ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Finasteride is a potent 5&agr;-reductase inhibitor that has shown limited success in men treated for benign prostatic hyperplasia (success is defined as a decrease in the symptoms associated with urinary tract obstruction, and as increases in the urinary flow rate). 5&agr;-reductase is necessary for the prostatic conversion of testosterone to dihydrotesterone (DHT), the specific steroid that stimulates prostate transitional zone growth. Finasteride reduces the size of the prostate gland by 20%, but this does not correlate well with improvement in symptoms.Finasteride is well absorbed after oral administration and, while the rate of absorption may be slowed postprandially, the presence of food has no effect on the total bioavailability. Finasteride is widely distributed, but since its pharmacological effects are very specific to inhibition of 5&agr;-reductase, and since only the prostate gland, the scalp, and the genital skin contain high concentrations of this enzyme, few adverse reactions will be seen in other organ systems.Finasteride undergoes extensive hepatic metabolism to essentially inactive metabolites, which are eliminated through the bile and urine. The terminal elimination half-life (t½z) is 4.7 to 7.1 hours; but despite this, slow accumulation occurs with multiple doses. Values of t½zare higher in elderly men, but no dosage adjustments are necessary. Likewise, no dosage adjustments are necessary for patients with renal dysfunction, since the metabolites which accumulate are relatively inactive and well tolerated, and because greater faecal excretion of the metabolites occurs in these patients. The effect of hepatic dysfunction on the metabolism of finasteride is unknown.Therapeutic doses of finasteride produce a rapid and pronounced effect in reducing both plasma and prostate tissue levels of DHT. Doses below 0.5 mg/day do not produce much suppression of DHT levels, and doses above 5 mg/day have little additional benefit. A single dose of finasteride suppresses serum DHT levels for up to 4 days, longer than would be expected from the serum terminal elimination half-life (t½z) of the drug: this is probably due to the high affinity that finasteride has for the 5&agr;-reductase enzyme. Serum testosterone levels increase in patients receiving finasteride, but are not normally outside the upper limits of the normal range. Serum prostate-specific antigen (PSA) levels decrease with finasteride administration; the baseline for investigation of prostate cancer with elevated PSA levels should be one-half of the normal range.In responders to finasteride, the prostate gland shrinks in volume by about 20%, urinary flow rate improves by approximately 3 ml/s, and symptoms are relieved. The response to finasteride appears to be maximal at doses of 5 mg/day. For most men receiving finasteride, these effects will persist for at least the 5 years that long term studies have been conducted. Serum DHT levels increase again when finasteride therapy is discontinued, probably resulting in the return of the hyperplasia, decreased urine flow and obstructive symptoms.Finasteride is well tolerated, with loss of libido and sexual potency being the most commonly reported adverse reactions. No drug interactions with finasteride have been reported.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Nifedipine is a short-acting calcium antagonist formulated into several different oral preparations, each of which offers a distinct drug release profile. Of these, the nifedipine gastrointestinal therapeutic system (GITS) affords (rate)-controlled-release (CR) and once-daily administration. Although it is recognised that CR drug formulations may enhance the treatment compliance of patients by reducing the number of daily doses, there are several pharmaceutical, pharmacokinetic and pharmacological considerations which may influence the ultimate selection of a particular dosage form.The formulation design of the nifedipine GITS involves an osmotic pump process which provides approximately zero-order delivery of the drug. This mechanism serves to prevent the possibility of dose dumping, but more importantly allows for maintenance of the relatively constant plasma drug concentrations assumed necessary to maintain smooth control of blood pressure. The pharmacokinetic characteristics of the nifedipine GITS have been evaluated in both single- and multiple-dose studies. The GITS formulation provides drug concentrations which reach a plateau within 6 hours after administration of a single dose, and continue at that concentration until at least 24 hours after administration. In this way large fluctuations in plasma drug concentrations are avoided, which may improve the efficacy and tolerability of the drug. Although a trend showing a small increase in the 24-hour plasma nifedipine concentrations has been observed by our group from some single-dose studies, it does not appear to be clinically relevant. One potentially important disadvantage of the GITS compared with ‘naturally’ long-acting agents is that the ‘intrinsic’ pharmacokinetic properties of nifedipine may be exposed in poorly compliant patients, leading to extended periods of subtherapeutic drug concentrations.Drug delivery by the nifedipine GITS is unaffected by changes in pH and gastrointestinal (GI) motility, but the rate of drug release can increase slightly with food intake (although absolute bioavailability remains unchanged). No studies have been conducted to determine the average GI transit time of this particular dosage form, but it is possible that inadequate retention may occur in some patients, perhaps leading to less optimal clinical outcomes. For example, the median GI transit time for both oxprenolol and metoprolol Oros drug delivery systems has been reported as 27.4 hours, with individual times ranging from 5.1 to 58.3 hours. The possibility of inadequate GI retention of the nifedipine GITS is perhaps more likely in patients who have pre-existing GI motility disorders or who are taking other medications that enhance GI motility.The interaction between grapefruit juice and nifedipine is interesting, considering that the exact mechanism involved has yet to be determined. Nonetheless, inhibition of presystemic metabolic processes (probably involving liver enzymes but possibly also enzymes contained within the wall of the small intestine) is likely to be a factor in the increased bioavailability of nifedipine observed in individuals coingesting grapefruit juice. Thus, potential nifedipine formulation differences with respect to the degree of interaction with grapefruit juice may occur if a significant degree of extrahepatic metabolism is involved.The majority of clinical trials with the nifedipine GITS have assessed its efficacy in patients with mild-to-moderate essential hypertension, and have found it to be at least equivalent to other dosage forms of the drug. Since there is limited information available directly comparing the efficacy and adverse effects of the different types of nifedipine formulation, little attention has been focused on this subject. However, modifying the rate and duration of nifedipine release may profoundly affect the clinical performance of this drug. A slower rate of intravenous nifedipine infusion has been shown to reduce the incidence of vasodilator-related adverse effects and to improve blood pressure control. Therefore, these advantages may also apply to reduced rates of oral nifedipine absorption. Another important advantage of the nifedipine GITS is that the trough/peak effect ratio following once-daily administration is maintained above a value of 0.5 to 0.66, as is now typically suggested for antihypertensive therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

This article reviews the literature on the plasma concentration-effect relationships for benzodiazepines, in humans and in experimental animals. Only literature that explicitly links pharmacokinetics to pharmacodynamics is included. The following questions are evaluated.Can concentration-effect relationships be demonstrated?If so, are these relations stable?Are the influences of specific factors such as age and disease on these relationships established?It is clear that, when studies are conducted and interpreted appropriately, relations can be found for a wide range of benzodiazepine effects. These include objective measures such as electroencephalography, semisubjective measures such as psychomotor performance, and subjective measures such as mood/sedation scales. A generally applicable model of the relationship which will allow prediction of effect is, however, not yet established. The relationship appears to be dependent on route and rate of administration, because of factors such as distributional delay, formation of active metabolites and, probably, acute tolerance. Furthermore, intra- and interindividual variability is considerable, probably due to varying experimental conditions and intrinsic interindividual differences.The limited data available on factors influencing the plasma concentration-effect relationships for benzodiazepines demonstrate clear changes in the pharmacodynamics after multiple doses, suggesting the development of tolerance, and a subsensitivity in patients with panic disorder. The influence of factors such as age, disease and drug interactions on the pharmacokinetic-pharmacodynamic relationship remains less clear.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS