Dual Antiplatelet Therapy Prior to Expedited Carotid Surgery Reduces Recurrent Events Prior to Surgery without Significantly Increasing Peri-operative Bleeding Complications.

OBJECTIVE: A daily Rapid-Access TIA Clinic was introduced in 2008, where symptomatic patients were started on 75 mg aspirin + 40 mg simvastatin by the referring doctor, before attending the clinic. Following clinic assessment, patients with 50-99% stenoses were transferred to the vascular unit for carotid endarterectomy (CEA). In two audits (n = 212 patients), the median delay from transfer to the vascular unit to undergoing CEA was 3 days, during which time 28 patients (13%) suffered recurrent neurological events. It was hypothesized that early introduction of dual antiplatelet therapy (by adding clopidogrel 75 mg once parenchymal haemorrhage was excluded in the TIA clinic) might significantly reduce recurrent events between transfer to the surgical unit and undergoing CEA. METHODS: Prospective audit in 100 consecutive, recently symptomatic patients receiving dual antiplatelet therapy. Endpoints were: prevalence of recurrent events between transfer from the TIA clinic and undergoing CEA; rates of spontaneous embolization prior to undergoing CEA; and prevalence of haemorrhagic complications RESULTS: The median delay from symptom to CEA was 8 days (IQR 5-15). The median delay between transfer from the TIA clinic to CEA was 3 days (IQR 2-5), during which time three patients (3%) suffered recurrent TIAs. This represents a fivefold reduction compared with previous audit data (OR 4.9, 95% CI 1.5-16.6, p = .01) and was matched by a fourfold reduction in the prevalence of spontaneous embolization from 39/189 (21%) previously to 5/83 (5%) in the current audit (OR 4.1, 95% CI 1.5-10.7, p = .0047). The 30-day death/stroke rate was 1%. There were three haemorrhagic complications: stroke caused by haemorrhagic transformation of an infarct; exploration for neck haematoma; and debridement and skin grafting for spontaneous shin haematoma. CONCLUSION: Early introduction of dual antiplatelet therapy was associated with a significant reduction in recurrent neurological events and spontaneous embolization prior to CEA, without incurring a significant increase in major peri-operative bleeding complications.

Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naïve HIV-1-infected patients (the ARTEN study).

OBJECTIVES: Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV-1-infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV-1-infected patients) study compared prospectively ritonavir-boosted atazanavir (ATZ/r) 300 mg/100 mg once daily (qd) with immediate release nevirapine (NVP) 200 mg twice daily or 400 mg qd, each combined with fixed-dose tenofovir 300 mg/emtricitabine 200 mg qd in 569 ARV-naïve HIV-1-infected patients. Lipid profiles and CR from baseline to week 48 are reported. METHODS: Changes from baseline to week 48 in fasting plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), TC:HDL-c ratio, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and total triglycerides (TG) were determined. The Framingham algorithm was used to estimate CR. Analysis was by intention-to-treat (ITT) with last observation carried forward (LOCF) for missing data. RESULTS: At week 48, NVP treatment resulted in significantly greater mean increases from baseline in TC (24.4 vs. 19.6 mg/dL; P=0.038), HDL-c (9.7 vs. 3.9 mg/dL; P<0.0001), LDL-c (15.0 vs. 10.4 mg/dL; P=0.011) and ApoA1 (0.18 vs. 0.08 g/L; P<0.0001) but not ApoB (0.02 vs. 0.02 g/L) compared with ATZ/r treatment. ATZ/r use was associated with higher mean TG increases (27.80 vs. 0.02 mg/dL; P=0.0001). Significantly greater mean decreases in TC:HDL-c and ApoB/ApoA ratios were observed with NVP vs. ATZ/r (P=0.0001 and P=0.008, respectively). Framingham CR scores were low and comparable between the arms, with only a slight mean increase from baseline to week 48 of 0.70 for NVP and 0.80 for ATZ/r [difference -0.069; 95% confidence interval (CI) -0.61 to 0.46; P=0.80]. CONCLUSIONS: In ARV-naïve patients with low CR at the outset, NVP showed a potentially less atherogenic lipid profile compared with ATZ/r.

Transforming growth factor (TGF)-beta mimics and anti-TGF-beta antibody abrogates the in vivo effects of cyclosporine: demonstration of a direct role of TGF-beta in immunosuppression and nephrotoxicity of cyclosporine.

BACKGROUND: Cyclosporine (CsA) has been shown to induce the expression of transforming growth factor (TGF)-beta both in vitro and in vivo. It is hypothesized that the efficacy as well as the side effects of CsA are mediated by TGF-beta. This study was planned to investigate whether anti-TGF-beta mitigated and TGF-beta reproduced the in vivo effects of CsA to directly prove this hypothesis. METHODS: B6AF1 (H2b/k.d) mice were divided into groups and received the following: CsA, vehicle (olive oil), CsA + anti-TGF-beta1 antibody, TGF-beta1, or vehicle phosphate-buffered saline/bovine serum albumin. All studies were carried out at 10 and 28 days after the last day of CsA administration with the exception of the exogenous TGF-beta experiments, which were performed 5 days after exogenous TGF-beta administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [3H]thymidine uptake; TGF-beta protein levels were quantified by ELISA. TGF-beta, collagen, and fibronectin gene expression was studied using reverse transcriptase-polymerase chain reaction, and histopathological analysis was made on periodic acid-Schiff- and trichrome C-stained thin kidney sections. RESULTS: CsA treatment resulted in decreased ex vivo proliferation of splenocytes, an increase in TGF-beta protein in the sera, and renal histopathological changes including tubular swelling, vacuolization, thrombotic microangiopathy, and increased expression of TGF-beta, collagen and fibronectin genes. All of these findings were blocked by anti-TGF-beta antibody. CONCLUSION: The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-beta levels and suggests that TGF-beta at least in part mediates CsA's beneficial and detrimental effects.

Tacrolimus induces increased expression of transforming growth factor-beta1 in mammalian lymphoid as well as nonlymphoid cells.

BACKGROUND: We and others have reported that cyclosporine (CsA) induces increased expression of transforming growth factor-beta1 (TGF-beta1) in vitro as well as in vivo. In view of similarities between tacrolimus and CsA with respect to immunosuppressive mechanisms, we determined whether tacrolimus, in a fashion similar to CsA, induces TGF-beta1 hyperexpression in mammalian cells. METHODS: We studied the induction of TGF-beta1 mRNA by tacrolimus using reverse transcription-polymerase chain reaction and Northern blot analysis in normal human T cells and A-549 cells (human lung adenocarcinoma cell line), a cell line used to study the biology of TGF-beta and the induction of TGF-beta1 by CsA. We also measured the induction of TGF-beta1 protein by tacrolimus in activated human T cells, peripheral blood mononuclear cells, and A-549 cells, using sandwich enzyme-linked immunosorbent assay. RESULTS: A significant increase in the TGF-beta1 mRNA expression was observed after treatment of T cells or A-549 cells. Tacrolimus treatment resulted also in heightened production of TGF-beta1 protein by activated T cells, A-549 cells, or peripheral blood mononuclear cells activated with anti-CD3, phytohemagglutinin, and concanavalin A. CONCLUSIONS: Our observations that tacrolimus stimulates TGF-beta1 hyperexpression in mammalian cells suggest a unifying mechanism for the immunosuppressive as well as nephrotoxic properties of tacrolimus, as the multifunctional TGF-beta1 is a potent immunosuppressive and fibrogenic cytokine.

Providing evidence of efficacy for a new drug.

There are many issues to consider when designing an efficacy package for drug registration. Generally in Europe and the United States, two or more confirmatory trials demonstrating efficacy (p < 0.025, one-tailed) of the test treatment versus a suitable control group must be conducted with a priori definition of a primary efficacy endpoint. Exceptions are possible, and there is always extensive discussion whenever less is proposed or more is required. Every aspect of the basic requirement can be questioned: number of trials; choice of control groups; selection of primary efficacy variables(s); levels of significance; one-tailed versus two-tailed test. These issues will be discussed, and justification is given when proposals are made for deviations from standard practice. Differences between Europe and the U.S. are discussed for certain disease entities. Because the assessment of the weight of evidence in favour of a drug effect is difficult to quantitate, if not impossible, no definitive guidance can be given that is suitable for all circumstances and countries.

Short report: ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. The East Germany Collaborative Trial Group.

OBJECTIVE: To identify appropriate dosages of ramipril and hydrochlorothiazide (HCT) when given in combination once a day for the treatment of essential hypertension. DESIGN: A 2- or 4-week placebo run-in followed by 6-week, double-blind, parallel-group phase: 4 x 3 factorial (2.5, 5 and 10 mg ramipril; 12.5 and 25 mg HCT; all six combinations; placebo). SETTING: Office practice (21 centres). PATIENTS AND PARTICIPANTS: Patients with mild-to-moderate essential hypertension (World Health Organization stage I-II; supine diastolic blood pressure 100-115 mmHg in last 2 weeks of run-in): 581 enrolled, 534 randomly assigned to double-blind therapy and 517 completed. MAIN OUTCOME MEASURES: Reduction in supine and standing blood pressure. RESULTS: In pairwise comparisons, the combinations of 5 mg ramipril with 12.5 and 25 mg HCT and 10 mg ramipril with 12.5 mg HCT consistently produced significantly greater blood pressure reductions than their respective components. Response surface analyses were performed, and a stairstep model was constructed to characterize the shape of the dose-response surface. The combinations involving 5 and 10 mg ramipril with 12.5 and 25 mg HCT were again more effective than their components. Withdrawals and adverse effects were minimal for all treatments. A large drop in serum potassium was observed on 25 mg HCT, but not on combination therapy. Addition of ramipril appeared to reduce the hyperuricaemic effect of HCT. CONCLUSIONS: Several dosage combinations of ramipril plus HCT produced significantly greater blood pressure reductions than the monotherapies at the same dosages. Overall, the combination of 5 mg ramipril and 25 mg HCT gave the best mean reduction. Combination therapy with ramipril plus HCT was safe and effective for patients with mild-to-moderate essential hypertension.

Combination of ramipril and hydrochlorothiazide in the treatment of mild to moderate hypertension--Part 2: An open long-term study of efficacy and safety.

In an open, multicenter extension of a short-term study, 159 patients with mild to moderate hypertension were treated with either ramipril monotherapy or a combination of ramipril and hydrochlorothiazide for up to 1 year. Patients started with either 5 mg ramipril once daily (responders in the short-term study) or a combination of ramipril 5 mg plus hydrochlorothiazide 25 mg once daily. The dose could be adjusted and nonresponders to ramipril monotherapy could have hydrochlorothiazide added. In the 38 patients treated with ramipril monotherapy, the largest drop in mean blood pressure (BP) had already occurred in the previous short-term study; from Week 2 in the long-term study, the BP remained stable with means below 150/90 mmHg. In the 83 patients treated with the combination for 50 weeks or more, mean BP continued to decrease until around Week 10 in the long-term study while therapy was being adjusted. Thereafter, it also remained stable with means below 150/85 mmHg. Both treatment groups showed good mean reductions at end point, as did the group of 38 patients treated with the combination for less than 50 weeks. High response rates (84-95%) were seen in all groups at end point. The combination was well tolerated and the efficacy of ramipril in combination with hydrochlorothiazide was maintained over the 1-year period of investigation.

Combination of ramipril and hydrochlorothiazide in the treatment of mild to moderate hypertension: Part 1--A double-blind, comparative, multicenter study in nonresponders to ramipril monotherapy.

In a parallel-group multicenter study, the efficacy and safety of combination therapy with ramipril 5 mg plus hydrochlorothiazide 25 mg were compared double-blind with those of 5 mg and 10 mg ramipril monotherapy in patients with mild to moderate hypertension who had not responded adequately to ramipril 5 mg alone. Patients were initially treated single-blind for 1 week with ramipril 2.5 mg and 3 weeks with ramipril 5 mg. Of 240 patients enrolled, 165 were subsequently classed as nonresponders (diastolic blood pressure > 90 mmHg) and were randomized to one of the three double-blind treatments for a further 4 weeks. In the double-blind phase, the mean reductions in supine systolic and diastolic blood pressures at end point were significantly greater in the 5 mg plus 25 mg combination group (11.6/10.6 mmHg) than in the groups receiving ramipril 5 mg (6.2/5.9 mmHg; both p < 0.01) and ramipril 10 mg (7.4/7.1 mmHg; both p < 0.05). The proportion of responders at end point was also higher for combination therapy (72%) than for monotherapy (48% for ramipril 5 mg and 62% for ramipril 10 mg). All three treatments were well tolerated. Analysis of laboratory values revealed no clinically important changes.

The analysis of a multiple-dose, combination-drug clinical trial using response surface methodology.

We consider the situation where a multiple-dose, combination-drug clinical trial is conducted to identify one or more combinations that satisfy regulatory requirements. Generally, these requirements involve a compound hypothesis with multiple comparisons. The min test has been shown to be an optimal alpha-level test for testing a single combination drug. Analysis procedures in a multiple-dose, combination-drug study have typically involved classical ANOVA models or multiple regression models in a response surface methodology (RSM) framework. An inferential procedure based on an ANOVA model uses a screening test to address multiple comparison issues and multiple min tests to explicitly identify combinations satisfying regulatory requirements. An exploratory procedure based on RSM modeling is used to build a segmented linear model and a stairstep linear model to describe dose-response relationships. The two procedures are mutually supportive of one another in providing a broader assurance in the identification of effective combinations.

Five-drug antiemetic combination for cisplatin chemotherapy.

A combination of metoclopramide, dexamethasone, droperidol, lorazepam, and diphenhydramine was used in prophylaxis of high-dose (greater than or equal to 100 mg/m2) or moderate dose (greater than or equal to 50 mg/m2) cisplatin. Sixty minutes prior to starting cisplatin, 16 mg dexamethasone, 50 mg diphenhydramine, and 0.5 mg lorazepam were given orally (PO). Droperidol 1 mg was given intramuscularly (IM) 15 minutes prior to beginning cisplatin. Repetitive doses of intravenous (IV) metoclopramide, 2 mg/kg in 75 ml 5% dextrose in water over 15 minutes was given 30 minutes prior to, and at 1 1/2, 4 1/2, and 7 1/2 hours after beginning cisplatin chemotherapy. Only patients with nausea and/or vomiting received subsequent doses of 2 mg/kg metoclopramide IV every 3 hours as needed. Patients refractory to metoclopramide were given 1 mg droperidol IM and 50 mg of diphenhydramine PO every 6 hours. There were 19 men and 9 women with a median age of 58 (range 31-75) years. Complete protection from nausea and vomiting in all courses of treatment occurred in 17 (61%) patients. In 63% and 70% of the 57 evaluable courses, there was neither nausea nor vomiting, during the first 24 hours after cisplatin. When present, nausea was mild and the median number of vomiting episodes was 2 (range 1-3). This antiemetic regimen was well tolerated. Toxicities were mild and occurred in 3 patients (angioneurotic edema, transient episode of facial twitching, and heaviness of tongue, respectively). The 5-drug antiemetic combination can prevent cisplatin-induced nausea and vomiting in a majority of patients.

Antihypertensive efficacy, tolerance, and safety of ramipril in young vs. old patients: a retrospective study.

The efficacy, tolerance, and safety of ramipril, an angiotensin-converting enzyme inhibitor, were assessed in 502 patients from five multicenter, double-blind studies who had mild-to-moderate essential hypertension. Each study was designed with a 4-week placebo run-in phase followed by 6 weeks of treatment with ramipril or one of five other antihypertensive treatments. A total of 412 young patients (17-65 years of age) and 90 old patients (66-87 years) in these studies received single daily doses of 5 or 10 mg of ramipril. At the end point of treatment, mean reductions in supine systolic blood pressure (19.4 mm Hg in young patients, 17.8 mm Hg in old) were significantly different, whereas mean reductions in supine diastolic blood pressure (13.3 mm Hg in young patients, 12.5 mm Hg in old) showed no significant difference. The number of responders was similar in both age groups: 68.6% and 71.1% of young and old patients respectively. No clinically relevant trends were observed in biochemical and hematological variables. Ramipril was well tolerated by both young and old patients, and there was little evidence that it was less safe in the elderly.

Antihypertensive efficacy, tolerance, and safety of long-term treatment with ramipril in patients with mild-to-moderate essential hypertension.

A total of 555 hypertensive patients took part in a 2-year multicenter, open-label study to determine the efficacy, tolerance, and safety of long-term therapy with ramipril. In the beginning, all patients were to receive 5 mg of ramipril/day. The dosage was then adjusted in accordance with response to treatment and ranged from 1.25-20 mg of ramipril daily. Of these patients, 129 also received 25 mg of hydrochlorothiazide daily at some point during the trial. To evaluate whether tolerance to ramipril developed during long-term treatment, a subgroup of 202 patients was analyzed for efficacy maintenance. Prior to enrolling in the 2-year study, these patients had received ramipril monotherapy in a short-term, double-blind study and had been classified as responders, i.e., their diastolic blood pressure had been maintained at less than or equal to 90 mm Hg. At the end of 104 weeks of treatment, 45.9% of patients were on 2.5 mg of ramipril alone and 43.6% were on 5 mg of ramipril alone. Only four patients required the addition of 25 mg of hydrochlorothiazide. No clinically important changes occurred, and kidney function was well maintained. The most frequently reported adverse events excluding intercurrent illnesses were dizziness/vertigo (6%), asthenia (4%), nausea (3%), headache (2%), and abdominal pain, gastrointestinal disorder, rash, and increased cough (1% each). Ramipril was safe, effective, and well tolerated in the long-term treatment of patients with mild-to-moderate essential hypertension.

Efficacy and safety of ramipril in combination with hydrochlorothiazide: results of a long-term study.

Hypertensive patients from a double-blind study comparing 5 mg of ramipril, 10 mg of ramipril, and 5 mg of ramipril + 25 mg of hydrochlorothiazide (HCTZ) were enrolled in an open 1-year extension study with ramipril and concomitant HCTZ. The starting dose of ramipril was 5 mg/day. Patients were given 25 mg of HCTZ in addition only if their diastolic blood pressure (DBP) was higher than 90 mm Hg. During treatment, the investigator was permitted to adjust the dosage of ramipril and HCTZ according to BP response and tolerance. A total of 159 patients were included in the 1-year study (86 men, 73 women, mean age of 54 years). One hundred twenty-one of the 159 patients received the combination of ramipril + HCTZ at some point in the study, 83 of them for more than 50 weeks. Thirty-eight patients were treated with ramipril alone over the entire study. In patients treated with ramipril monotherapy throughout the study, the largest drop in blood pressure occurred before visit 1. In patients treated with ramipril + HCTZ for greater than or equal to 50 weeks, the mean blood pressure continued to fall up to around week 10, while the therapy was being adjusted. Subsequently, the mean blood pressures remained low and fairly stable in both treatment groups. Similar results were seen in patients treated with the combination for less than 50 weeks. Adverse events were reported in 11 of the 38 patients in the ramipril group, in 22 of 83 patients treated with the combination for more than 50 weeks, and in 9 of 38 patients treated with the combination for 50 weeks or less. The analysis of the laboratory values revealed no general deterioration. It can be concluded that ramipril alone and in combination with HCTZ is an effective and safe drug for the long-term treatment of essential hypertension.

Carcinogenic and genotoxic activity of extracts from contaminated sediments in western Lake Ontario.

In order to investigate the putative association between chemical contamination in western Lake Ontario and high prevalences of fish tumors, sediments from Hamilton Harbour and Oakville Creek in Lake Ontario and reference sites in non-polluted areas of Ontario, Canada were collected and extracted for organic contaminants. Sediment extracts from Hamilton Harbour had the highest concentrations of polychlorinated biphenyls and organochlorine insecticides (ppb) and contained very high concentrations of polynuclear aromatic hydrocarbons (ppm); although the levels of these compounds varied widely with sampling location in the harbor. A sediment extract from Hamilton Harbour was mutagenic in the Ames bacterial assay, both with and without microsomal activation. High levels of aromatic DNA adducts were induced in cultured mouse C3H1OT1/2 cells after in vitro exposure to Hamilton Harbour sediment extract. In two separate carcinogenicity experiments involving a sac fry microinjection assay with rainbow trout (Oncorhynchus mykiss), Hamilton Harbour sediment extract induced hepatocellular carcinomas in fish. No hepatic neoplasms were observed in fish that had been treated with sediment extract from Oakville Creek, or with extract from a reference sediment. The significance of these results is discussed in relation to the distribution of neoplasms in feral fish within western Lake Ontario.

Clinical trial of high-dose oral medroxyprogesterone acetate in the treatment of metastatic breast cancer and review of the literature.

Recent studies have suggested that there are benefits from the use of high-dose parenteral medroxyprogesterone acetate (MPA) in the treatment of metastatic breast cancer. The present study was designed to assess the efficacy and toxicity of high-dose oral MPA in women with clinical parameters suggesting potentially hormonally sensitive metastatic breast cancer. The first 28 patients received 800 mg/day, and 11 of them had received no previous hormone (NPH) therapy. The response rate (complete plus partial) was 63% for those receiving NPH and 12% for those receiving previous hormone (PH) therapy. Toxicity was significant at these doses, especially for women treated for more than 5 weeks. Toxic effects included excessive weight gain, Cushingoid facies, worsening of diabetes mellitus, and other stigmata suggestive of hypercorticism. Nineteen other patients were treated at 400 mg/day with a 60% response rate for 10 NPH patients and 44% for patients with PH treatment. Toxicity was less severe in these patients. The median time to treatment failure was 23 weeks, and to survival, 119 weeks for all treated patients. Moderately high (400 mg/d) and higher dose (800 mg/d) oral MPA are capable of inducing reasonable response rates in patients with NPH treatment. The toxicity of these regimens was significant--profound weight gain was dose limiting in some patients. While effective, high-dose oral MPA is unlikely to supplant tamoxifen as first-line therapy in metastatic breast cancer.

A double-blind study to compare the efficacy, tolerance and safety of two doses of the angiotensin converting enzyme inhibitor ramipril with placebo.

In a randomized, double-blind trial, 2 doses of ramipril (2.5 and 5 mg once daily) were compared with placebo in patients with mild to moderate essential hypertension. A 2-week placebo run-in phase was followed by 4 weeks of treatment. Eighty-six patients entered the study and 17 withdrew during the course of the study. Both doses of ramipril appeared to be more effective than placebo in reducing blood pressure, but significant differences between 2.5 mg of ramipril and placebo were not found in any statistical analyses. In the endpoint analyses (taking the last measurement from each patient), the patients receiving 5 mg of ramipril had significantly larger decreases in blood pressure than the patients receiving placebo (t tests: standing systolic, p less than 0.001; supine diastolic, p less than 0.05; standing diastolic, p less than 0.05) and also than the patients receiving 2.5 mg of ramipril (standing systolic, p less than 0.05). It appears from the results of this study that the minimum effective dosage of ramipril is 5 mg once daily. No clinically relevant side effects or clinically relevant changes in laboratory values were observed.

Oral contraceptive use and blood pressure in a German metropolitan population.

The relationship between blood pressure (BP) and oral contraceptive (OC) use in women has been examined with the data from the Munich Blood Pressure Study (MBS), a cross-sectional study with follow-up of a random sample of 3198 Munich citizens aged 30-69 (response rate 69.3%). Multiple linear and logistic regression analyses were run with BP as the dependent variable and age, OC use, obesity, alcohol consumption, and smoking habit as the independent variables. All second and third order interactions between the independent variables were tested during a backward stepping procedure. OC use appeared as a significant main effect in most of the analyses. The coefficient of the OC variable was about 3 in the linear regression analyses for both systolic BP and diastolic BP, indicating an increase of about 3 mmHg in the systolic and diastolic BP of the OC users. An analysis of the change in BP after one year in relation to change in OC user status has also been made. It was observed that women ceasing to use OC had a clear decrease in BP while those starting to use OC had on average an increase in BP.

PIP: A random sample of 3198 persons aged 30-69, as part of the Munich Blood Pressure Study, revealed that oral contraceptive use raises blood pressure. Data were collected from December 1980 to May 1981, and from January to March 1982, on the same subjects. Each participant was interviewed about risk factors for about 30 minutes in a sitting position, and his pressure measured 3 times afterward with the Hawksley Random Zero sphygmomanometer. There were 113 women using pills, 32 different brands. Multiple linear and logistic regression analyses were run with blood pressure as the dependent variable, and age, pill use, obesity, alcohol consumption, and smoking habit as the independent variables. Pill use appeared as a significant main effect in most of the analyses. Based on the coefficient of the pill variable in the linear regression, an increase of about 3 mm Hg in both systolic and diastolic pressures was demonstrated. It was observed that women stopping oral contraception had a clear decrease of 7.2 mm Hg systolic, and 2.8 mm Hg diastolic pressure, and those beginning oral contraception appeared to have an increase in pressure, if the results were adjusted for regression toward the mean. Even a slight increase of 3 or 4 mm Hg in blood pressure, when added to other risk factors such as obesity, smoking, and age, may increase the overall risk for cardiovascular disease considerably.

[Office visits and physical well-being of hypertensive patients. Results of the Munich blood pressure study]. / Arztbesuche und physisches Befinden von Hypertonikern.

The relationship between the frequency of physician visits, self-reported health of hypertensives and the awarenes, treatment and control of hypertension has been investigated, using data from the Munich Blood Pressure Study I (1980/81), a study with 2216 participants of a random sample of the adult population of Munich (30-69 y.). As hypothesized, the chance of detecting and treating high blood pressure increased with the frequency of physician visits. However, frequent physician visits did not guarantee an effective treatment of hypertension. 33% of the treated hypertensives who visited their physicians more than ten times in the preceding year failed to show normotensive or borderline blood pressure values. Additionally it could be seen that the awareness, treatment and control of hypertension was closely related to the number of self-reported chronic diseases and self-reported physical well-being. A relationship between social variables and treatment status was only observed for men: among hypertensive men, the proportion who were treated increased with the number of years of education but decreased with the number of household members.

Effect of tryptophan on informosomal and polyribosome-associated messenger RNA in rat liver.

The possible role that informosomal mRNA may play in the stimulation of hepatic protein synthesis induced by the acute administration of tryptophan was investigated. L-tryptophan (30 mg/100 g body weight) tube-fed to rats induced an increase (20%) in the amount of polyribosome-associated poly(A+)mRNA in the liver within 1 hour. On the other hand, the amount of the informosomal poly(A+)- mRNA revealed no significant increase or decrease. The size of the increase in the polyribosome-associated poly(A+)mRNA pool was equal to the entire amount of informosomal poly(A+)mRNA present in the hepatic cells. Therefore it was concluded that the failure to detect a significant decrease in the size of the informosomal mRNA pool indicated that the increase in the polyribosome-associated poly(A+)mRNA must be due to a different mechanism, such as enhanced nuclear-to-cytoplasmic translocation of nuclear poly(A+)mRNA, which had been reported earlier. To determine whether any qualitative or quantitative changes occurred in the RNA sequences along with the increase in poly(A+)mRNA following tryptophan administration, DNA/RNA hybridization studies were conducted by using hepatic polyribosome-associated poly(A+)- mRNA from tryptophan-treated and control rats. Although qualitatively no new species of mRNA were detected in the mRNA from tryptophan-treated rats, kinetic analysis of the hybridization curves indicated that there was a shift or accumulation of hepatic poly(A+)mRNA belonging to the intermediate and possibly the high frequency classes of polyribosome-associated poly(A+)mRNA in the livers of the tryptophan-treated rats.