Pharmacokinetics and hemodynamic effects of long-term nisoldipine treatment in hypertensive patients

In six patients with essential hypertension, the pharmacokinetics of nisoldipine were investigated before, during, and after 4 weeks of treatment. On day 1, nisoldipine was infused intravenously (i.v. 2 mg in 2 h); on day 2, oral nisoldipine treatment (10-mg tablets twice daily) was started for 4 weeks. During this period, patients came to the hospital six times, on which occasions blood samples were taken for the determination of trough and peak concentrations of nisoldipine. After 4-week treatment, the infusion experiment was repeated. In the first infusion experiment, systemic clearance was 1.02 +/- 0.23 L/min (mean +/- SD), terminal half-life (t1/2) was 15.4 +/- 6.7 h, and volume of distribution was 5.9 +/- 1.8 L/kg. After 4 weeks, these parameters had not changed significantly. Nisoldipine lowered blood pressure (BP) in all patients, whereas forearm blood flow and heart rate (HR) increased. Neither were the hemodynamic changes different after the oral treatment period, although basal BP was lower than before oral treatment. No accumulation of nisoldipine occurred during the 4-weeks treatment period.     

The influence of diet and dimethylhydrazine on the large intestine of vervet monkeys: scanning and transmission electron microscope studies

The study was designed to identify diet and carcinogen-dependent ultrastructural changes in the epithelium of macroscopically normal colonic mucosa in primates. Seventy adult female vervet monkeys were divided into seven equal treatment groups. Four received a Western high-fat low fibre diet (WD), two a prudent low-fat higher fibre diet (PD) and one a control low-fat high fibre diet (CD). Three groups (2 WD, 1 PD) received dimethylhydrazine intramuscularly at 14 day intervals. After 18 months, monkeys of two groups on the WD were transferred to the PD (WD----PD) and 30 months later all were killed. Mucosae of caecum, colon transversum and rectum were examined by scanning and transmission electron microscopy and showed close similarity to that of humans. Rectal mucosae showed increased surface goblet cell secretory activity, mucin production and microvillar changes related to WD and WD----PD. The enhancing effect of a carcinogen on ultrastructural changes such as cellular pleomorphism, cytoplasmic interbridging, nuclear and nucleolar irregularities and appearance of argentaffin cells in the free surface epithelium were noted predominantly in high-fat treated animals. Such changes observed in the upper part of crypt, orifice and free surface epithelium can be characteristic for precancerous change and could be utilised practically in the detection of precursor lesions of the colon.     

Liver transplantation: patients' experiences

The Dutch orthotopic liver transplant programme was evaluated recently. This article focuses on the physical functioning, the pattern of activities, the social functioning and the level of wellbeing of 31 transplant patients. Data were generated by means of questionnaires and interviews. The majority of the patients look upon themselves as 'healthy'. Their physical potential has greatly improved. Three-quarters of the patient group think they are able to go back to work. However, from the interviews it appears that one third of the patient group suffered from more or less serious psychological problems following transplantation.     

In vitro modulation of cisplatin cytotoxicity by sparsomycin inhibition of protein synthesis

Inhibition of protein synthesis can alter cellular responsiveness to the classical anticancer drugs. The in vitro response of Chinese hamster ovary (CHO) cells to cisplatin with or without sparsomycin (Sm) was studied with the use of [3H]leucine and [methyl-3H]thymidine incorporation and clonogenic assay. Pretreatment of exponentially growing CHO cells with 1 microgram Sm/ml for 3 or 5 hours decreased [3H]leucine incorporation by 20% and resulted in significant resistance to cisplatin (P = .005). Sm in a concentration of 10 micrograms/ml reduced [3H]leucine and [methyl-3H]thymidine incorporation after 3 hours by 92 and 84%, respectively, and resulted in potentiation of the cisplatin cytotoxicity (P = .004). This effect was the same in the case of nonproliferating cells (P = .005), while protection due to Sm (1 microgram/ml) was seen only during cell proliferation. Simultaneous incubation and postincubation with Sm proved to have much less or no potentiating effect on cisplatin. The mechanisms of both protection and potentiation are still not clear, but our data indicate that Sm is a promising drug for further studies on the modulation of the cancer cell response to classical anticancer drugs.     

Recombinant human interferon alpha increases oestrogen receptor expression in human breast cancer cells (ZR-75-1) and sensitizes them to the anti-proliferative effects of tamoxifen

Exposure of ZR-75-1 human breast cancer cells for 48 h to human recombinant interferon alpha (IFN alpha) resulted in increased expression of oestrogen receptors as measured in a whole cell binding assay. This effect was inversely proportional to dose being significant following treatment with 10-100 IU IFN ml-1 and was only observed at a low initial cell plating density. The extent of the increase in oestrogen receptor levels ranged from 1.2- to 7.2-fold following treatment with 10 IU IFN ml-1. No increase in progesterone receptor expression was observed under the same experimental conditions. Concentrations of IFN which increased oestrogen receptor levels had no effect on cell proliferation. IFN (500 IU ml-1) inhibited cell proliferation and the combination of this treatment with tamoxifen (2 microM) had a greater anti-proliferative effect than either drug alone although there was no evidence of synergism. However, a 5-day pretreatment of cells with IFN (10 IU ml-1) markedly sensitised them to the growth-inhibiting effect of a subsequent 6-day exposure to tamoxifen.