ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03911.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The anemia of chronic renal failure often contributes to the poor functional status in patients with renal insufficiency and results primarily from decreased erythropoietin production. Recombinant human erythropoietin (rHuEpo) results in clinical and symptomatic improvements in patients with anemia of chronic renal failure. Treatment with rHuEpo also improves the quality of life in these patients. Resistance to rHuEpo therapy is not uncommon, however, and often is related to iron deficiency resulting from rapid erythropoiesis during rHuEpo therapy. Interestingly, rHuEpo‐treated patients may continue to develop iron deficiency while receiving oral iron. Alternatively, parenteral iron is effective in replenishing iron stores and sustaining erythropoiesis in patients treated with rHuEp

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03912.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Visual art was used to teach the biopsychiatric model of addiction to audiences in the Caribbean, Europe and Mideast. Art slides were tangentially linked to slides of pharmacological data. Stylistically dense art was processed by the intuitive right brain while spare notational pharmacological data was processed by the intellectual (rationalistic) left brain. Simultaneous presentation of these data enhanced attention and retention. This teaching paradigm was based on the nonliterate methods developed by Medieval architects and refined by Italian Renaissance philosopher, Marsilio Ficino.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03913.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Recent articles and advertisements suggest that drug design is within the reach of any chemically oriented scientist who obtains the latest three‐dimensional computer graphics programs for his personal computer. This sort of “rational” drug design has however had limited success. When it has been successful, it has required the rigorous application of computational chemistry. Bowen et al. in their accompanying paper provide a summary of a number of approaches and the assumptions involved. The papers by McDonnell et al. and Hendry describe two different approaches: utilizing molecular genetics to test the effective interaction in vitro of ligands with their receptors and utilizing the model structure of DNA as a blueprint for the structure of the intracellular targets of

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03914.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Ball‐and‐stick mechanical models, typically associated with chemists, have been helpful in understanding structural problems and the relationship between structure and biologic activity. With progress in computer speed, graphics performance, and software innovation, molecules of biological interest can be subjected to rigorous calculations. Computational chemistry and biology are rooted in the belief that theoretical physics can be used to calculate accurate molecular structures. Although in its infancy, computer‐assisted molecular modeling is gaining attention and acceptability as an increasing number of researchers turn their attention toward rational molecular design. The trend to use theoretical methods can be traced to the greater availability of computer graphics workstations, decreasing computer costs, faster central processing units, more robust algorithms, and “user‐friendly” software codes. Every major pharmaceutical company has invested in these resources to reduce the time it takes to design and develop pharmaceutical agents. Because of the vast financial and manpower investments needed to introduce a single drug, medicinal chemists and pharmacologists are interested in understanding and predicting drug action at the molecular level. Although drug action is still poorly understood, molecular modeling should reduce some of the labor in the development of pharmaceut

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03915.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Steroid hormones, vitamins, and thyroid hormone are potent chemical messengers that exert dramatic effects on cell differentiation, homeostasis, and morphogenesis. These molecules, though diverse in structure, share a mechanistically similar mode of action. The effector molecules diffuse across cellular membranes and bind to specific high affinity receptors in the target cell nuclei. This interaction results in the conversion of an inactive receptor to one that can interact with the regulatory regions of target genes and modulate the rate of transcription of specific gene sets. The recent cloning and characterization of the functional receptors for these hormones has been enlightening as to the individual steps involved in steroid signal transduction. In addition, emerging evidence suggests that receptor function can be influenced by cell and promoter context indicating that it may be possible to develop tissue specific or tissue‐restricted drugs. The concept that a single receptor can modulate gene transcription in a cell‐specific manner is of great medical and pharmaceutical importance. The focus of this review is to highlight the recent developments in the steroid receptor field and to illustrate the novel approaches been undertaken to identify novel pharmaceutic

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03916.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Why certain chemical structures and not others are present in nature has been a recurring question raised by scientists since the first organic natural products were characterized. Of equal interest has been elucidating what structural features within any given class of organic molecules are responsible for biological activity. Historically, the lack of satisfactory answers to both questions has relegated the development of biologically active molecules either to serendipity or to exhaustive synthesis and biological testing of large numbers of compounds. This frustration is particularly evident in the pharmaceutical industry where the development of drug agonists and antagonists is often time consuming, tedious and expensive. Fortunately, this picture is beginning to change as more information is derived from modern molecular modeling techniques including characterization of the active sites in enzymes and the ligand binding sites in receptors. Over the past 15 years another approach has emerged based upon a series of discoveries made in our laboratories with molecular models. Namely, many biologically active small molecules have been found to possess complementary stereochemical relationships with gene structure. These relationships have proven useful in understanding constraints imposed by nature on the structures of small molecules and in correlating structure with activity among certain classes of compounds. Recently, computer graphics and energy calculations have confirmed salient observations lending credence to what promises to be a powerful and rapidly evolving technology for designing new safe and effective drugs.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03917.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Influence of application site of a new transdermal clonidine, M‐5041T(M), on its pharmacokinetics and pharmacodynamics were evaluated in eight human subjects. One patch of M‐6 mg was applied for 3 days on the right chest (first trial), on the left arm (second trial), and on the upper abdomen (third trial). Blood samples for clonidine concentration were taken, and blood pressure (BP) was measured for a 120‐hour postapplication period. Plasma concentrations of clonidine increased after application of M in each trial. This parameter in the second trial was significantly greater than that of the first and third trials. The values of maximum plasma concentration and area under the plasma concentration‐time curve in the second trial were greater than those of other trials, but the differences did not reach significance. The BP‐lowering effect of M in the second trial was significantly greater than that of the third trial. These results suggest that the plasma concentrations of clonidine after application of M and its hypotensive effect are affected by the site of application in human

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03918.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M‐5041T (M), and its safety were evaluated after single and repeated applications. In the single‐application study, one patch of M (4 mg → 6 mg → 8 mg) was applied for 3 days in eight healthy subjects. In the repeated‐application study, first (0–72 hours), second (72–144 hours), and third (144–216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single‐application study, plasma clonidine concentration increased in a dose‐dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half‐life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP‐lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated‐application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly. Two subjects complained of orthostatic vertigo caused by hypotension and were dropped out of the study. Mild erythema and systemic adverse effects were reported. These results suggest that M is a promising tool for the treatment of hypertension without unacceptable skin reactions. Orthostatic change in BP should be monitored care

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03919.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The object of this study was to examine prospectively the effects of itraconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (QTc intervals) of single‐dose terfenadine in six healthy volunteers. It was designed as a prospective cohort study with each subject serving as his own control, set in an outpatient cardiology clinic. The participants were six healthy volunteers (two men, four women; ages 24–35) not taking any prescription or over‐the‐counter medications. Single‐dose terfenadine administration (120 mg) was accompanied by pharmacokinetic profiles and serial determination of the QTc interval for 12 hours. The subjects then began daily oral itraconazole (200 mg each morning) for 7 days. Repeat pharmacokinetic and pharmacodynamic determinations were made after administration of a second dose (120 mg) of terfenadine while receiving itraconazole. The main outcome measures were terfenadine and acid metabolite serum concentrations; corrected QT intervals as determined by 12‐lead electrocardiogram (ECG); and presence or absence of late potentials as determined by signal‐averaged ECGs over 150 cardiac cycles. There were significant changes in the pharmacokinetic parameters of acid metabolite after treatment with itraconazole. All subjects had detectable levels of unmetabolized terfenadine after addition of itraconazole, which was associated with QT prolongation. There was no evidence of late depolarization as manifested by an increase in QRS duration found using signal‐averaged electrocardiography. Itraconazole influences the metabolism of terfenadine in normal volunteers and results in the accumulation of unmetabolized parent drug associated with altered cardiac repolarization. This drug combination sh

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03920.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY