***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: AIMS This study constituted the first administration of the oral platelet inhibitor , sibrafiban  , to humans . The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44 - 3888 , the active principle of sibrafiban , after single ascending oral doses of sibrafiban . Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44 - 3888 . METHODS The study consisted of three parts . Part I was an open ascending-dose study to determine target effect ranges of sibrafiban . Part II , a double-blind , placebo-controlled , parallel-group study , addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect . Part III was a double-blind , placebo-controlled , ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban . RESULTS At sibrafiban doses between 5 mg and 12 mg , the pharmacokinetics of free Ro 44 - 3888 in plasma were linear whereas those of total Ro 44 - 3888 were non-linear because of the saturable binding to the glycoprotein IIb-IIIa receptor . Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml-1 . At sibrafiban doses up to 2 mg , ADP-induced platelet aggregation was inhibited by 50 % , whereas the inhibition of TRAP-induced platelet aggregation was about 20 - 30 % . At the higher doses , ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg . Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban ( 5 - 7 min , > 30 min in one case ) . At a sibrafiban dose of 12 mg , the stopping criterion for dose escalation ( prolongation of the Ivy bleeding time > 30 min in three out of four subjects per dose group ) was reached . The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters ( AUC and AUE ) were below 20 % , thus lying well within the pre-set level of acceptance . CONCLUSIONS With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters , linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations , Ro 44 - 3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of  arterial thrombosis  in patients with acute coronary syndrome AMD3100 is a small‐molecule CXCR4 antagonist that has been shown to induce the mobilization of CD34 + hematopoietic progenitor cells from bone marrow to peripheral blood . AMD3100 has also been shown to augment the mobilization of CD34 + cells in cancer patients when administered in combination with granulocyte colony‐stimulating factor ( G‐CSF ) ( filgrastim ) . The purpose of this study was to characterize the exposure‐response relationship of AMD3100 in mobilizing CD34 + cells when administered as a single agent in healthy volunteers Reciprocal control of platelet function in the circulation has been proposed for the platelet‐produced platelet proaggregatory prostanoid thromboxane A2 ( TxA2 ) and the vascular endothelium‐produced antiaggregatory prostanoid prostacyclin ( PGI2 ) . Forty drug‐free healthy subjects were given a single dose of ibuprofen ( 0 , 8 , 10,12 , or 14 mg/kg ) in a r and omized , double‐blind study . Blood sample s were drawn 0 , 2 , 4 , and 6 hours and 7 days after dosing for determination in serum ( from untreated or in vitro indomethacin‐treated portions of the blood ) of TxA2 and PGI2 by radioimmunoassay of their stable metabolites ( TxB2 and 6‐keto‐PGFlα ) . Maximal platelet release of TxA2 ( untreated serum ) was lower in all drug groups 2 , 4 , and 6 hours after dosing . There was no significant decrease in PGI2 release . All doses of ibuprofen ( except 0 mg/kg ) induced essentially identical plasma levels at the times of measurement ( postpeak decline ) , and effects could not be distinguished by dose for 8 , 10 , 12 , or 14 mg/kg at these times . It is concluded that ibuprofen induces antiplatelet effects for at least 6 hours while preserving normal antiplatelet mechanisms Dexmedetomidine , a selective α2‐adrenoceptor agonist , was administered to five healthy male volunteers in single intravenous doses of 12.5 , 25 , 50 , and 75 µg as part of a placebo‐controlled study . The drug caused dose‐dependent decreases in systolic and diastolic blood pressure . A small initial hypertensive response was observed after injection of the two highest doses . Heart rate was decreased . The concentration of norepinephrine in plasma was decreased significantly ( by up to 92 % ) , and the decrease was dose‐dependent . No significant drug‐induced alterations were observed in plasma renin activity or in the concentrations of atrial natriuretic peptide and arginine vasopressin in plasma . Other drug effects included dose‐dependent impairment of vigilance and stimulation of growth hormone secretion . Plasma Cortisol levels were unaffected . Dexmedetomidine is a potentially useful tool for studies of the physiology and pharmacology of α2‐adrenoceptors in human beings and may have therapeutic applications in clinical conditions in which sedative and sympatholytic effects are considered beneficial , such as premedication for anesthesia and surgery The pharmacodynamic profile of bisoprolol , a new beta 1-selective adrenoceptor antagonist , was investigated in four independent studies including 36 healthy male volunteers . Using the model of exercise-induced tachycardia ( ET ) the beta-adrenoceptor blocking properties of bisoprolol ( 2.5 - 40 mg ) were examined in comparison to metoprolol ( 50 and 100 mg ) , propranolol ( 40 and 80 mg ) and atenolol ( 50 and 100 mg ) . The maximal reduction of ET was achieved between 1 and 4 h following single oral administration . The dose-response relationship using individual maximal reduction of ET showed , on a molar basis , that bisoprolol is about 5 , 7 and 10 times more effective than propranolol , atenolol and metoprolol , respectively . In the model of insulin-induced hypoglycaemia bisoprolol behaved as a beta 1-selective adrenoceptor antagonist . There was a good correlation ( r = 0.94 ) between the log bisoprolol concentration and the reduction in exercise-induced tachycardia . Bisoprolol is a potent new cardioselective beta-adrenoceptor antagonist with a competitive action at beta 1-adrenoceptors Twelve healthy volunteers each received acute doses of placebo and 5 , 10 , 15 and 20 mg of midazolam .  Seven subjects were tested before and 1 , 4 and 7 h after treatment . Five subjects were given the same five treatments nocturnally and tested the following morning , 10 - 12 h after treatment . Tests on various measures of sedation ( choice reaction time and critical flicker fusion ) and of drowsiness ( line analogue rating scales ) showed midazolam at 15 and 20 mg dose levels to be a potent sedative agent . The present results suggest that the activity of midazolam is at a maximum 1 h after ingestion and that the effects of the drug have dissipated 7 h after treatment The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris . After administration of 30 , 60 and 120 mg of isosorbide dinitrate , the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy ( p less than 0.01 ) . Reduction in st and ing systolic blood pressure was greater during acute than during sustained therapy ( p less than 0.001 ) . This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy , but was not dose-related and was demonstrable for only 4 hours during sustained therapy . Compared with placebo therapy , exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy . During acute therapy , administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg . During sustained therapy ( 15 mg four times daily ) , exercise tolerance increased to the same magnitude as with doses of 30 , 60 or 120 mg four times daily . In most patients , near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily . It is concluded that during sustained therapy with isosorbide dinitrate , partial tolerance to the antianginal and circulatory effects develops rapidly To assess the tolerability , pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol‐O‐methyltransferase ( COMT ) inhibitor tolcapone in healthy volunteers Summary The dose-effect relationship of an i.v . bolus of synthetic h-GRF-44 on growth-hormone and prolactin secretion has been studied . Seven healthy adult volunteers received in a r and om order h-GRF-44 2.5 , 5 , 10 , 20 , 40 and 80 µg and a placebo . Plasma growth hormone ( GH ) was determined between 30 min before and 240 min after injection , the area under the curve ( AUC ) and the peak GH level being used to assess the response . For both parameters a dose-effect relationship was observed . Doses as low as 2.5 µg were capable of eliciting a rise in GH plasma levels in few patients . Above 40 µg the dose-effect curves tended to plateau , although the decrease in the slope of the dose-effect curve at the peak was more marked . Intersubject variability was large , so precise determination of the minimal effective dose as well as the lowest dose giving a maximal effect was not possible . The available evidence suggests that the i.v . dose of synthetic h-GRF-44 ( SR 95228 ) which is likely to promote GH release into the blood stream in most healthy adults is within the range 40–100 µg . In these healthy adults unwanted effects were infrequent with these low doses . Unlike previous experience with higher doses of another synthetic h-GRF-44  , prolactin secretion in this study was not affected To underst and the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin ( epoetin alfa ) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration SQ 28,668 is a structural analog of thromboxane A2 . It inhibits the effects of thromboxane in vitro . Fifty‐six healthy male subjects were given either placebo or three equal daily doses of SQ 28,668 ranging from 25 to 1200 mg . Plasma drug concentrations increased in a dose‐dependent manner . The shape of the plasma drug concentration‐time curve was consistent with enterohepatic recirculation . The effects of SQ 28,668 on ex vivo platelet aggregation suggested that SQ 28,668 is a specific competitive antagonist of thromboxane A2 with a platelet receptor dissociation constant ( estimated by Schild analysis ) of about 19 nmol/L. Approximately 94 % occupation of thromboxane receptors by SQ 28,668 was required to produce a small but measurable increase of the template bleeding time . Dose‐ranging studies of antithrombotic drugs are difficult and expensive . For this reason , a method was developed that allows estimation of the dose of a thromboxane receptor antagonist that would be expected to be therapeutically equivalent to a given dose of aspirin Pain and hyperalgesia , the perceptual companions of tissue injury and inflammation , are thought to be in part attributable to the sensitization of primary afferent nociceptors by endogenously released chemicals , such as bradykinin . Bradykinin ( 0.1 to 10 nmol in 10 µl ) evoked a dose‐dependent pain , hyperalgesia to heat stimuli , and wheal and flare when injected in a double‐blind manner into the volar forearm intradermally . Though hyperalgesia to mechanical stimuli is a conspicuous feature of inflammatory pain , none was measurable for any of the bradykinin doses in response to grade d nylon monofilament probes . 
    Output:
    
Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs , extending a result that was previously documented for very few compounds