Sildenafil in the treatment of erectile dysfunction in men with diabetes: demand, efficacy and patient satisfaction.

The objective of this study is to describe the eligibility, consumption, efficacy and patient satisfaction when treating men with diabetes with Sildenafil. The study is a prospective, self-reported, flexible-dose study. In total, 45 patients with diabetes (type 1 or 2), complaining of erectile dysfunction, were treated with Sildenafil over a 12-week period. Efficacy was assessed using a patientlog, a general satisfaction questionnaire and the International Index of Erectile Function (IIEF). Of 326 men, 192 reported erectile dysfunction, 79 did not fulfil the criteria for Sildenafil treatment and 49 declined to participate. In the group of 33 (age 45-75 y, mean+/-s.d.: 58.1+/-7.2) completing the study, erectile function was significantly improved (P < 0.0001). A total of 12 patients (36.4%) experienced no treatment effect at all. Eligibility and desire for treatment was low. Sildenafil is far from being a 'cure all' in the treatment of ED in diabetes.

Interaction of sulfonylureas and exercise on glucose homeostasis in type 2 diabetic patients.

OBJECTIVE: To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. RESEARCH DESIGN AND METHODS: Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. RESULTS: Heart rate, VO2, and lactate responses to exercise were comparable (P > 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P < 0.05). At the start of exercise, glucose concentrations were similar between experiments (P > 0.05). The rate of decrease in glucose during exercise was higher (P < 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P < 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P < 0.05). In contrast, glucose clearance was identical (P > 0.05). CONCLUSIONS: In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise.

Chromosome aberrations and pharmacokinetics in patients receiving tauromustine as either a single or a repeated dose.

Tauromustine (TCNU) is an exploratory drug that has demonstrated activity in various solid tumors. We examined chromosome aberrations and plasma levels of the drug in two groups of patients receiving either a single dose of 130 mg/m2 or 40 mg/m2 on 3 consecutive days. Peak plasma concentrations (mean +/- SD) were obtained at a similar time after both treatments, i.e., at 38 +/- 25, 32 +/- 24, 28 +/- 14, and 40 +/- 26 min after administration of 130 mg/m2 on day 1 and after that of 40 mg/m2 on days 1, 2, and 3, respectively. In addition, the cumulative area under the curve (AUC value) determined after administration of 40 mg/m2 x 3 was similar to that noted after treatment with a single dose of 130 mg/m2, i.e., 180 and 179 micrograms min ml-1, respectively. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40 mg/m2 producing 5.5% CAs and 130 mg/m2 yielding 20.9% CAs at 24 h after treatment. In addition, although the drug concentration declined to a level under the detection limit between the daily treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180 +/- 62.8 and 179 +/- 115 micrograms min ml-1, respectively.

Soluble interleukin-2 receptor and soluble CD8 antigen levels in serum from patients with non-resectable lung cancer.

In a preliminary longitudinal study two women with histologically verified adenocarcinoma of the lung, without simultaneous infectious or inflammatory conditions, were seen every 2 weeks until death. In one of the patients serum soluble interleukin-2 receptor (sIL-2R) levels rose progressively while the levels for the other patient increased during the second half of the observation period. Serum soluble CD8 antigen (sCD8 Ag) showed a pattern dissimilar to the one for sIL-2R. In a retrospective cross-sectional study circulating levels of sIL-2R and sCD8 Ag were measured before explorative thoracotomy in a total of 65 patients with histologically proven non-resectable carcinoma of the lung. The sIL-2R levels were significantly increased independently of histological subclassification while sCD8 Ag was increased only in patients with small-cell lung cancer. There was no correlation between pre-operative values and length of survival.

Biological assays for interleukin 1 detection. Comparison of human T lymphocyte, murine thymocyte and NOB-1 assays.

Various biological assays are used for qualitative and quantitative measurements of interleukin 1 (IL-1) in supernatants from cell cultures. The purpose of the present study was to compare the specificity and variability of three cellular IL-1 bioassays: the PHA co-stimulatory human T lymphocyte proliferation assay, the PHA co-stimulatory murine thymocyte (THY) proliferation assay, and the 2-step NOB-1 conversion assay. Three different ways of IL-1 unit calculation, based on a semi-logarithmic plot, a double-logarithmic plot, or a probit-analysis plot were also compared. The T lymphocyte assay can be used only to demonstrate qualitative differences in IL-1-like activity, whereas the THY assay is excellent as a semi-quantitative assay, with a low intra-assay variability, but also with a low specificity. The NOB-1 assay is probably more specific with respect to IL-1 measurement, although, with a high intra-assay variance. The THY and the NOB-1 assays both have a high inter-assay variability, and measurement of samples from longitudinal clinical studies must be done in one and the same analysis if quantitative differences are to be illustrated. Probit analysis for unit calculation is recommended. To generate a consensus view as to assay performance, collaborative laboratory studies are needed.

TCNU in adenocarcinoma of the lung: a phase II study with divided doses.

TCNU, a new water soluble nitrosourea, has in preclinical studies shown higher activity when given as divided doses compared with one day single treatment. Accordingly, 38 consecutive patients with non-resectable adenocarcinoma of the lung received TCNU 40 mg/m2 p.o. daily for three days every 4 weeks. The response rate among 37 evaluable patients was 14%, median response duration was 17 weeks (range 5-57+ weeks) and median survival 22 weeks (range 3-96+ weeks). Hematologic toxicity was pronounced, especially thrombocytopenia, and 57% of the patients had WHO grade 3 or 4 WBC or platelet count. Overall, dose reduction or delay of treatment due to hematologic toxicity was necessary in 66% of the patients. This, together with the limited activity, renders TCNU in the present dose and schedule unsuitable for further investigations in this disease entity.

Pharmacokinetics of tauromustine in cancer patients. Phase I studies.

The pharmacokinetic properties of tauromustine (TCNU) were studied in 31 cancer patients who participated in phase I trials. The patients received single oral doses of tauromustine in the range of 20-170 mg/m2. Plasma samples were taken over 24 h after administration and analysed for tauromustine by reversed-phase liquid chromatography. Parent TCNU could be demonstrated in the plasma of all patients. Its absorption was rapid (tmax = 38 +/- 22 min), the half-life was 57 +/- 22 min (mean +/- SD), and maximal concentration (Cmax) and AUC values were linearly related to the dose level. Thus, our study does not indicate dose-dependent pharmacokinetics for the drug in the range of 20-170 mg/m2. Thrombocytopenia was the dose-limiting toxicity of TCNU; the reduction of platelet counts appeared to be linearly related to the log dose and Cmax and AUC values. TCNU appears to exhibit pharmacokinetic properties that are different from those of other nitrosoureas, which might be important for the clinical effect of the drug.

A phase I clinical evaluation of 1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]-1-nitrosou rea (TCNU).

TCNU (1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]-1-nitrosour ea) is a newly developed water-soluble nitrosourea based on the endogenous aminoethanesulphonic acid taurine. TCNU was in an extended phase I trial given orally every 4-8 weeks using a stepwise dose escalation from 20 to 170 mg/m2. One hundred and thirty-nine patients received a total of 323 courses. Minor haematologic toxicity was observed in 12 patients treated at dose levels less than 70 mg/m2. Thrombocytopenia WHO grades 1-4 occurred in 43% (55/127) and leucopenia WHO grades 1-3 in 45% (57/127) of the patients treated at dose levels greater than or equal to 70 mg/m2. Nausea and vomiting was recorded in about half the patients despite the use of metoclopramide. At the initial dose level 41 patients received greater than or equal to 3 courses of TCNU. Cumulative leucopenia and thrombocytopenia occurred in 3/41 and in 12/41 patients, respectively, while reversible hepatotoxicity was observed in two patients. Antitumour activity was observed in patients with advanced squamous cell, adeno- and large cell carcinoma of the lung. The recommended starting doses for phase II trials with TCNU are as follows: heavily pretreated patients 90 mg/m2, minimally/-moderately pretreated patients 110 mg/m2 and previously untreated patients 130 mg/m2 with TCNU given every 4-5 weeks, the repeated doses and intervals being adjusted to individual tolerance.