Study Group. Toward a better definition of the restless legs syndrome. Mov Disord. 1995;10:634-642. 4. Willis T. De Animae Brutorum. London, England: Wells and Scott; 1672. 5. Ekbom KA. Restless legs: a clinical study. Acta Med Scand Supp. 1945;158:1-122. 6. Allen RP, Earley CJ. Validation of the Johns Hopkins restless legs severity scale. Sleep Med. 2001;2:239-242. 7. Allen RP, Abetz L, Washburn T, Earley CJ. The impact of restless legs syndrome (RLS) on sleep and cognitive function. Eur J Neurol. 2002;9(suppl 2):50. 8. Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26:925-935. 9. Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164: 196-202. 10. Ulfberg J, Nystrom B, Carter N, Edling C. Restless Legs Syndrome among workingaged women. Eur Neurol. 2001;46:17-19. 11. Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord. 2001;16:1159-1163. 12. Tachibana N, Tanigawa T. Prevalence and clinical characteristics of restless legs syndrome among Japanese industrial workers. Neurology. 2003;60(suppl 1):A38. 13. Tan EK, Seah A, See SJ, Lim E, Wong MC, Koh KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord. 2001;16:577-579. 14. Hening W, Walters AS, Allen RP, Montplaisir J, Myers A, Ferini-Strambi L. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:237-246. 15. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey—Manual and Interpretation Guide. Boston, Mass: Health Institute, New England Medical Center; 1993. 16. Nichols DA, Kushida CA, Allen RP, et al. Validation of RLS diagnostic questions in a primary care practice. Sleep. 2003;26:A346. 17. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17:739-743. 18. Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MH; Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:560-583. 19. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve. 1996;19:670-672. 20. Banno K, Delaive K, Walld R, Kryger MH. Restless legs syndrome in 218 patients: associated disorders. Sleep Med. 2000;1:221-229. 21. Ondo W, Tan EK, Mansoor J. Rheumatologic serologies in secondary restless legs syndrome. Mov Disord. 2000;15:321-323. 22. Salih AM, Gray RE, Mills KR, Webley M. A clinical, serological and neurophysiological study of restless legs syndrome in rheumatoid arthritis. Br J Rheumatol. 1994;33:60-63. 23. Chesson AL Jr, Wise M, Davila D, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine report. Sleep. 1999;22:961-968.
Report "RESTLESS LEGS SYNDROME"


We like to think of the Riptide 41 as a high performance gentleman's racer. It is designed to be sailed efficiently with a crew of between 6 and 8 rather than the 10-12 persons commonly found on a racing boat of this size, and it has comfortable accommodations for everyone on the boat. With its ultralight weight carbon construction, large rig and water ballast it is fast upwind and down over the full range of sailing conditions. The Riptide 41 is currently under construction at Jim Betts' in Anacortes, WA, right along side the Riptide 35 Mk II.


If it is the transmission causing the stall, I have seen 2 faulty solenoids and one stuck lock-up valve. If it was the torque converter itself, it would probably kill the motor when put into any drive range, forward or reverse. Login to read more.


text:
El Edificio del Jockey Club es un edificio en la capital uruguaya Montevideo, en el Barrio Centro sobre la Avenida 18 de Julio entre las calles Andes y Convención. El edificio fue construido en 1920. El arquitecto para la construcción fue el francés José P. Carré. Arquitectónicamente, el edificio es del eclecticismo. Aquí está la sede del Jockey Club.

Galería

Bibliografía
 Guía Arquitectónica y Urbanística de Montevideo. Intendencia Municipal de Montevideo u. a., Montevideo u. a. 2008, ISBN 978-9974-600-26-3, S. 64, 139.

Enlaces externos

 Jockey Club

Centro (Montevideo)
Edificios y estructuras de Montevideo
Arquitectura de 1920

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The article offers a look at the combinatorial logic as the logic of signs operating in the most general sense. For this it is proposed slightly reformulate it in terms of introducing and replacement of the definitions.
V. I. Shalack. Semiotic foundations of logic // Логические исследования / Logical Investigations. 2018. Т. 19. № 1.


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Those products I am selling on the KND Quality Life is to provide the kendoists with the bokuto. Please support me by shopping at KND Quality Life at Amazon, Zazzle and Kendo Apparel.


text:
require 'text_adventure/room'
require 'text_adventure/version'
require 'text_adventure/player'
require 'text_adventure/world'

module TextAdventure
  # Your code goes here...
end

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