Hormonal effects of toremifene in breast cancer patients.

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the "prolactin reserve capacity" of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of tormifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH-induced prolactin release was suppressed by tormifene after an 8-week period. No clinical response-related tendency was found.

A new triphenylethylene compound, Fc-1157a. I. Hormonal effects.

The basic pharmacological and biochemical properties of a new antiestrogen, Fc-1157a, are described. Fc-1157a is bound specifically and with high affinity to estrogen receptors. The binding is competitive with estradiol. Fc-1157a treatment induces translocation of estrogen receptors from cytoplasm to nucleus. The turnover rate of nuclear estrogen receptors is markedly lower than with estradiol, but is more rapid than after tamoxifen. Fc-1157a is an almost pure antiestrogen in rat uterus, but has intrinsic estrogenic activity in mouse uterus. In animal experiments Fc-1157a has shown antitumor properties, which are described in the companion paper.

Pharmacokinetics of ftorafur after intravenous and oral administration.

The pharmacokinetics of ftorafur (FT), an antineoplastic agent, has been studied in seven cancer patients by determining concentrations of the unchanged compound in serum after single IV and PO doses of 2 g FT. Serum drug concentrations were determined by a new quantitative thin-layer chromatographic method. After IV administration, the mean half-lives of the distribution phase and elimination phase were 1.0 h and 7.6 h, respectively. Total serum clearance was 69 ml/h . kg and the apparent volume of distribution was 0.66 l/kg. Following PO administration there was a short lag-time, 11 min, before the appearance of FT in peripheral serum, and the maximum concentration in peripheral serum was achieved in 3.2 h. Oral absorption was complete and no significant first-pass metabolism could be observed. FT elimination, measured in serum taken from the portal vein and a peripheral vein, occurred substantially at the same rate after IV and PO administration. In contrast, after the PO dose FT appeared in the portal serum significantly earlier than in the peripheral serum, resulting in a difference of 1.7 h in the time of maximum serum concentration. This indicates fast gastrointestinal absorption of FT but hepatic retention (without metabolism) before the appearance of FT in the peripheral serum.

Trimethoprim alone in the treatment of urinary tract infections: eight years of experience in Finland.

In Finland the usage of trimethoprim (TMP) alone constitutes about 25% of all drug usage for urinary tract infections. Despite this widespread use the proportion of TMP-resistant strains is almost same as it is in countries where only the combination of trimethoprim-sulfamethoxazole (TMP-SMZ) has been used. In general, strains resistant to TMP were seldom found; only in closed wards did the use of trimethoprim result in an increase in the proportion of resistant strains. In the treatment of acute urinary tract infections, TMP alone (dose, 160 mg taken twice daily for seven days) gave a result as good as that of TMP-SMZ (94.5% vs. 90.6%) and a better result than cephalexin (98.3% vs. 82.1%). TMP proved suitable as a single agent in the treatment of urinary tract infections in outpatients. In a study of long-term treatment, TMP (dose, 100 mg taken once daily), was more effective than nitrofurantoin, methenamine hippurate, TMP-SMZ, or placebo. Fewer adverse effects were associated with TMP than with the other drugs.

Pharmacokinetics of propranolol and sotalol in hyperthyroidism.

The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160 mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p less than 0.05) and its clearance was increased (p less than 0.005), whereas there was no difference in its serum t 1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.

Secondary prevention of recurrent urinary tract infections. Comparison of the effect of placebo, methenamine hippurate, nitrofurantoin and trimethoprim alone.

290 patients with recurrent urinary tract infection were treated with either placebo, methenamine hippurate, nitrofurantoin or trimethoprim. 38.9% of the patients had chronic pyelonephritis and 23.8% azotemia. During the follow-up period of 1 year 63.2% recurred in the placebo group, 34.2% in the methenamine hippurate group, 25.0% in the nitrofurantoin group and 10.4% in the trimethoprim group. 62.5% of the recurrences in the trimethoprim group were associated with trimethoprim-resistant strains. However, such strains appeared only in 6.5% of the patients treated with trimethoprim, compared with 16.2% in the placebo, 8.3% in the nitrofurantoin and 11.0% in the methenamine hippurate groups. Side-effects were mild and occurred most frequently in the nitrofurantoin group (13.9%).

Plasma clearance of propranolol and sotalol and hepatic drug-metabolizing enzyme activity.

The role of hepatic drug-metabolizing enzyme activity for plasma propranolol and sotalol levels was investigated in 68 patients with hypertension or angina pectoris by comparing elimination rate with antipyrine kinetics and cytochrome P-450 content in the liver. All subjects were resistant to or had hepatotoxic reaction to previous treatment. Plasma antipyrine clearance and cytochrome P-450 content in biopsies were related to propranolol elimination from plasma, the best fit being obtained with the clearance values. Sotalol plasma clearance was not related to any indirect or direct reflector of the hepatic drug-metabolizing enzyme system. The results demonstrate that plasma clearance of the short-acting beta blocker, propranolol, depends on the activity of hepatic drug-metabolizing enzyme system and indicates a trial with a drug such as sotalol which is not dependent on liver metabolizing capacity.

Effect of food, food constituents and fluid volume on the bioavailability of sotalol.

The effect of food, some food constituents, and large volumes of fluid taken with the drug on the relative bioavailability of sotalol has been examined in five healthy volunteers. Each subject received an oral 160 mg dose in six different experimental schedules. Venous blood samples were drawn 1, 2, 3, 4, 6 and 8 hrs after the dosing, and sotalol concentrations in serum were determined fluorometrically. The results indicate that large volumes of fluid delay but do not affect the extent of sotalol absorption. Food, especially milk, decreases the bioavailability of the drug and an interaction with calcium seems to be the major reason for the reduced absorption.

Naproxen concentrations in serum, synovial fluid, and synovium.

Naproxen levels in serum, synovial fluid and synovium of eighteen patients with "classical" or "definite" rheumatoid arthritis and chronic knee effusion were studied. After oral administration of 250 mg naproxen twice daily, naproxen levels in synovial fluid were found to be more than half as high as in serum. Even in synovium itself naproxen levels were appreciable.

Effect of trimethoprim on the occurrence of drug-resistant coliform bacteria in the faecal flora.

The occurrence of drug-resistant coliform bacteria was studied in the faecal flora of 30 persons receiving for 3 weeks either trimethoprim alone, a combination of sulphamethoxazole and trimethoprim, or a combination of sulphamethoxydiazine and sulphamethoxazole. Bacterial sensitivity was tested against trimethoprim, sulphamethoxazole-trimethoprim, sulphamethoxazole, and sulphaisodimidine. After treatment with trimethoprim alone, no increase in the occurrence of strains resistant to either trimethoprim or sulphonamides was observed. After treatment with sulphamethoxazole-trimethoprim, the faecal flora contained an increased percentage of sulphonamide-resistant coliforms but significantly less than found after treatment with sulphamethoxydiazine-sulphamethoxazole. In the persons receiving the sulphonamides only, a rapid increase in sulphonamide-resistant coliforms was observed. During the whole study, only one trimethoprim-resistant coliform strain was detected.

Serum levels and half-life of sotalol in chronic renal failure.

The elimination of sotalol was studied in 25 patients with chronic renal failure. All patients were given a single 160 mg dose of sotalol orally and their sotalol serum levels were determined after 4, 6, 8, 10 and 12 hours. The elmination of sotalol was distinctly slower as the serum creatinine concentration rose. The half-lives, calculated graphically, were in lenear ratio to the serum creatinine values (r = 0,91; p less than 0.001). In accordance with the results, it is probable that sotalol accumulates in chronic renal insufficiency. Since beta-blockers may impair renal function, even in therapeutic concentrations, the dosage of sotalol, in particular, must be reduced in patient with kidney disease.