Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator.

PURPOSE: New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro- 1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies. METHODS: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25-200 mg. Standard pharmacokinetic parameters were assessed. RESULTS: In the single-dose study, time to reach peak concentration (tmax) ranged from 1.3 h to 4.0 h; peak concentration (Cmax) ranged from 15 ng/ml to 445 ng/ ml; and the estimated terminal elimination half-life (mean +/- SD; t1/2) was 24.8 +/- 7.0 h. In the repeated-dose study, tmax ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. Cmax ranged from 295 ng/ml to 1,043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t1/2 at all dose levels was 29.7 +/- 1.5 h (overall mean +/- SD). Strong linear correlations between the dose and Cmax and between the dose and the area under the curve were observed in both studies. CONCLUSION: Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens.

The effects of glycopyrrolate on oral mucous host defenses in healthy volunteers.

UNLABELLED: We studied the effects of glycopyrrolate on oral mucous host defenses. Single IV doses of glycopyrrolate (4 microg/kg) or placebo were administered to 12 healthy volunteers in a randomized, double-blinded, cross-over study. Salivary flow rates and the concentrations/activities of total protein, amylase, and nonimmunologic (lysozyme, lactoferrin, myeloperoxidase, total salivary peroxidase, and thiocyanate) and immunologic (total immunoglobulin A, immunoglobulin G, and immunoglobulin M) mucous host defense factors were determined for paraffin-stimulated whole saliva before and 1, 3, 6, 12, 24, and 48 h after drug administration. Glycopyrrolate serum concentrations were determined before and 2, 4, 6, 10, 15, and 30 min and 1, 2, 3, 6, 12, and 24 h after IV drug injection. Salivary flow rates were decreased significantly for 12 h after glycopyrrolate injection, compared with saline injection. The concentrations of immunologic and nonimmunologic defense factors were increased in the glycopyrrolate group, and differences between the groups were found for all factors (P < 0.05-0.001) except lysozyme and total salivary peroxidase. In contrast, because of the reduced flow rate, the output of all defense factors into the saliva was decreased after glycopyrrolate injection, compared with saline injection. Glycopyrrolate thus decreases the output of salivary host defense factors into the oral cavity. IMPLICATIONS: Glycopyrrolate induces long-lasting hyposalivation and decreases the secretion of salivary immunologic and nonimmunologic defense factors in healthy volunteers.

A medication database--a tool for detecting drug interactions in hospital.

OBJECTIVE: Drug interactions may lead to life-threatening injuries. More often, however, they lead to slow recovery, induce slight symptoms or result only in potential injury. Therefore, clinicians are not always aware of using potentially interacting drug combinations. An on-line alarming system of potential drug interactions was developed in Turku University Central Hospital. In the present study, we utilised the system to find out the incidence and nature of potential drug interactions occurring in a representative hospital patient population. METHODS: Computerised anatomical therapeutic chemical (ATC)-coded patient medication data of 2547 patients, treated in two internal medicine wards, were combined with an ATC-coded rule base of drug interactions. All potential drug interactions in the study population were searched for. RESULTS: A total of 326 potentially serious drug interactions were detected in the study population. The number of patients in this group was 173, i.e. 6.8% of all patients had one or several drug combinations which might have led to serious clinical consequences. Concomitant use of calcium and fluoroquinolones (decreased absorption) was the most common mistake (66 prescriptions). CONCLUSIONS: Potentially inappropriate drug combinations seem to occur frequently. Structured and coded medication data can be utilised efficiently to detect potential drug interactions in hospital. Computerised online monitoring and automatic alarming of potentially hazardous drug combinations might help clinicians to prescribe more safely, but further development of the system is needed to avoid unnecessary alarms.

Ocular effects and systemic absorption of cyclopentolate eyedrops after canthal and conventional application.

Ocular effects and plasma concentrations of cyclopentolate were studied in 8 volunteers after eyedrop application with two methods. While recumbent two 30 microliters drops of 1% cyclopentolate hydrochloride were instilled in randomized order either conventionally to the lower conjunctival cul-de-sac or on the inner canthus with eyes closed, followed by immediate opening of the eyes. The cycloplegic responses as well as the extent and time of maximal mydriasis did not differ significantly between the two methods. None of the parameters describing the systemic absorption of the drug differed between the treatment groups. Conventionally applied drops caused slightly longer subjective discomfort. Instilling eyedrops on the inner canthus with eyes closed is an alternative method to deliver ocular cyclopentolate with similar efficacy and safety as the conventional technique. This method could be useful especially when treating non-cooperative children.

Ethanol and the absorption of oral penicillin in man.

The effect of alcohol on the pharmacokinetics of phenoxymethylpenicillin was studied in six healthy volunteers. Ethanol had no influence on peak penicillin serum concentrations, times of the penicillin peaks, elimination half-lives (t1/2), AUC0-8h values and 24-h urinary excretion.

Correlation of serum lipids with diabetes control in sulfonylurea-treated diabetic patients.

The relationships between fasting blood glucose, glycosylated hemoglobin A1, and several lipid parameters were studied in 67 non-insulin-dependent diabetic patients (19 men, 48 women) being treated with tolbutamide, chlorpropamide, or glibenclamide. All patients were over 60 yr of age with a mean age of 76.4 +/- 6.7 yr (+/- SD). There were positive associations between fasting blood glucose and serum cholesterol, LDL cholesterol, and serum triglycerides. A strong association between total cholesterol and triglycerides was also evident. Diabetes control and HDL cholesterol did not correlate with each other. A weak inverse correlation existed between fasting blood glucose and the HDL cholesterol/total cholesterol ratio. HDL cholesterol concentrations were low in the diet- and drug-treated diabetic patients. No deleterious sulfonylurea effects on cholesterol, LDL cholesterol, and triglyceride concentrations or HDL cholesterol/total cholesterol ratio were noted.

Rapid high-pressure liquid chromatographic method for analysis of phenoxymethylpenicillin in human serum.

A selective high-pressure liquid chromatographic method for the determination of phenoxymethylpenicillin in human serum is described. The technique is based on the single extraction of the drug from acidified serum with diethyl ether. Chloramphenicol is used as internal standard. The chromatographic system consists of a reversed-phase C-18 column; the mobile phase is acetonitrile-0.01 M potassium acetate buffer (20:80 [vol/vol]; pH 6.5). The method can accurately measure serum penicillin concentrations down to 30 micrograms/liter with 500 microliter of sample. The coefficient of variation for intraassay variability of penicillin is between 1.5 and 4.9% in the range of 0.125 to 16.00 mg/liter. The extraction efficiency is 78.5 +/- 6.8% (+/- standard deviation; n = 9), and the calibration graph is linear in the concentration range studied. Pharmacokinetic data, obtained with the present method from seven healthy volunteers, are presented.