Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and pharmacokinetics (0.4 mg/kg) with bioavailability determination

Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18 +/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of 0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally (i.n.) in a cross-over protocol with a one-week wash-out period between each. In series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min, without a significant difference between 0.2 and 0.4 mg/kg doses for any of the studied parameters. In series 2, after intranasal midazolam administration of 0.4 mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5 min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and reliable sedation, adapted to laboratory piglets.     

The effectiveness of a pyriprole (125 mg/ml) and a metaflumizone (150 mg/ml) combined with amitraz (150 mg/ml) spot-on treatment in preventing Phlebotomus perniciosus from feeding on dogs

A controlled clinical trial was performed to assess the effectiveness of a pyriprole (125 mg/ml) and a metaflumizone (150 mg/ml) combined with amitraz (150 mg/ml) spot-on treatment (recommended dosage) in preventing adult female sandflies (Phlebotomus perniciosus) from feeding on dogs. Sandfly mortality was also assessed. Twelve beagle dogs were used in the study. Prior to treatment they were checked for their attractiveness to sandflies, ranked accordingly to generate partner triplets of equivalent sensitivity to sandflies: four control dogs, four treated with the pyriprole and four with the metaflumizone spot-on. The dogs were challenged with 50 unfed adult female sandflies (8-10 days old), in cages for one hour on Day 1 and Day 7. The sandflies were checked for blood feeding and mortality at one hour, 24 hours and 48 hours after exposure to the dogs. A very poor anti-feeding effect (near 7%) was seen on sandflies with the metaflumizone combined with amitraz and no antifeeding effect was seen with pyriprole. The sandfly mortality effect as a result of exposure to treated dogs was under 20% for the two spot-on. The two formulations could not be proposed in a leishmaniosis prevention program.     

Effect of a single dose (600 mg) of albendazole on Loa loa microfilaraemia

The problem of Loa-encephalopathy, which may occur after ivermectin treatment of patients harbouring high Loa microfilarial loads, might be solved if one could find a treatment regimen bringing about a significant but progressive decrease in the Loa microfilaraemia. A trial was performed in Central Cameroon, whose aim was to follow up for 10 months, and to compare the changes in the Loa microfilarial loads in two groups of patients, one treated with a single dose (600 mg) of albendazole (Alben, SmithKline Beecham) given with fatty food, and the other treated with mebendazole (100 mg, twice a day, generic tablets) at a fasting state. The microfilarial loads remained stable in the mebendazole group, whereas a significant decrease in microfilaraemia was recorded in the albendazole group (initial median load: 230 microfilariae per 50 microliters; median load ten months after: 84 microfilariae per 50 microliters). This should encourage further trials to evaluate the effects and the safety of two- or three-day albendazole regimens in patients infected with Loa loa.     

Metabolic effect at six and twelve months of cyproterone acetate (2 mg) combined with ethinyl estradiol (35 micrograms) in 31 patients

The metabolic effects of cyproterone acetate (2 mg) combined with a new dose level of ethinyl estradiol (35 micrograms) were studied over a one-year period in 31 patients presenting moderate clinical hyperandrogenism. The following tests were performed before treatment, at 6 and 12 months, an oral glucose tolerance test (OGTT) with measurement of insulinemia, total cholesterol, HDL cholesterol and the LDL + VLDL/HDL ratio, A1 and B apoproteins. At six months and at one year of treatment, the weight and body mass index (kg/m2) were not modified. Glucose tolerance and insulinemia had not changed significantly at one year. Lipid test results showed an increase in triglycerides, as well as in total and HDL cholesterol levels. However, the LDL + VLDL/HDL and A1/B apoprotein ratios did not change during the study. We conclude from these results that the new combination does not have any adverse effects on glucose tolerance and has a predominantly estrogenic effect on lipid parameters, characterized by increases in total cholesterol, HDL cholesterol and triglycerides.     

Overnight (1 mg) dexamethasone suppression testing reliably distinguishes non-cushingoid obesity from Cushing's syndrome.

To determine the sensitivity of the overnight 1-mg dexamethasone suppression test in diagnosing Cushing's syndrome, we evaluated the cortisol responses of 55 subjects (25 non-obese individuals with body mass index less than 25 kg/m2, 20 obese individuals with body mass index greater than 30 kg/m2, and 10 patients with surgically proven Cushing's syndrome) following ingestion of 1 mg dexamethasone at midnight. The basal 8 AM plasma cortisol levels among non-obese and obese individuals and patients with Cushing's syndrome were 310 +/- 85, 377 +/- 91, and 813 +/- 270 nmol/L, respectively. Following 1 mg of dexamethasone, Cushing's syndrome patients showed minimal suppression of cortisol to 609 +/- 180 nmol/L (P = 0.79). Non-obese and obese individuals suppressed to 18.7 +/- 6.0 nmol/L (P less than 0.001) and 22 +/- 7.1 nmol/L (P = 0.003), respectively. The results demonstrated similar cortisol responses to overnight dexamethasone suppression in obese and non-obese groups, and clearly distinguished these subjects from those with Cushing's syndrome. Obesity is not a confounding factor in the 1-mg dexamethasone suppression test.     

Low-dose flutamide (125 mg/day) as maintenance therapy in the treatment of hirsutism

OBJECTIVE: To evaluate the safety and efficacy of a low dose of flutamide (125 mg/day) in maintaining the clinical results already obtained using a higher dose (250 mg/day), in women suffering from hirsutism. METHOD: Forty-three women suffering from hirsutism of varying origin received 250 mg/day of flutamide as an initial treatment for 12 months and, subsequently, 125 mg/day of flutamide for an additional 12 months as a maintenance treatment. Hirsutism was evaluated by the Ferriman-Gallwey score, and hair diameter and hair growth rate were determined by a special image analysis processor. Biochemical, clinical and hormonal parameters were evaluated in basal conditions and every 2-6 months. RESULTS: The significant decrease in the hirsutism score, hair diameter and hair growth rate during the initial treatment period was confirmed at the end of the maintenance treatment period. Androgen levels decreased up to the end of the initial treatment period and partially decreased during the maintenance treatment. During the initial treatment period, 4 subjects showed an increase of aspartate aminotransferase and alanine aminotransferase and dropped out. During the maintenance treatment period, no side effects or complications were observed. CONCLUSION: Satisfactory management of hirsutism with flutamide seems to be represented by an initial treatment period using 250 mg/day to achieve satisfactory results, followed by a long maintenance treatment period using 125 mg/day.