ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04632.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis‐retinoic acid in patients with acute promyelocyte leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all‐trans‐retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocyte leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinoge

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04633.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Regulatory approval times of new chemical entities (NCEs) in Australia, Canada, Sweden, the United Kingdom (UK), and the United States (US) were compared. The approval times of a set of common 25 NCEs and a larger set of unmatched NCEs were very similar in Australia, Canada, Sweden, and the US, with median approval times from 23 to 29 months. The median approval time in the UK was approximately 11 months. Analysis of the data showed that the approval times in Australia, Sweden, and the UK were not significantly affected by the therapeutic classification of the drug, the amount of additional data requested and received, or the submission date. In Canada, the date the drug submission was received and the frequency of additional data requests significantly affected the approval times. In the US, the date the drug submission was received and the frequency of additional data received significantly affected the approval times. The therapeutic classification of the drug did not significantly affect the approval time in Canada or the US.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04634.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

The clinician plays a key role in the detection and diagnosis of adverse drug reactions (ADRs). The diagnosis of ADRs, however, is a complex task. In the past, there were no systematically applied diagnostic criteria for ADRs, no formal methods of case analysis, no standardized epidemiologic approaches, and a limited knowledge of mechanisms. This resulted in the overdiagnosis of ADRs, which has negative consequences such as limiting treatment options. Recently, there have been various improvements in the diagnosis of ADRs, such as the development of standardized decision aids and of in vitro diagnostic tests. This article briefly reviews some of this knowledge, discusses the role of in vivo and in vitro rechallenge, and summarizes a probabilistic approach for collecting relevant information and diagnosing ADRs. The intention is to increase awareness of the different approaches for diagnosing ADRs as well as to stimulate researchers to continue to collect pharmacoepidemiologic information, study the pharmacologic, immunologic, and genetic factors involved in the pathogenesis of drug reactions, and develop and test new diagnostic instruments under various clinical conditions.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04635.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

The acetylator phenotypes of 200 Saudi diabetics and an equal number of control subjects of the same origin were determined by measuring the peak height ratio of two urinary caffeine metabolites, 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU) and 1‐methylxanthine (1MX), using a simplified high‐performance liquid chromatographic method. Urine samples were collected from the diabetics and the control subjects who regularly drink coffee, tea, or caffeinated beverages as part of their normal daily diet. The patients were classified as either type 1 (insulin‐dependent) (28 patients) or type 2 (insulin‐independent) diabetics (172 patients) according to standard criteria. The reproducibility of acetylator phenotype was established by examining the peak height ratio of AFMU/1MX in 18 diabetics and 6 control subjects on different days. Significant differences in the proportion of rapid acetylators were observed between type 1 (53.6%) and type 2 (33.7%) diabetics (P ≤ .0436), and between the control group (26%) and the overall diabetics (36.5%) (P ≤ .024) or those with type 1 disease (P ≤ .0028). Also, there was a significant (P ≤ .0436) association between rapid acetylator status and

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04636.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

The harmonic and arithmetic mean values for volume of distribution at steady state, half‐life, and clearance of intravenous cyclosporin‐A were calculated using an index set of 22 renal transplant candidates to determine if harmonic mean values provide a less biased estimate of central tendency than arithmetic mean values. Cyclosporin‐A was measured using a nonspecific radioimmune assay method. The arithmetic mean value for volume of distribution was 16% larger than calculations by the harmonic mean method. Similarly, the arithmetic mean half‐life and clearance values were larger than harmonic mean values by 10% and 15%, respectively. However, 95% confidence intervals for these pharmacokinetic parameters overlapped. When these mean pharmacokinetic parameter values were used to predict actual values in a test group of 22 renal transplant candidates receiving cyclosporin‐A, similar levels of precision were demonstrated by either method. Both methods produced positively biased predictions for volume of distribution and clearance. However, these differences were not significant. These findings suggest there is little practical value for the use of harmonic mean calculations to describe the central tendency of pharmacokinetic parameters of cyclosporin‐A under the conditions studied. The value of harmonic mean values for pharmacokinetic parameters in other patient populations or with other assay methods for cyclosporin remain to

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04637.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04638.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Pharmaceutical enantiomers often exhibit different pharmacodynamic and pharmacokinetic properties. Stereospecific chromatographic assays are available to separate these stereoisomers. Therapeutic agents often contain chemical functional groups (e.g. amino, hydroxyl, carbonyl, and carboxylic acid). These can be reacted with enantiomerically pure reagents to give diastereoisomers suitable for analysis on achiral gas chromatographic (GC) and high performance liquid chromatrographic (HPLC) columns. Alternatively, derivatized or underivatized drugs may be resolved on chiral chromatographic phases. A wide variety of GC (e.g. amino acid, cyclodextrin, and metal‐complex) and HPLC (mobile phase additive, crown ether, π‐π interaction and related phases, protein, cyclodextrin, polysaccharide, methacrylate and amide polymer, and ligand exchange) columns are commercially available. This article reviews the chromatographic separation of enanti

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04639.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Many biologically active synthetic drugs contain chiral centers, although they are used as racemic mixtures. Enantiomers are hard to distinguish in the chemical laboratory but are readily discriminated in the body and differ in their biological activities and disposition. The pharmacokinetic profiles of enantiomers can be variable, especially for drugs with a first‐pass effect and enantioselective pharmacokinetic monitoring should be carried out. Ultimately, whether to exploit a racemate or a single enantiomer in therapy is a multi‐faceted decision to which drug disposition data have important contributions to m

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04640.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed as racemates (i.e., an equal proportion of two enantiomers). Although enantiomers of racemic drugs often differ from one another in their pharmacodynamic and pharmacokinetic properties, bioequivalence assessments are made using nonstereospecific assays. Such an approach may provide a poor assessment of therapeutic equality. This can be true particularly for drugs with complicated pharmacokinetics and those that exhibit extensive stereoselectivity in their disposition kinetics. Accordingly, examples of bioequivalence studies based on stereospecific assays have started to appear in the literature. Fortunately, facile stereospecific assays have become available in the last several years for many drugs. Consequently, regulatory agencies have started to take the issue of stereochemistry into consideration in the assessment of bioequivalence, particularly from the standpoint of generic substitution.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb04641.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY