ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01880.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The two main advantages of controlled drug delivery systems are: maintenance of therapeutically optimum drug concentrations in the plasma through zero‐order release without significant fluctuations; and elimination of the need for frequent single dose administrations. The oral and other therapeutic systems in human use have validated the concept that controlled continuous drug release can minimize the daily dose of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. By minimizing patient intervention, a design feature of therapeutic systems, compliance is automatically enhanced.Oral drug delivery systems, in particular, have required innovation in materials science to provide materials biocompatible during prolonged contact with body tissues, bioengineering to develop drug delivery modules, and clinical pharmacology for elucidation of drug action under conditions of continuous controlled drug administration.Recent work in advanced oral delivery has been primarily focused on liposome technology and the concept that substances that are normally destroyed by the stomach can be protected long enough before they could be absorbed downstream. For cost and patient convenience, oral delivery certainly would be an attractive method. The nature of biologic substances, however, with their unique technical problems, will probably limit greatly those that can be delivered orally. Besides, where delivery rate control is critical, oral delivery, even when possible, would probably be insufficiently precise. Oral delivery would also limit the substance to bloodstream delivery to the disease site.Even so, oral controlled drug delivery systems will likely find primary usefulness in specific carefully controlled therapies and prophylactic situations with due regard for drug interactions. This system represents a potentially very significant therapeutic modality. These delivery systems will find usefulness primarily in certain well‐defined and well‐controllable areas with due regard for individual patient variations. The purpose of the present article is to review oral controlled‐release drug delivery systems, with particular emphasis on the practical aspects of testing and fabricating these systems and the underlying mechanisms by which control over drug release rate is accom

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01881.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

To facilitate the availability of important new therapeutic agents, the Food and Drug Administration (FDA) in the mid‐1970s began assigning therapeutic ratings to investigational new drugs and holding end‐of‐phase II conferences with drug sponsors. To determine whether these initiatives are associated with faster approvals, we examined new drug application (NDA) review times of new chemical entities (NCEs) approved during the 12‐year period 1978 through 1989. Mean NDA review time for 1A drugs (22.5 months) was 22% shorter than that for 1B drugs (28.7 months), which in turn was 25% shorter than that for 1C drugs (38.4 months). For drugs approved during the recent 4‐year period 1986 through 1989, however, the gap between 1A and 1C review times has narrowed considerably from 19 to 9 months. When drugs were grouped by FDA reviewing division, 1A drugs had the shortest mean review time in each division except the Cardio‐Renal Division; in that division, 1B drugs had the shortest mean review time. Mean NDA review time for drugs that had end‐of‐phase II conferences (28.6 months) was 15% shorter than that for drugs without such conferences (33.7 months). These results suggest that NCEs that receive 1A or 1B ratings and are the subject of end‐of‐phase II conferences benefit by having s

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01882.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low‐density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high‐density lipoprotein (HDL) cholesterol levels. Their effects on low‐density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid®, Parke—Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG‐CoAreductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhab

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01883.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

To test the hypothesis that renal failure alters the disposition of cibenzoline in humans, an absolute bioavailability and elimination kinetic study was performed. We used the simultaneous administration of a stable isotope variant (SASIV). Eight healthy volunteers and eight matched hemodialysis patients each received simultaneously an 80‐mg intravenous infusion of 15N‐2‐cibenzoline and a single 80‐mg cibenzoline capsule. Cibenzoline plasma concentrations were assayed by a gas chromatographic—mass spectrometric assay. A compartment‐independent kinetic analysis showed a plasma clearance of 707 mL/min and an elimination half‐life of 7.3 hours after the intravenous dose in healthy volunteers. In renal‐failure patients, cibenzoline clearance decreased to 224 mL/min and half‐life increased to 22.4 hours. Decreased plasma clearance was due to decreases in both renal and nonrenal clearance. Absolute bioavailability was 83% and 90% in healthy volunteers and renal‐failure patients, respectively. Hemodialysis accounted for only 13

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01884.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01885.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Circadian influence of trichlormethiazide on serum electrolyte levels, lipid levels, and glucose levels were evaluated in 12 hypertensive patients. One tablet of trichlormethiazide (2 mg) was given once a day at 7:00amor 7:00pmfor 8 weeks. The study was done by a crossover design. Twenty—four‐hour urine was collected, and fasting blood samples were obtained during the control period and at the end of each treatment period. The 24‐hour urine level increased slightly after treatment with trichlormethiazide in the morning and evening trials. Urinary excretion of sodium also increased slightly in the morning trial and increased significantly in the evening trial. Serum concentrations of potassium and chloride decreased, and serum uric acid level increased after trichlormethiazide treatment. No significant difference was observed in these parameters between morning and evening trials. Fasting blood glucose levels increased after trichlormethiazide treatment. The increment in blood glucose levels was greater in the evening trial than in the morning trial. These data indicate that the influence of trichlormethiazide on glucose tolerance might vary with its administration

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01886.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin‐converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose‐tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once‐daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6%(P<.05,compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE act

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01887.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The decrease in renal blood flow (RBF) observed in patients with hypertension can be increased with converting enzyme inhibition (CEI). It is unknown whether the decrease in RBF observed with age can also be increased with CEI. This study compared the short‐ and long‐term effects of captopril monotherapy in young (65 years) hypertensive patients. Captopril effectively decreased blood pressure in both groups (diastolic blood pressure<90 mm Hg), with the young patients requiring a lower dose (.7 mg/kg) than the elderly patients (1.2 mg/kg). Creatinine and para‐aminohippurate clearances were maintained in both groups, with a decrease in renal vascular resistance being observed in the younger patients. Serum aldosterone levels fell significantly after each dose of captopril at all phases of the study, with no change observed in plasma renin levels. Atrial natriuretic peptide (ANP) level was increased in the elderly patients receiving placebo (48.8 ± 8 pg/mL) when compared with the young subjects (24 ± 3.8 pg/mL). Captopril did not alter ANP levels in eithe

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01888.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Cyclosporine (CsA) is a potent immunosuppressive compound, and its metabolites have previously been shown to have pharmacologic activity. The aldehydic metabolites have been isolated and are a metabolic intermediate after the conversion of CsA to its most active hydroxylated metabolite. The in vitro sensitivity of alloreactive T‐lymphocytes, which are generated from a mixed lymphocyte reaction and propagated from organ transplant biopsy specimens to the aldehydic metabolites of CsA, was tested. In secondary proliferative assays in the presence of varying concentrations of CsA and the aldehydes, the concentration required to inhibit proliferation by 50% was 50 to 150 ng/mL for CsA and 3150 to 3500 ng/mL for the aldehydes. Pretreatment of alloreactive cells with CsA or the aldehydes did not alter cell viability, as tested with dye exclusion, or cell reactivity on reculturing. These studies concluded that the structural modification formed by metabolism of CsA to the aldehydic structure eliminates its antiproliferative activity on T‐lymphocy

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb01889.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY