摘要:

The renin‐angiotensin system (RAS) functions as a primary regulator in the short‐term and long‐term control of blood pressure. Pharmacologic inhibition of the RAS with angiotensin‐converting enzyme (ACE) inhibition is effective for treating systemic hypertension and congestive heart failure. As a more specific therapy, the development of renin inhibitors has evolved through various approaches: specific renin antibodies, peptides developed from prosegments of renin precursor, oligopeptides related to pepstatin a universal inhibitor of aspartyl proteinase enzyme, and analogs of angiotensinogen (the renin substrate). Angiotensinogen analogs are promising as therapeutic agents because of high potency, metabolic stability, and good oral bioavailability. Ongoing research is directed towards the application of renin inhibition, the treatment of various cardiovascular disorders, and as a biological probe for understanding the role of the RAS in control of blood pressure and blood

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04000.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Genetic polymorphisms of drug metabolizing enzymes are well recognized. This review presents molecular mechanisms, ontogeny and clinical implications of genetically determined intersubject variation in some of these enzymes. Included are the polymorphic enzymes N‐acetyl transferase, cytochromes P4502D6 and 2C, which have been well described in humans. Information regarding other Phase I and Phase II polymorphic pathways, such as glutathione and methyl conjugation and alcohol and acetaldehyde oxidation continues to increase and are also discussed. Genetic factors effecting enzyme activity are frequently important determinants of the disposition of drugs and their efficacy and toxicity. In addition, associations between genetic differences in these enzymes and susceptibility to carcinogens and teratogens have been reported. Ultimately, the application of knowledge regarding these genetic factors of enzyme activity may guide medical therapy and minimize xenobiotic‐induced dise

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04001.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Naltrexone, a specific opiate receptor antagonist, is used clinically in the treatment of heroin addiction and more recently, for the treatment of dyskinesia associated with Huntington's disease (HD). Naltrexone may act as a potential hepatotoxin, as reflected in the elevation of transaminase levels. However, one study concluded that, for a brief treatment period of 12 weeks, there is no contraindication to naltrexone treatment based solely on increased hepatic enzyme values. This study monitored liver transaminase levels, in ten HD patients receiving daily doses, between 50 mg/day and 300 mg/day, of naltrexone for periods of 10 to 36 months. Serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were obtained before treatment and at intervals of 1 to 4 months during treatment. Only one of the ten patients treated with naltrexone had increased levels of both SGOT and SGPT, whereas one other patient showed elevated levels of SGPT. These elevations, which initially appeared dose related decreased to normal limits with continued treatment. Because many of the patients were receiving other medications, a combination of drugs with naltrexone may contribute to the increased transaminase levels seen in two of the patients. In summary, chronic administration of naltrexone in doses up to 300 mg/day for periods up to 36 months does not significantly change hepatic function, as measured by SGOT and SGPT levels.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04002.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Sudden, unexpected death due to cocaine in young otherwise healthy individuals occurs in an idiosyncratic manner and is commonly felt to be arrhythmogenic in nature, although the exact cause of death is rarely documented. In addition to indirect sympathomimetic actions, cocaine is a potent sodium channel blocking drug and, in this regard, most closely resembles agents such as flecainide. We suggest that sudden death due to cocaine is proarrhythmic in nature, occurring under similar circumstances as that due to specific antiarrhythmic drugs.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04003.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Duplex sonography was used to assess the effects on hepatic blood flow after administering 0.6 mg nitroglycerin (NTG) sublingually to ten healthy volunteers. The study was a randomized, placebo‐controlled, cross‐over study in which subjects were studied on three separate occasions. Each visit involved administering either placebo or NTG followed by estimation of blood flow through a particular branch of the hepatic artery, portal vein, and hepatic vein every minute for 15 minutes after NTG and placebo administration. Two hours later, subjects were crossed over to the other treatment and the same vessel branch was again examined for 15 minutes. Total blood flow increased 7% in the portal vein and 27% in the hepatic vein during NTG treatment, but did not change significantly in the hepatic artery. Vascular resistance was increased in the hepatic artery and decreased in the portal and hepatic veins after NTG. Qualitatively, flow changed dramatically in the hepatic vein after NTG with the disappearance of normal retrograde flow. The results indicate that nitroglycerin effects hepatic blood flow through the portal and hepatic veins with a decrease in vascular resistance in the portal and hepatic veins and an increase in resistance in the hepatic art

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04004.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The authors studied the antihypertensive effect and tolerability of a new sustained‐release formulation of nifedipine 50 mg once a day, in comparison with nifedipine retard 20 mg twice a day in patients with mild or moderate primary arterial hypertension. Both treatments significantly lowered blood pressure with no difference in daily blood pressure profile. At steady state, the two drugs determined comparable plasma levels of nifedipine as measured immediately before the morning dose. After a 12‐month treatment, the new formulation of nifedipine still displayed satisfactory blood pressure control in both supine and standing positions, with no change in tolerability throughout the study. In conclusion, this new sustained‐release formulation of nifedipine has similar efficacy and tolerability to conventional treatment with nifedipine retard 20 mg twice

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04005.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The pharmacokinetic disposition of 200‐ and 400‐mg doses of a novel carbacephem, loracarbef, was determined over a dose interval on day 8, after ingestion of drug doses twice daily for 7 days, in 20 young, healthy volunteers of both genders. Drug was analyzed in plasma, urine, saliva, vaginal secretions, and fecal filtrate. Peak plasma concentration was proportional to dose for both men (4.0 ± 1.3 and 8.8 ± 3.4 mg/L) and women (8.0 ± 5.6 and 15.3 ± 3.3 mg/L), and the observed time to peak increased from 1 to 2 hours with the increased dose. Apparent volume of distribution was greater in men than women (0.385 ± 0.114 versus 0.270 ± 0.075 L/kg; P<.03). The drug was virtually quantitatively excreted unchanged in urine, and its renal clearance exceeded creatinine clearance in all subjects. Renal loracarbef clearance correlated with neither weight‐corrected dose nor creatinine clearance in these healthy subjects. There was no evidence for drug accumulation in the body with chronic ingestion. Loracarbef was detected in the fecal filtrate of seven volunteers, but did not account for more than 7% of the daily dose. Loracarbef was detected in vaginal secretions of two of five volunteers who ingested the 400‐mg dose. No drug was detected in saliva obtained just before dose ingestion. These data are consistent with complete bioavailability for an oral beta‐lactam antibiotic drug that is virtually completely eliminated unchange

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04006.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto‐quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200, and 400 mg, and multiple doses of 300 mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG), or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09, and 1.88 μg/mL at doses of 100, 200, and 400 mg, respectively. The mean half‐lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3, and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% of the doses. The mean salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400 mg. The Cmax, AUC, and urinary excretion rates were not altered by food intake, whereas the Tmaxwas prolonged slightly. In the multiple‐dose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 support further t

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04007.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The authors compared, in a double‐blind, randomized, crossover study in 13 healthy adult volunteers, the single‐ and multiple‐dose pharmacokinetics, relative bioavailability, and side effects of a new oral sustained‐release formulation of codeine (SRC) containing 150 mg codeine base, with oral immediate‐release codeine phosphate (IRC). Sustained‐release codeine was given at a dose of 150 mg every 12 hours for 5 doses; IRC was given at a dose of 60 mg (2 × 30 mg) every 4 hours for the first 3 doses, and 30 mg every 4 hours thereafter for 12 doses. Plasma codeine levels were determined using a sensitive and specific high‐performance liquid chromatography method and corrected for dose administered and codeine base equivalent. Mean values for single‐dose pharmacokinetic parameters for SRC and IRC, respectively, were: Cmaxof 217.8 and 138.8 ng/mL; Tmaxof 2.3 and 1.1 hours; AUC0‐infof 1202.3 and 1262.4 ng • mL−1• hour−1; and t1/2el of 2.6 hours for both formulations. Their respective mean steady‐state pharmacokinetic parameters were: Cmaxof 263.8 and 222.9 ng/mL; Tmaxof 3.2 and 1.1 hours; AUC0–12hof 1576.4 and 1379.1 ng • mL−1• hour−1; and t1/2el of 2.8 and 2.3 hours. These results indicate comparable bioavailability between both formulations with SRC providing delayed peak plasma levels. The sustained‐release character of SRC can be explained by a delayed absorption, which is not limiting to drug elimination. Sustained‐release codeine provides higher plasma codeine levels over a broader time interval

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04008.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The assessment of compliance is critical in the evaluation of the effectiveness of a new therapeutic agent. Fifteen patients with transfusion‐dependent β‐thalassemia, many of whom had previously demonstrated erratic compliance with deferoxamine, were enrolled in a clinical trial of a new oral iron chelator, 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one (L1). Their compliance with this medication was estimated by several existing methods and the novel Medication Event Monitoring System (MEMS). Overall compliance as assessed by the MEMS was 78.5 ± 13.0% of prescribed doses taken, significantly lower than the corresponding rates calculated by pill counts and diaries (91.5 ± 9.2% and 94.1 ± 4.3%, respectively). However, several serious problems were encountered with the MEMS, mostly in the form of incorrect use of the device by the patients. Disclosure of the nature of the MEMS and the compliance monitoring process did not alter the rate of adherence with L1 therapy. Compliance as determined by pill counts did not differ between the 1st and 2nd 6‐month periods. Although not reaching statistical significance, a trend towards better L1 compliance occurred in those patients in whom serum ferritin levels decreased. Patients who filled at least 50% of their diaries had significantly better compliance by pill counts than those who completed less than 50% of their diaries (95.9 ± 4.1% and 86.5 ± 11.1%, respectively). Steady‐state L1 trough concentrations and 24‐hour urinary iron excretion did not correlate with L1 compliance. Given the limitations of the available techniques for monitoring compliance, including the new MEMS device, a combination of methods should be used in the evaluation of medication compliance during the in

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb04009.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY