Human Pharmacological Studies Research Articles

Endothelin: from molecule to man.

peptide, endothelin-1 [6], a more potent endotheliumBackground derived vasoconstrictor and pressor agent even than angiotensin II, was of major interest to the cardiovascular Until relatively recently, the vascular endothelium was thought to act as little more than a passive barrier to research community, and followed closely on the identification of the endothelium-derived relaxing factor (EDRF) diffusion. However, in the last few years, with the discovery of prostacyclin, nitric oxide and endothelin-1, a central role as nitric oxide [7]. At this early stage it was difficult to gain access to more than small quantities of synthetic has emerged for the endothelium in the regulation of vascular smooth muscle cell tonus and growth, immunologendothelin-1. However, it was clear that local infusion techniques could allow delineation of the vascular effects of ical reactivity, blood coagulation and lipid metabolism. This field of research has matured rapidly (Figure 1) and, in a endothelin-1 more clearly, with greater safety, and with lower doses, than would be the case with systemic dosing. recent foresight exercise on behalf of the British Heart Foundation, Medical Research Council and Wellcome Trust In collaboration with Dr John Clarke and Professor Attilio Maseri at the Royal Postgraduate Medical School, we began [1], the vascular endothelium was identified as the area commanding the highest priority in cardiovascular research clinical pharmacology studies at St George’s Hospital in London in 1988, and our first pharmacodynamic observations over the next 10 years. My own interest in this area originally developed while were published the following year [8]. Subsequent progress in endothelin research [9, 10] has working in the MRC Blood Pressure Unit in Glasgow. Observations in the first clinical trial of a renin inhibitor in maintained an extremely rapid pace such that we were able to perform the first human pharmacology studies with an man suggested the functional importance of a vascular reninangiotensin system [2] and, later, at St George’s Hospital in inhibitor of endothelin generation, phosphoramidon, in 1992 and with an endothelin receptor antagonist, BQ-123, London I was able to show this by combining forearm plethysmography techniques with brachial artery infusions in 1993. Indeed, after only 8 years, the clinical development of drugs targeting the ‘endothelin system’ in cardiovascular of locally active doses of angiotensin I, angiotensin II, bradykinin and angiotensin converting enzyme (ACE) disease is now well advanced [11]. The first major clinical study in heart failure patients was reported in 1995 [12] and inhibitors [3, 4]. Surprisingly, these studies demonstrated in vivo that the endothelium of the forearm resistance vessels phase III trials should begin shortly. From a combination of fundamental and applied research it has become apparent has a considerable capacity to generate angiotensin II locally, equivalent to that of the pulmonary circulation [4, 5]. that the ‘endothelin system’ is of central importance to the maintenance of normal cardiovascular function in healthy The discovery in 1988 of the novel 21 amino acid man and that endothelin-1 is likely to be a key mediator in the pathophysiology of cardiovascular disease. The main aim of this paper is to review current knowledge of the endothelin system; particularly its physiological function in the cardiovascular system and its role in cardiovascular disease. Although I will focus on human pharmacology and physiology, and in particular on the work of our group in Edinburgh, it must be recognised that all of the major advances in clinical research have depended critically on the identification and development of selective pharmacological probes through work on animal and isolated tissues. A subsidiary aim of this review is to demonstrate that clinical pharmacology studies can provide a critical contribution to our understanding of human cardiovascular physiology and pathophysiology, and to the process of early drug development and identification of suitable therapeutic targets.

Comparison of some properties of pronethalol and propranolol. 1965.

Comparison of some properties of pronethalol and propranolol. 1965.

Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies

Purpose : To review the human central nervous system pharmacology of cisplatin, factors that affect cisplatin uptake in tumors, and use alone and with radiation for the treatment of primary brain tumors. Methods and Materials : The authors review their own prior published and unpublished experience and data published by other groups on the above issues. Results : Cisplatin is one of the most active chemotherapy drugs available for the treatment of solid tumors. It is synergistic with several other agents, including radiation. While it attains only low concentrations in the normal central nervous system, concentrations and plasma-tissue transfer constants for human intracerebral tumors are comparable to those in extracerebral tumors. Tumor type appears to be a more important determinant of platinum concentration than is tumor location, and gliomas do achieve lower concentrations than do other intracerebral or excracerebral tumors. Several other factors have also been identified that correlate with concentrations of cisplatin achieved in human tumors. While cisplatin alone and in combination with other drugs does have some degree of efficacy against primary brain tumors, combining it with cranial irradiation has generally not resulted in any substantial improvement in outcome to date, although some individual studies have been somewhat encouraging. New approaches are currently under investigation. Conclusion : Human pharmacology studies provide a rationale for use of cisplatin in the treatment of human brain tumors, and human and in vitro studies suggest some manipulations that might potentially further augment tumor platinum concentrations. While clinical studies suggest that cisplatin combinations may be of some value vs. human primary brain tumors and brain metastases, and while in vitro studies suggest that cisplatin potentiates radiation efficacy, no combination of cisplatin plus radiation yet tested has appeared to be superior to radiation alone.

The antiinflammatory effect of theophylline

Antiasthma drug development, for the most part, seems based on three classes of therapeutic agents. Many new sympathomimetic and corticosteroid drugs with increased specificity for the lung have been introduced. The third class of drugs, the xanthines, is still best represented by the prototype drug theophylline. After a brief review of the chemical history of antiasthma xanthines (the first limited attempts to develop novel derivatives 30 to 40 years ago), and some recent structure-activity findings, this article discusses the pharmacology of a selected xanthine derivative, enprofylline (3-propylxanthine). In various experimental systems and in patients, enprofylline shares antiasthmatic effects with theophylline; however, enprofylline is the more potent of the two (>1 to 2 μg/ml plasma are effective concentrations of enprofylline). At present, enprofylline, which lacks diaphragmatic and central nervous system stimulatory actions, has been shown to be at least as clinically efficacious as theophylline in obstructive lung disease. Further work is needed to elucidate the target cells and mechanism(s) of action involved in bronchodilatory and anti-inflammatory effects of the xanthines. Growing numbers of animal and human pharmacologic studies show that enprofylline it without many of theophylline's extrapulmonary effects—in particular the excitatory ones. Perhaps most significantly, enprofylline does not produce central nervous system stimulant behavioral effects, including seizures. If and when enprofylline becomes available as an alternative drug, increased attention will probably be focused on the significance of other theophylline actions (gastric secretion, release of free fatty acids, vasoconstriction, diuresis, etc.) that are not shared by enprofylline. The differences in action profiles can probably be explained by the fact that enprofylline is a poor, and theophylline a potent, antagonist of the purine nucleoside adenosine, which may have a number of inhibitory physiologic functions.

Future Potential Applicability of Sucralfate in Gastroenterology

Sucralfate plays an important role in peptic ulcer disease, reflux esophagitis, stress erosions and bleeding, and as adjunctive therapy in variceal sclerosis. In accordance with its pharmacologic characteristics, however, one may readily envisage disease states worth investigating, such as irradiation-induced mucosal damage of the esophagus. Especially the combination of external and intraluminal radiotherapy via the after-load technique may cause substantial and occasionally long-standing ulceration of the esophageal lining and discomfort. Several conditions of the stomach deserve further study. Increasingly common is gastric mucosal damage induced by aspirin or non-steroidal anti-inflammatory drugs. On the basis of its various pharmacologic principles sucralfate should theoretically offer protection against such lesions, and, in fact, there are human pharmacologic and clinical studies available supporting this idea. Another disease entity in which sucralfate should be studied in more depth is that of biliary alkaline reflux gastropathy as often seen after gastric surgery. Sucralfate should also be evaluated in those difficult clinical conditions known to be resistant to any therapeutic attempt with currently available drugs, such as erosive varioliform gastritis and hypertrophic gastropathy with heavy inflammation of the mucosa and giant coarsening of the gastric rugae. The results obtained with sucralfate in variceal sclerosis are indeed intriguing, even though the mechanism is not understood. It has been shown that sucralfate has some efficacy in patients with hemorrhagic gastritis. In many patients receiving chemotherapy, mucosal damage may occur both in the mouth and throughout the gastrointestinal tract, including the small bowel.(ABSTRACT TRUNCATED AT 250 WORDS)

State-related changes in norepinephrine regulation in anorexia nervosa

Anorexia nervosa, characterized by distortion of body image and fear of fatness ieading to profound weight loss, regularly includes symptoms of depression and anxiety, as well as altered appetite, energy metabolism, and cardiovascular function. Studies in laboratory animals and indirect pharmacological studies in humans suggest that norepinephrine dysregulation could play a role in these symptoms. Previous studies have reported that anorexic patients at low weight have significantly reduced levels of norepinephtine and/or its metabolites in plasma and 24-hr urinary samples (Hahni et al. 1978; Gross et al. 1979). Initial longitudinal follow-up studies suggest that these measures of norepinephrine activity increased toward normal values as anorexic patients gained weight (Gross et al. 1979; Reiderer et al. 1982). Emerging data have suggested that norepinephrine and/or its metabolites in plasma and urine are not consistently low in unde~eight anorexic patients (Kaye et al. 1985). Thus, Biederman et al. (1984) reported that urinary excretion of the major norepinephrine metabolite 3-me~oxy-4-hy~xphenyle~ylene glycol (MHPG) was low in a group of depressed an-

Human pharmacological studies of a defined low molecular weight heparin fraction (Fragminr) evidence for a simultaneous inhibition of factor Xa and IIa (thrombin)

The effect of a low molecular weight heparin (FragminR) (20–80 U/kg) was studied in 10 healthy male volunteers after intravenous administration. Clotting ab-abnormalities are extensive shortly after injection, lasting for 1 – 2 hours depending on heparin dosage. Dilute thrombin time, showing a close correlation to anti-F-Xa activity, is as sensitive as anti-F-Xa. The parallel time course of dilute thrombin time and anti-F-Xa activity clearly demonstrates that LMWH has an effect on F-IIa lasting as long as that of F-Xa. After subcutaneous administration clotting abnormalities are only slight with 40–60 U/kg, in contrast to the intravenous study. The platelet system remains unchanged.

Development of safer xanthine drugs for treatment of obstructive airways disease

Antiasthma drug development, for the most part, seems based on three classes of therapeutic agents. Many new sympathomimetic and corticosteroid drugs with increased specificity for the lung have been introduced. The third class of drugs, the xanthines, is still best represented by the prototype drug theophylline. After a brief review of the chemical history of antiasthma xanthines (the first limited attempts to develop novel derivatives 30 to 40 years ago), and some recent structure-activity findings, this article discusses the pharmacology of a selected xanthine derivative, enprofylline (3-propylxanthine). In various experimental systems and in patients, enprofylline shares antiasthmatic effects with theophylline; however, enprofylline is the more potent of the two (>1 to 2 μg/ml plasma are effective concentrations of enprofylline). At present, enprofylline, which lacks diaphragmatic and central nervous system stimulatory actions, has been shown to be at least as clinically efficacious as theophylline in obstructive lung disease. Further work is needed to elucidate the target cells and mechanism(s) of action involved in bronchodilatory and anti-inflammatory effects of the xanthines. Growing numbers of animal and human pharmacologic studies show that enprofylline it without many of theophylline's extrapulmonary effects—in particular the excitatory ones. Perhaps most significantly, enprofylline does not produce central nervous system stimulant behavioral effects, including seizures. If and when enprofylline becomes available as an alternative drug, increased attention will probably be focused on the significance of other theophylline actions (gastric secretion, release of free fatty acids, vasoconstriction, diuresis, etc.) that are not shared by enprofylline. The differences in action profiles can probably be explained by the fact that enprofylline is a poor, and theophylline a potent, antagonist of the purine nucleoside adenosine, which may have a number of inhibitory physiologic functions.

The sympathetic nervous system and hypertension in primary aldosteronism.

To assess the role of the sympathetic nervous system in mineralocorticoid hypertension in humans, results from 24 patients with aldosterone-producing adenoma were compared with those in 27 appropriately matched essential hypertensive subjects and 26 normotensive subjects. Resting plasma catecholamine levels averaged 292 +/- 140 (SD) pg/ml in patients with aldosterone-producing adenoma, 305 +/- 101 in patients with essential hypertension, and 260 +/- 120 in normotensive subjects; none of the differences among the three groups was significant. With head-up tilt (60 degrees for 10 min) plasma catecholamine levels increased similarly in the aldosterone-producing adenoma and essential hypertensive groups (up to 681 +/- 111 and 611 +/- 57 pg/ml respectively, NS). beta-Blockade (propranolol, 10 mg i.v.) in eight aldosterone-producing adenoma patients decreased heart rate (from 78 +/- 5 to 68 +/- 3 beats/min, p less than 0.005) and cardiac output (from 5.5 +/- 0.4 to 4.6 +/- 0.3 liter/min, p less than 0.001), but left mean blood pressure unchanged (127 +/- 4 to 127 +/- 2 mm Hg). Combined alpha- and beta-blockade with phentolamine and propranolol in five patients with aldosterone-producing adenoma produced no detectable changes in blood pressure. Thus, results from biochemical, functional, and pharmacological studies in humans showed no evidence of enhanced peripheral sympathetic activity in the hypertension of primary aldosteronism.

Human pharmacological studies of a new transdermal system containing nitroglycerin.

A new transdermal therapeutic system (TTS) for the administration of nitroglycerin (NTG) was tested in human pharmacological studies in 26 healthy volunteers. Plasma concentrations and haemodynamic responses were determined after the application of the system in different dosages. The concentrations of NTG reached in the plasma were uniform and dose-related, i.e. dependent on the drug-release area, and showed only minor inter-individual variation. They remained almost constant as long as the system was in contact with the skin. Renewal of the system caused no appreciable change in the plasma concentration. The haemodynamic effects, like those of all nitrates, were not clearly related to the dose administered, and were not always dependent on the plasma concentration. Upon repeated application, NTG-TTS was well tolerated locally and systemically and led to no alteration in blood chemistry or haematological parameters. The typical nitrate headaches disappeared after a few days. The presence of the system on the skin caused no discomfort or inconvenience.

Effect of Sodium Cyanate on Plasmodium falciparum In vitro

Sodium cyanate at concentrations as low as 0.5 mM inhibited the growth of Plasmodium falciparum (FCR-3 Strain) utilizing the Trager-Jensen continuous culture system. At concentration higher than 1 mM, the parasites were irreversibly destroyed. Utilizing synchronized cultures, the relative susceptibilities of early and late trophozite forms were examined, and it was found that both developmental forms were equally susceptible to the action of cyanate. Pretreatment of red cells with sodium cyanate prior to infection did not alter the intracellular growth of the parasite. Consequently, the effect of the drug is likely to be on the parasite per se rather than the red cell. The mechanism of action is probably the carbamylation of essential, parasite proteins that eventually impair growth and/or function. Published pharmacological studies in humans would predict that the level of cyanate at which growth inhibition occurs in vitro can be achieved in vivo and that the adverse effects will likely be minimal for short treatment periods.

Human pharmacology studies with a new, orally active stimulant of cardiac adrenergic beta-receptors

The effects of single oral doses of 5, 10, and 20 mg. of a new cardioselective β-stimulant, preparation C 50,005 A-Ba , were tested and compared with the response to placebo in eight healthy volunteers (four aged 23 to 26 years and four aged 49 to 55 years). The compound induced a doserelated increase in myocardial contractility (reduction of 17 to 24 msec. in PEP c) and in heart rate, which was accelerated by 8 to 20 beats/minute by comparison with the placebo values. The rise in systolic pressure observed in response to C 50,005 A-Ba was both dose-related and dependent on the age of the subjects; in the younger group there was an increase of 16 to 31 mm. Hg and in the older group an increase of 7 to 21 mm. Hg. A slight decrease in diastolic pressure was noted, which was likewise more prominent in the younger subjects. These changes were ascribed to a decrease due to aging in the responsiveness of the adrenergic β-receptors to stimulation. The effects of the compound set in quickly, reached their maximum within 30 to 60 minutes, and persisted for about 4 hours. The only side effects observed were slight palpitations. Depression of the ST segment was noted in one 55-year-old subject and was interpreted as a manifestation of latent coronary disease. In view of this finding, it seems possible that the preparation could be used as a diagnostic agent for a simple test of coronary function. Continuous E.C.G. recordings over a period of 5 3 4 hours , including three ergometer tests at submaximum effort, showed that by comparison with placebo, C 50,005 A-Ba caused a slight increase in the frequency of isolated ventricular and supraventricular premature contractions, and also in the incidence and intensity of sinus arrhythmias not due to respiration. Essentially the same changes in cardiac rhythm were observed in four young volunteers during continuous E.C.G. recordings over a period of 9 hours in response to the repeated administration of C 50,005 A-Ba in a dosage of 15 mg. three times a day on two consecutive days. The differences from the corresponding placebo values were, however, not statistically significant. C 50,005 A-Ba is thus an orally active cardiostimulant agent with a high degree of β 1-receptor selectivity and with only a very slight arrhythmogenic potential. It is well tolerated and could afford beneficial effects in the treatment of heart failure or as a countermeasure in therapy with β-blockers.

TRH in Depressive Illness

Among the four hypothalamic-releasing hormones (TRH, SRIF, LHRH, and MIF) with central nervous system actions and possibly with psychotropic properties, TRH is the one most systematically studied. Animal pharmacological data has confirmed the activity of TRH as a centrally acting agent with a widespread neurophysiological role independent of the pituitary-thyroid axis; and human pharmacological studies revealed that the computer EEG profile of TRH resembles psychostimulant drugs and secondary amine tricyclic antidepressants. Corresponding with this are the clinical findings that TRH produces a rapid but transient improvement in unipolar depression in women, a sense of increased energy and well-being, or increase of interest, desire and drive for work, food, and sex. In spite of the equivocal findings in some of the clinical studies, a recent investigation raised the possibility that a transient favorable response to TRH may identify a patient population responsive to maprotilline, or other norepinephrine uptake inhibitors.

Modified technique used in human bioassay of four butyrophenone derivatives in psychoneurotic patients.

Too often, following animal and acute human pharmacologic studies, insufficient information is available for the efficient and safe design of an adequately controlled double blind study in man. The single blind human bioassay of psychopharmacologic drugs, utilizing a spectrum of clinical conditions, may provide a rough estimate of the dose‐response relationship for clinical improvement, the dose‐response relationship for toxic effects, and an estimate of diagnostic categories in which potential usefulness may be established by double blind evaluation. This procedure avoids the expense of large numbers of toxicologic studies and provides the first screening for actual rejection of a drug from more complex and expensive thorough clinical investigation. The use of the modified technique is illustrated by studies with four butyrophenone derivatives (R‐1625, R‐1647, R‐1892, and R‐2167) in 151 patients. The dose‐response curves for these drugs, including the ED50 and the TD50 of each, were obtained in psychoneurotic outpatients and were found to correlate well with the ED50 for animal conditioned avoidance behavior block and with the LD50 in mice.