Dose-finding Clinical Trial Research Articles

Centrally active nonhormonal hot flash therapies

Given the problems associated with hormonal therapy, and the prominent problem of hot flashes in menopausal women, there is a need for nonhormonal agents to alleviate hot flashes. Several compounds that appear to act on the central nervous system have been investigated. Potential mechanisms for their effects on hot flashes have been described. Bellergal (no longer available on the US market, where it was known as Bellergal-S), a combination preparation sedative that consists of low-dose phenobarbital, ergotamine tartrate, and levorotatory alkaloids of belladonna, is an old agent that was popular approximately 20 years ago; however, there is limited suggestion of efficacy for this agent. Clonidine, an older antihypertensive drug, is another centrally active agent that has been studied. Randomized trials have demonstrated that it clearly works for reducing hot flashes, but the magnitude of efficacy is somewhat limited. Toxicity from this agent limits its utility in the clinic. Methyldopa is another centrally active agent that has been studied but to a more limited degree. It appears to have minimal efficacy and too much toxicity to make it clinically useful. Anecdotal observations from a number of sources suggested that newer antidepressants can alleviate hot flashes. This led to pilot trials of venlafaxine and paroxetine, with results suggesting benefit from both drugs. Subsequently, randomized, placebo-controlled, double-blind clinical trials of venlafaxine, paroxetine, and fluoxetine were conducted. All 3 of these clinical trials demonstrated statistically significant reductions in hot flashes with these newer antidepressants compared with placebo. Pilot trials of citalopram and mirtazapine, 2 other newer antidepressants, have also suggested efficacy. Toxicity evaluations have suggested that these agents are, again, well tolerated by the majority of patients. A recent trial, however, was unable to demonstrate any benefit for fluoxetine or citalopram over a placebo. Anecdotal observations also suggested that gabapentin was helpful for alleviating hot flashes. This led to pilot trials that again suggested efficacy. Subsequently, 2 large placebo-controlled, randomized, double-blind clinical trials were conducted. Both of these demonstrated statistically significant efficacy for gabapentin compared with a placebo. This drug is relatively well tolerated by most patients. Thus, centrally active nonhormonal agents clearly do decrease hot flashes in women. The most efficacious and clinically appropriate agents for use are newer antidepressants and gabapentin. Continued evaluation of the efficacy and toxicity of these agents is ongoing.

Recombinant LH in Support of Recombinant FSH in Female Hypogonadotropic Hypogonadism—Evidence of Threshold Effect

Recombinant LH in Support of Recombinant FSH in Female Hypogonadotropic Hypogonadism—Evidence of Threshold Effect

Aminosidine plus sodium stibogluconate for the treatment of Indian kala-azar: a randomized dose-finding clinical trial

This randomized, open sequential design trial was set up to assess the efficacy, tolerability and toxicity of 20 d courses of combined intramuscular aminosidine and sodium stibogluconate at various dosages in patients with newly-diagnosed kala-azar in Bihar, India. Three successive studies of 96 patients each were originally planned with aminosidine administered at 12, 6 and 3 mg/kg/d, respectively. For each aminosidine dosage, patients were randomly assigned to receive sodium stibogluconate at 20, 10 or 5 mg/kg/d of antimony. Ninety-six patients were enrolled and assigned aminosidine 12 mg/kg/d as scheduled. In the subsequent study with aminosidine at 6 mg/kg/d, the trial was interrupted after 40 patients had entered owing to inadequacy of the treatment. With aminosidine 12 mg/kg/d the success rates with sodium stibogluconate at 20, 10 and 5 mg/kg/d were 88%, 71% and 72%, respectively and did not differ significantly. With aminosidine 6 mg/kg/d, 69%, 50% and 46% of patients were cured with the same sodium stibogluconate doses, respectively; again, there was no significant difference between the subgroups. The overall success rate with aminosidine at 12 mg/kg/d (76%) was significantly higher than that with 6 mg/kg/d (55%) (odds ratio = 2·69; 95% confidence interval, 1·11–6·4). Patients improved clinically and the treatments were equally well tolerated. The combination of aminosidine 12 mg/kg/d and sodium stibogluconate 20 mg/kg/d for 20 d appears to be an effective and safe replacement in Bihar for sodium stibogluconate alone for ⩾40 d.

Combination of quinine, quinidine and cinchonine for the treatment of acute falciparum malaria: correlation with the susceptibility of Plasmodium falciparum to the cinchona alkaloids in vitro

Thirteen patients with acute symptomatic uncomplicated falciparum malaria were enrolled in an open, randomized, phase 2, dose-finding clinical trial of a fixed dosage combination of quinine, quinidine and cinchonine (LA40221, Sanofi Recherche, France), which contained equal parts of the 3 alkaloids and was administered orally every 8 h in doses of 400 mg (7 patients) or 500 mg (6 patients) for 7 d. There was prompt clearance of parasitaemia and fever in all patients. The mean clearance times (±standard deviation) of parasitaemia, fever and other symptoms were 29 ± 11·0 h, 10·7 ± 4·1 h and 14·9 ± 9·7 h respectively for the 400 mg dose group, and 35 ± 20·0 h, 16 ± 7·0 h and 17·6 ± 8·7 h respectively for the 500 mg dose group. There was no recrudescence of parasitaemia during the 28 d observation period. Minor gastrointestinal side effects occurred in 2 patients, but there was no major side effect. Haematological, biochemical and other measurements were not adversely altered by treatment. QTc prolongation occurred in 3 patients—2 from the 400 mg and 1 from the 500 mg dose group. Testing in vitro against Plasmodium falciparum isolates from 47 patients (including the 13 patients enrolled in the trial) of the combination and its individual components suggested that the relative potencies in vitro, in decreasing order, were quinidine, LA40221, cinchonine and quinine. The minimum inhibitory concentrations were 0·32, 0·64, 0·64 and 1·28 μmol/litre of blood-medium mixture respectively, and the 50% inhibitory concentrations were 0·083, 0·11, 0·12 and 0·22 μmol/litre of blood-medium mixture. The respective 99% inhibitory concentrations were 0·27, 0·45, 0·50 and 1·20 μmol/litre of blood-medium mixture.

Experiences with pro-urokinase and potentiation of its fibrinolytic effect by urokinase and by tissue plasminogen activator

Pro-urokinase is a single chain, precursor form of two chain, 54,000 Mr urokinase. Although originally isolated from urine, pro-urokinase is also found in blood, where it is believed to participate in natural fibrinolysis alongside tissue plasminogen activator (t-PA). These two plasminogen activators share the property of inducing fibrin-selective plasminogen activation, but many of their other properties, including their modes of action, are dissimilar. A comparison of some of the clinically relevant properties of pro-urokinase and t-PA is provided. A multicenter, dose-finding clinical trial of native pro-urokinase is underway in the United States and in West Germany. At the time of this writing, 110 patients with angiographically proved acute coronary thrombosis have been treated. The findings from one center are summarized in some detail and the overall experience is reviewed. Preliminary evidence for a potentiating effect on pro-urokinase-induced thrombolysis by urokinase is presented. The findings suggest that a bolus of urokinase (200,000 IU) at the outset increases the reperfusion rate from 60 to greater than 80% and shortens the lysis time from about 50 to 30 minutes. A modest (19%) but significant (p less than 0.05) decrease in fibrinogen accompanied thrombolysis by urokinase/pro-urokinase. Nonetheless, significant bleeding complications in the multicenter study have, to date, not been encountered and it is suggested that this may be related to pro-urokinase's sensitivity to inactivation by thrombin and lack of potentiation by heparin.(ABSTRACT TRUNCATED AT 250 WORDS)