Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist.

The aim of this study was to investigate the relationships between plasma concentrations of losartan, an orally active angiotensin II inhibitor, its active metabolite EXP3174, and angiotensin II blockade. Six healthy subjects received single oral doses of 40, 80, or 120 mg losartan and placebo at 1-week intervals in a crossover study. Angiotensin II blockade was assessed by the blood pressure response to exogenous angiotensin II before and after losartan administration. EXP3174 reached higher plasma concentrations and was eliminated more slowly than its parent compound; its levels paralleled the profile of angiotensin II blockade closer than losartan. Inhibition of the pressure response was dose dependent. The Hill-shaped relationship between response and EXP3174 concentration (or time-integrated variables) approached a plateau with 80 mg. The dose-dependent increase in plasma renin and angiotensin II exhibited a considerable individual scatter. We conclude that losartan produces a dose-dependent, effective angiotensin II blockade that is largely determined by the active metabolite EXP3174.

The impact of a skin cancer control education package for outdoor workers.

OBJECTIVE: To assess the impact of Telecom's "Cover yourself against skin cancer" campaign, which used marketing techniques to promote sun protection behaviour. METHOD: Quasi-experimental design assessing change from before to after the campaign in intervention versus control groups. The unit of observation was a team of lines staff. Use of hats, shirts and shade were observed and prevailing weather conditions were noted. The major results are based on 525 observations before the campaign and 460 after it. RESULTS: The campaign led to a significant improvement in shirt use (P = 0.02), and to an improvement in overall protection (P = 0.02). The campaign had no effect on hat use, or on use of shade. CONCLUSIONS: The "Cover yourself against skin cancer" campaign was demonstrated to be an effective tool for getting outdoor staff to increase their sun protection. The implications for health and safety education are discussed.

Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.

BACKGROUND: The purpose of the present study was to assess the inhibitory effect of DuP 753, an orally active angiotensin II receptor antagonist, on the pressor action of exogenous angiotensin I and II in healthy male volunteers. METHODS AND RESULTS: In the first study (single-dose study), eight volunteers were included in a 2-day protocol repeated four times at 1-week intervals. In each phase, a different dose of drug (2.5, 5, 10, 20, or 40 mg) or placebo was given. The peak systolic blood pressure response to a test-dose of angiotensin I was determined serially before and after oral administration of DuP 753 by continuously monitoring finger blood pressure using a photoplethysmographic method. DuP 753 reduced the systolic blood pressure response to angiotensin I in a dose-dependent fashion. Three, 6, and 13 hours after the 40-mg dose, blood pressure response decreased to 31 +/- 5%, 37 +/- 6%, and 45 +/- 3% of the control values (mean +/- SEM, n = 7), respectively. In the second study, 29 volunteers were treated for 8 days with either a placebo or DuP 753 (5, 10, 20, or 40 mg p.o. q.d.) and challenged on the first, fourth, and eighth days with bolus injections of angiotensin II. Again, the inhibitory effect on the systolic blood pressure response to angiotensin II was clearly dose dependent. Six hours after 40 mg DuP 753, the systolic blood pressure response to the test-dose of angiotensin II was reduced to 37 +/- 7%, 40 +/- 4%, and 38 +/- 6% of baseline values (mean +/- SEM, n = 6) on days 1, 4, and 8, respectively. With this latter dose, there was still a blocking effect detectable 24 hours after the drug. Similar to angiotensin converting enzyme and renin inhibitors, DuP 753 induced a dose-dependent increase in plasma renin that was more pronounced on the eighth than on the first day of drug administration. In these normal volunteers, no consistent clinically significant side effects were observed. There was no evidence for an agonist effect. CONCLUSIONS: DuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.

Clinical development of moricizine as an antiarrhythmic agent.

The primary development of moricizine as an antiarrhythmic agent has occurred in the Soviet Union and the United States. The data in this presentation are based on the 1,844 subjects/patients (1,817 adults and 27 pediatric patients) who participated in 34 controlled studies and 3 uncontrolled compassionate-use programs conducted in the United States. Of the 1,817 adults, 443 received only placebo or comparative agents and 1,374 received moricizine in daily doses of 50 to 1,800 mg. A total of 1,190 adult patients (mean age 59 years) had ventricular arrhythmias classified as either benign (8%), potentially lethal (58%) or lethal (33%). Most patients had a history of greater than or equal to 1 cardiovascular disease, including coronary artery disease, previous myocardial infarction and congestive heart failure. Antiarrhythmic activity was assessed by four methods: 24-hour ambulatory electrocardiographic monitoring, programmed electrical stimulation, exercise tolerance tests, and global evaluation (only for some patients in the compassionate-use program). In addition, the effects of moricizine on symptoms associated with ventricular arrhythmias were assessed. The safety variables evaluated included adverse experiences, proarrhythmia, congestive heart failure, other cardiovascular effects, death, chest x-ray, ophthalmic examinations, neuroleptic phenothiazine effects and clinical laboratory tests.

Efficacy and safety of moricizine in patients with congestive heart failure: a summary of the experience in the United States.

Patients with ventricular premature beats (VPBs) and congestive heart failure (CHF) have an increased risk of sudden death, yet suppression of arrhythmia in this population is frequently complicated by proarrhythmia and by the negative inotropic effects of antiarrhythmic drugs. The purpose of this study was to evaluate the safety and efficacy of moricizine in patients with clinical CHF. The New Drug Application data base submitted to the Food and Drug Administration was analyzed. A total of 908 patients were treated with moricizine for ventricular arrhythmias; CHF developed in 49 of them (5.4%). Of the 908 patients, 374 had a history of CHF, 326 of whom tolerated moricizine for a mean of 97 +/- 217 days. New-onset CHF occurred only once (1/546 = 0.2%). Recurrence or exacerbation of clinical CHF during treatment with moricizine occurred in 48 of 374 patients (12.8%), 28 of whom continued to take moricizine with alteration in CHF therapy. The mean left ventricular ejection fraction (LVEF) of those patients in whom CHF developed was 26%. It is important to note that patients with a history of CHF were as likely to have suppression of VPBs (defined as greater than or equal to 75% reduction) as those without a history of CHF. In fact, suppression of arrhythmia was achieved as often in patients with LVEF less than 30% as in those with more preserved LVEF. Of the 374 patients with a history of CHF, 15 (4%) had a proarrhythmic event within 14 days of therapy. The incidence of sudden cardiac death in this group was 0.8%. These proarrhythmia rates compare favorably with those of other antiarrhythmic drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Complex ventricular arrhythmias associated with the mitral valve prolapse syndrome. Effectiveness of moricizine (Ethmozine) in patients resistant to conventional antiarrhythmics.

On the basis of epidemiologic studies, more than 10 million Americans have echocardiographic evidence of mitral valve prolapse. Although ventricular arrhythmias occur frequently (over 50 percent of patients with mitral valve prolapse), they rarely result in sustained ventricular tachycardia or sudden cardiac death. However, a common problem in clinical practice is a patient with mitral valve prolapse and symptomatic complex ventricular arrhythmias refractory or intolerant to both beta blockers and conventional type I antiarrhythmics. These drugs are known to have frequent side effects, toxicity, and proarrhythmic effects. In 17 patients with mitral valve prolapse who presented with symptomatic complex ventricular arrhythmias and who were unresponsive to an average of the three conventional agents, moricizine (Ethmozine) was effective in suppressing 90 percent of ventricular premature depolarizations, 99 percent of nonsustained runs of ventricular tachycardia, as well as all sustained runs of ventricular tachycardia, resulting in abolition of palpitations, dizziness, and syncopal episodes. Its efficacy as well as its low frequency of minor side effects makes it ideal for future consideration in the population with mitral valve prolapse, who are frequently young and may therefore require therapy for many years.

Elemental composition of fluid in the human Fallopian tube.

Relatively undisturbed samples of human oviduct fluid were obtained by aspiration into a Silastic catheter inserted through the fimbriated end of the oviduct during surgical laparotomy. The concentrations of Na, Cl, K, Ca, Mg, S and P were determined in picolitre aliquots of this fluid using X-ray spectrometry by electron probe excitation. Human tubal fluid has a unique elemental composition characterized by high concentrations of K and Cl, but low concentrations of Ca, relative to the range of normal human serum values. Na and Mg concentrations in oviduct fluid are similar to serum levels.

Elemental composition of rabbit antral fluid during preovulatory follicular swelling.

Electron probe microanalysis was used to determine the concentrations of Na, Cl, K Ca, Mg, S and P in samples of follicular fluid, ovarian vein serum and peripheral venous serum obtained from virgin rabbits at 2-h intervals up to 10 h after injection of hCG. Throughout this 10-h period the elemental composition of follicular fluid was essentially the same as that of blood serum. However, there was a significant drop in follicular fluid Ca relative to blood during the 10-h period which may reflect Ca involvement in the regulation of oocyte maturation. Significant differences were also found between follicles within rabbits for K and P concentrations.

Ouabain-sensitive fluid accumulation and ion transport by rabbit blastocysts.

1. By incubating 6-day post-coitum (p.c.) blastocysts in medium supplemented with either 20 mM-sucrose or 10 mM-KCl it was possible to show that the trophectoderm of the blastocyst prevents the concentration of K in the blastocoele fluid rising to external concentrations. 2. The concentrations of K in the blastocoele fluid are maintained predominantly by leakage of K from the trophoblast cells into the blastocoele and by ouabain-sensitive transport of K into the trophoblast cells from the blastocoele fluid. 3. Exposure of blastocysts to ouabain on the juxtacoelic, but not abcoelic, surface of the trophectoderm may inhibit blastocoele fluid accumulation.

Accumulation of steroids in rabbit preimplantation blastocysts.

The concentrations of progesterone, androstenedione, testosterone, oestrone and oestradiol were measured by radioimmunoassay in blastocysts and uterine fluid flushings collected from rabbits 110 to 159 h post coitum (p.c.). None of the blastocysts or uterine flushings contained detectable levels of androstenedione, testosterone or oestrone. All uterine flushings contained large amounts of progesterone and some of the flushings also contained oestradiol. A small amount of progesterone (approximately 7-5 pg/blastocyst) was first detectable in some blastocysts at 135 h p.c.; progesterone levels/blastocyst then increased progressively, reaching levels of about 122-158 pg/blastocyst at 159 h p.c. Micropuncture of blastocysts at 159 h p.c. indicated that greater than or equal to 90% of the progesterone in the embryo was in the blastocoelic fluid. Blastocysts from rabbit uterine horns containing oestradiol also contained oestradiol but those in which oestradiol was detected were never observed in uteri lacking the hormone. It is inferred that rabbit blastocysts accumulate both progesterone and oestradiol from uterine fluid.

Transport mechanisms in the preimplantation mammalian embryo.

Compaction is associated with major changes in the transport processes in preimplantation embryos. Before this time the processes are homocellular, in which all the component cells exchange materials across their cell membranes with a common environment. After compaction the outer trophoblast cells become organized into a simple, squamous epithelium which is capable of transcellular vectorial transport, that selectively controls the movement of materials into the embryo. Measurements of the intracellular concentrations and membrane permeabilities of Na+, K+ and Cl- in the mouse oocyte and two-cell embryo have demonstrated that they undergo significant changes during this period of development. The development of transcellular transport across the trophectoderm is fundamental in the regionalization of the embryo. These physiological mechanisms are involved in the formation of the blastocoele fluid, and may be dependent on the development of regionally located Na+, K+-ATPase on the juxtacoelic surfaces of the trophoblast cells.

Inhibition of L-methionine uptake and incorporation by chlorpromazine in preimplantation mouse embryos.

These studies indicate that chlorpromazine causes a rapid inhibition of the uptake and incorporation of L-[Me-3H]methionine in preimplantation mouse embryos in vitro. Concentrations of chlorpromazine from 10-5 M to 10-4 M inhibit L-[Me-3H]methionine uptake and incorporation in late four-cell embryos in 15 min. Concentrations of chlorpromazine from 2 times 10-5 M to 10-4 M inhibit uptake and incorporation in early blastocysts in 15 min to comparable degrees, suggesting that the effect of chlorpromazine on the early blastocyst is primarily on methionine transport, and not on protein synthesis. Lineweaver-Burk plots constructed from 15-min uptake values of methionine in the presence of various concentrations of chlorpromazine indicate that 5 times 10-5 M-chlorpromazine competitively inhibits methionine uptake in blastocysts, while 10-4 M-chlorpromazine non-competitively inhibits transport. Efflux experiments support the idea that chlorpromazine acts as an inhibitor of the active methionine influx processes, and not through acceleration of efflux. It is suggested that chlorpromazine may produce delayed implantation by directly affecting the preimplantation embryo, as well as through its known inhibitory effects on the hormonal functions of the maternal organism.