Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group.

PURPOSE: A double-blind, randomized, placebo-controlled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed. METHODS: Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner. RESULTS: The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. Kaplan-Meier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc chi2 probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group. CONCLUSIONS: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity.

Dose escalation study of the NMDA glycine-site antagonist licostinel in acute ischemic stroke.

BACKGROUND AND PURPOSE: Licostinel (ACEA 1021; 5-nitro-6, 7-dichloro-2,3-quinoxalinedione), a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke. METHODS: In this 5-center dose escalation trial, patients were enrolled within 48 hours of an ischemic stroke and treated with ascending doses of a short infusion of licostinel or a placebo. Adverse effects were assessed with clinical and laboratory measurements, and patient outcome was determined with the National Institutes of Health Stroke Scale. RESULTS: Sixty-four patients (44 treated with escalating doses of licostinel and 20 who received placebo) were treated. Lower doses of licostinel (0.03 to 0.60 mg/kg) were not associated with any significant adverse effects. Higher doses of licostinel (1.2 to 3.0 mg/kg) were associated with a variety of mild-to-moderate adverse effects including neurological and gastrointestinal complaints. No major psychotomimetic effects or significant safety concerns occurred. At the higher dose levels, peak plasma concentrations of licostinel were substantially higher than those required for neuroprotection in animal stroke models. A similar improvement in National Institutes of Health Stroke Scale scores over time was seen in both the placebo group and the licostinel-treated patients. CONCLUSIONS: A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients. Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists.

Re-engineering drug development: integrating pharmacoeconomic research into the drug development process.

Pharmacoeconomic research will be an increasingly important aspect of drug development as providers, third-party payers, and worldwide government health agencies use cost-effectiveness and quality-of-life data to assist in making decisions on optimal pharmaceutical treatment protocols, formulary listings, and reimbursement. It is in the best interest of pharmaceutical companies to have an established, well-integrated pharmacoeconomic research program that can respond to the dynamic health-care environment and proactively plan a program to optimize patient care. The new paradigm for pharmacoeconomic research will require establishment and successful management of many internal and external customer relationships. This article discusses one company's organization of these relationships and how they are integrated into the drug development process during each stage of the product life cycle.

Female androgenetic alopecia: a review.

This review of androgenetic alopecia (AA) in women provides a summary of hair physiology and biochemistry, a general discussion of AA, and a brief description of other types of hair loss in women. AA associated with signs of virilization is distinguished from AA alone.

Inhibition of renin release by analogues of adenosine in rabbit renal cortical slices.

Renal cortical slices obtained from male New Zealand rabbits were used to investigate the role of adenosine in the regulation of renin release. Isoproterenol produced a significant (p less than 0.01), twofold to threefold increase in renin release, that was both dose-dependent and time-dependent. Addition of either the l-phenylisopropyl or the N6-ethylcarboxamido derivative of adenosine attenuated this stimulation at concentrations as low as 10(-9) M or 10(-8) M, respectively. Higher doses of d-phenylisopropyladenosine (10(-6) M) or adenosine (10(-5) M) were necessary to significantly reduce the beta-adrenergic response (p less than 0.01). Inhibition was absent in slices preincubated with 10(-5) M 8-phenyltheophylline, a concentration that had no effect on either basal or stimulated renin release. The site of inhibition appeared to be distal to beta-adrenergic and prostaglandin receptors since l-phenylisopropyladenosine (10(-8) M) blocked stimulation by selective beta-adrenergic receptor agonists, prenalterol (10(-6) M) or salbutamol (10(-5) M), and by prostaglandin E1. These data suggest that adenosine and its analogues inhibit renin release and that this inhibition may be mediated by a receptor-dependent action on a common point in the pathway leading to release.

The effect of prostaglandin synthesis inhibition on the direct stimulation of renin release from rabbit renal cortical slices.

Prostaglandins have been hypothesized to have several mechanistic functions in sympathetically mediated release of renin. The rabbit renal cortical slice system was chosen to examine the prostaglandin dependency of renin release directly stimulated by either a direct adenylate cyclase activator, forskolin, or a beta-agonist, isoproterenol. In this study, we demonstrate that with forskolin (1 X 10(-5) M) or isoproterenol (1 X 10(-6) M), renin release was elevated 2-3 fold above control, and that this increase was shown to accompany a substantial increase in the tissue levels of cAMP (19.5 fold and 3.5 fold respectively). We also demonstrate that the increase in renin release produced by these compounds was not inhibited by cyclooxygenase inhibitors, indomethacin (25 microM) or eicosatetraynoic acid (30 micrograms/ml), nor was it inhibited by the selective prostacyclin synthesis inhibitor, U-51605 (30 micrograms/ml). Each of these inhibitors was demonstrated to block the synthesis of prostaglandins in the cortical slices at the concentrations used. Thus we propose that prostaglandins do not play a role in the induction of renin release resulting from elevated cyclic nucleotide levels or beta-adrenergic stimulation.

Mechanism of bradykinin-stimulated prostacyclin synthesis in porcine aortic endothelial cells.

Porcine aortic endothelial cells studied at confluence were found to synthesize both prostacyclin and prostaglandin E2. Addition of arachidonic acid, bradykinin, the calcium ionophore A23187 or thrombin stimulated prostaglandin formation, whereas addition of angiotensin II did not. Bradykinin was found to stimulate very potently arachidonic acid release from cells prelabelled with [3H]arachidonate, the response being dose-dependent and half-maximal at 8 ng/ml. The rate of release of label (primarily arachidonate) from cells was increased by bradykinin (100 ng/ml) approximately 8-fold, with a return to control levels by 10 min. The calcium ionophore, A23187, similarly released [3H]arachidonic acid from prelabelled cells; the rate of release was approximately linear for 15 min. Both bradykinin and ionophore A23187 stimulated [3H]arachidonate release from endothelial cell phospholipids, an effect which was abolished in a dose-dependent manner by mepacrine. Release in response to bradykinin was prevented by incubation in Ca2+-free medium. Trifluoperazine, a compound which can inhibit calmodulin-mediated events, blocked the release of label stimulated by bradykinin. These data indicate that the likely mechanism of bradykinin-stimulated prostaglandin production in endothelial cells involves the activation of a phospholipase via a Ca2+-calmodulin-dependent pathway.

Influence of kaolin-pectin suspension on steady-state plasma digoxin levels.

The effect of a kaolin-pectin antidiarrheal mixture on steady-state plasma levels of orally administered digoxin in subjects receiving chronic digoxin therapy was evaluated when the antidiarrheal and the cardiac glycoside were given concomitantly and when two doses of antidiarrheal were given, one 2 hours before and the other 2 hours after digoxin. Although simultaneous administration of both products decreased peak digoxin levels by 36 per cent, 24-hour areas under the curve were reduced by only 15 per cent, indicative of a slight decrease in digoxin bioavailability. In contrast, when their times of administration were separated by 2 hours, no evidence of a drug interaction was noted. Hence, the effect of one or two doses of kaolin-pectin suspension on steady-state plasma levels of digoxin appears inconsequential in patients on chronic digoxin therapy. Saliva levels were poorly correlated with plasma levels, presumably because of complexation in the oral cavity.

Intravenous infusion of prostacyclin sodium in man: clinical effects and influence on platelet adenosine diphosphate sensitivity and adenosine 3':5'-cyclic monophosphate levels.

Clinical tolerance, inhibition of platelet aggregation and intracellular platelet adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were evaluated in normal volunteers given i.v. infusions of prostacyclin sodium at rates up to 15 ng/kg/min. Short-term infusions (30 and 60 minutes) were tolerated at rates up to 10.0 ng/kg/min; higher rates produced headaches, anxiety, nausea and vomiting. Six-hour and 24-hour infusions were tolerated at rates up to only 4.0 ng/kg/min. Twenty-four hour infusions at 4 ng/kg/min produced a consistent 4-7 microM shift to the right in the platelet ADP dose-response curve; this platelet inhibitory activity did not diminish during the infusion. Prostacyclin sodium infusion elevated intracellular cyclic AMP levels, the increases corresponding to the onset of measurable inhibition of ADP-induced aggregation, although the magnitude of the increase did not necessarily reflect the degree of inhibition. Increased template bleeding times were seen with a greater than 10-microM shift in the ADP dose-response curve. We conclude that although prostacyclin sodium has a narrow safety margin, the drug does produce platelet inhibition at infusion rates generally tolerated by healthy volunteers.

The influence of indomethacin on the pharmacokinetics, diuretic response and hemodynamics of furosemide in the dog.

Indomethacin has the potential to interact with furosemide in a number of different fashions. We have investigated some of these possibilities in seven mongrel dogs that received furosemide (2 mg/kg i.v.). Plasma and urinary concentration of furosemide were measured by high performance liquid chromatography, diuretic response was assessed by urinary sodium excretion and renal blood flow and its distribution were estimated using the radioactive microsphere technique. Furosemide induced a prompt diuresis associated with a 50% increase in total renal blood flow. Intrarenal blood flow was preferentially increased in the inner cortical zones. Furosemide was rapidly eliminated with a renal clearance that was 35% of the total systemic clearance. Maximal sodium excretion was attained at plasma furosemide concentrations greater than 0.8 microgram/ml; below this concentration there was a linear relationship between plasma concentration and rate of sodium excretion. The ratio of sodium/furosemide concentration in urine rose to a plateau, then remained constant. Indomethacin pretreatment inhibited the hemodynamic response to furosemide. In addition, indomethacin reduced the renal and extrarenal clearance of furosemide by approximately 30%, but did not change the proportion of unchanged drug excreted in the urine. Although the diuretic response for any given plasma concentration of furosemide was reduced, the ratio of urinary sodium/furosemide concentration was not changed by indomethacin. Since the amount of furosemide reaching the urine was not altered, the total diuretic response was not significantly affected by indomethacin. From these observations we conclude that indomethacin alters the pharmacokinetics of the disposition of furosemide and furosemide-induced renal hemodynamic changes. However, our data indicate that the response of the renal tubule to furosemide secreted into tubular fluid is not changed by indomethacin.

Prostaglandin D2, another renal prostaglandin?

Prostaglandin (PG) D2 was biosynthesized by rabbit renal papillae incubates in vitro. Quantification of the renal prostaglandins by gas chromatography-mass spectroscopy demonstrated that the concentration of PGD2 generated by renal papillae was 1/6 to 1/10 the amount of PGE2 or about 1microgram/g tissue/30 min. Infusion of the sodium salt of PGD2 into the renal artery of the dog produced a dose related increase in renal blood flow and urine flow, free water clearance, sodium excretion and potassium excretion without changes in systemic hemodynamics. At low doses PGD2 increased renal blood flow to all cortical zones. Higher concentrations of PGD2 produced a shift in the intrarenal distribution of blood flow toward the juxtamedullary nephrons.

Enhanced renal prostaglandin production in the dog. The effect of sodium arachidonate in nonfiltering kidney.

Sodium arachidonate, 10(-5) g/kg per minute, was infused into the renal artery of a nonfiltering canine kidney in situ in order to determine the effects of enhanced prostaglandin synthesis on renal blood flow and its distribution in circumstances where prostaglandins produced in the medulla could not gain access to the cortex via tubular fluid. The contralateral normal kidney was also infused with sodium arachidonate and served as control. Radioactive microspheres were used to calculate the hemodynamic effects. In the nonfiltering kidney, the total renal blood flow increased after sodium arachidonate from a mean of 105 ml/min per 100 g to 146 ml/min per 100 g (P less than 0.01). This increase was completely abolished by prior treatment with indomethacin, 8 mg/kg, intravenously. The normal kidney responded qualitatively the same as the nonfiltering side. In both kidneys, blood flow increased significantly to all cortical zones except the outermost (zone 1), but the fractional distribution of renal blood flow was significantly increased only in the innermost cortex (zone 4). Since the kidneys were nonfiltering, the increase of renal blood flow during infusion of arachidonic acid cannot be explained by prostaglandins being transported from renal medulla to the cortex through renal tubules. Most likely prostaglandins are produced locally in the cortex and have only local effects.

Alteration of canine renal vascular response to hemorrhage by inhibitors of prostaglandin synthesis.

The involvement of prostaglandins in the redistribution of renal cortical blood flow to inner cortical nephrons during hemorrhagic hypotension was studied in the pentobarbital-anesthetized dog. Total renal blood flow and distribution of renal cortical flow were determined with the radioactive microsphere technique by dividing the cortex into four zones of equal thickness, zone 1 being outermost and zone 4 being juxtamedullary. Two inhibitors of prostaglandin synthesis were used: indomethacin 8 mg/kg and aspirin 100 mg/kg. The inhibitor or the vehicle was given intravenously prior to a control period which was followed by a hemorrhage sufficient to decrease arterial pressure by about one-third. The distribution of cortical flow was determined before hemorrhage, during hemorrhagic hypotension, and after transfusion. In the vehicle-treated dogs, total renal blood flow was well maintained, but flow redistributed to favor the inner cortical nephrons. This vasodilation in the inner cortex was blocked by both inhibitors of prostaglandin synthesis resulting in a decrease in total renal blood flow and relative ischemia of the juxtamedullary nephrons. Salicylate levels required to accomplish blockage of inner cortical vasodilaton were less than 7 mg/100 ml. These studies indicate that prostaglandins are responsible for the decreased vascular resistance of the inner cortical nephrons which results in the redistribution of blood flow during hemorrhage, and when prostaglandin synthesis is blocked, the kidney vasculature constricts during hemorrhage.

Interaction of quinidine with anticonvulsant drugs.

Drug-disposition studies of orally administered quinidine in four normal healthy volunteers indicated that phenobarbital and phenytoin reduced the half-life of quinidine by approximately 50 per cent (control, 3.0 to 6.1 hours, and with anticonvulsants, 1.6 to 2.6 hours). Alterations of similar magnitude in the apparent plasma clearance of quinidine after oral administration (control 20.0 to 32.0 liters per hour; with anticonvulsant 44.0 to 94.0 liters per hour) suggest that this effect is probably due to an increase in the rate of metabolism of quinidine, although decreased absorption cannot be entirely ruled out. In two index patients the concomitant use of anticonvulsant drugs resulted in inadequate blood levels of quinidine with standard dosages of that drug.