摘要:

Many drugs have one or more asymmetric centers and are administered as a racemate containing an equal mixture of enantiomers with different pharmacologic properties, routes, and rates of disposition in humans. For example, S‐warfarin is more potent than R‐warfarin, and is metabolized by different pathways. The S‐enantiomer is primarily oxidized, and the R‐enantiomer is metabolized by both oxidation and reduction. Nevertheless, because of the difficulty in separating and analyzing individual enantiomers, most pharmacokinetic and pharmacodynamic studies on drugs have been performed without considering the stereochemical factors. This is unfortunate, because a nonstereoselective approach to the study of chiral drugs precludes insight into potential valuable information that may be relevant to drug development and evaluation. On the other hand, when the pharmacologic properties (including activity, disposition, and interaction with the other enantiomer) of enantiomers have been defined, manipulation of the enantiomeric ratio or use of the pure enantiomer can be pursued to optimize therapeutic e

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04069.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Myocaradial reperfusion after prolonged periods of ischemia may result in the acceleration and exacerbation of ventricular injury. This is associated with intramitochondrial calcium overload and gross alterations in ultrastructure. Prostaglandins (PGs) (e.g., PGE2, PGE2α, thromboxane A2, PGI2) are synthesized by the heart during myocardial infarction, and cardiotoxic influences of arachidonate on contractile recovery with enhanced efflux of enzymes occur after reperfusion. Accumulation of arachidonic acid in early ischemia indicates degradation of phospholipids as structural components of myocyte membranes. One major cause for reperfusion‐induced exacerbation of ischemic damage is a free radical‐induced peroxidation of lipids with cellular disruption. On reperfusion, both vasoconstrictive and dilator PGs are released from platelets, myocytes, and endothelium, and flushed downstream. This may cause additional vasoconstriction in the microcirculation of normally and/or hypoperfused cardiac regions. Locally released vasodilating PGs can improve cardiac perfusion and prevent plugging of blood elements, thereby antagonizing cell destruction during flow restoration. Several drugs are available that modify blood cell and myocyte arachidonate metabolism, and may favor synthesis of dilating and antiaggregatory

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04070.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Beta‐receptor‐blocking agents are commonly used in the management of various cardiovascular diseases. Recently, esmolol, a pharmacokinetically novel cardioselective beta‐receptor‐blocking agent, has been introduced for use in the treatment of critically ill patients. It is devoid of intrinsic sympathomimetic activity and in doses used clinically, it has no direct depressant effect on the heart. Esmolol is an ester and is metabolized by choline‐esterase to ASL 8123, an inactive molecule. Esmolol has an elimination half‐life of nine minutes which accounts for its ultra‐short duration of action. This unique pharmacokinetic property provides two advantages over other longer‐acting beta‐receptor‐blocking agents. First, the magnitude of beta‐receptor blockade can be titrated to a desired level. Second, if adverse effects are experienced, reducing the dosage or terminating the infusion results in rapid reversal of its pharmacological effects. Another ultra‐short‐acting, non‐cardioselective beta‐receptor blocking agent, flestolol is undergoing clinical evaluation. Esmolol has been approved for the management of supraventricular tachycardia. The clinical safety of these novel drugs will expand the use of beta‐receptor‐blocking agents in the management of cardiovascular di

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04071.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

Thirty‐one medically stable, elderly males (age 75 ± 8.3 yrs) participated in a prospective study evaluating the accuracy of 16 methods of estimating creatinine clearance. Serum creatinine values were determined on the mornings of days 1, 4, and 5 to assure stable renal function. On the morning of day 3, a 24‐hour urine collection was initiated. A statistically significant correlation existed between the measured and estimated clearance values for all 16 formulas. The correlation (r<0.65) was lower than that in previously published studies, however. Five of the formulas (1A, 5A, 5B, 7A, 7B) demonstrated no statistical difference between mean measured and estimated values. In this population, formula 2B was the least biased and formula 9B the most accurate. For all 16 methods, the bias was minimal and the relative accuracy of the estimated methods was comparable. The results support using methods to estimate creatinine clearance only as a rough bedside prediction of renal function in elderly m

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04072.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

We previously demonstrated a modest but significant protective effect of inhaled gallopamil (D600), the methoxy derivative of verapamil, against methacholine‐induced bronchoconstriction; however, the duration of the protective effect of this and other calcium channel blockers is unknown. We therefore evaluated the duration of this protective effect in 15 asthmatic subjects in a prospective, placebo‐controlled trial. Methacholine challenges (Cockcroft method) were performed 2 hours before and 30 minutes after the administration of placebo, and 1 mg and 10 mg of inhaled gallopamil. Gallopamil did not alter resting airway caliber, but significantly increased the concentration of methacholine required to decrease the FEV 20% 30 minutes after the dose. Results with both the 10‐mg and 1‐mg doses were significantly different from placebo, but not from each other. The duration of this protective effect was transient in the group as a whole; the mean drug activity ratios were not significantly different with this sample 2.5 hours after the dose. Thus the short duration of effect limits the potential clinical usefulness of gallopamil in suppressing the signs and symptoms of chronic

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04073.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

The analgesic efficacy of a single 50‐mg preoperative dose of flurbiprofen was compared with ACC‐30 (aspirin 375 mg, codeine 30 mg, caffeine 30 mg) and a placebo. Forty patients scheduled for the surgical removal of impacted maxillary third molars were enrolled in a double‐blind, randomized study. Using a within‐subject design we compared the analgesic efficacy of (1) preoperative flurbiprofen 50 mg with placebo in 20 patients, and (2) preoperative ACC‐30 with placebo in 20 other patients. Using a between‐group design, we then compared the analgesic efficacy of (3) each drug given preoperatively and postoperatively, and (4) each drug given postoperatively only. Patients rated 2 pain dimensions, intensity and unpleasantness, hourly for 8 hours after the presurgical dose. The results of this study indicate that better analgesia was obtained when flurbiprofen was given preoperatively compared to only after surgery. Conversely, preoperative administration of ACC‐30 did not demonstrate any significant influence on postsurgical analgesia. When comparing the 2 drugs, flurbiprofen proved to be superior in providing pain relief only when it was given prior to surgery. There was no difference between them when given only after surgery. Side effects were moderate and not significantly different between patients receiving flurbiprofen and those rec

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04074.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY

摘要:

A double‐blind, randomized analgesic trial was carried out in 150 patients undergoing surgical removal of their 2 impacted lower wisdom teeth. The analgesic efficacy of effervescent acetaminophen 500 or 1000 mg in a 2‐dose regimen was compared with that of diflunisal 500 mg in a single dose. Each dose was taken when subjectively needed and the pain intensity was measured on a visual analog scale during the 10‐hour period after first medication. The best pain reduction was achieved with diflunisal. The difference between diflunisal 500 mg and acetaminophen 1000 mg was significant, as was that between acetaminophen 1000 and 500 mg. The peak effect after the first dose occurred later but was greater with diflunisal than with acetaminophen. Patients needing analgesics at low pain intensities seemed to discriminate better between treatments, and the efficacy of acetaminophen was weakly dependent on the initial pain intensity. This intensity was difficult to predict, and only a poor correlation was found between the initial pain intensity and the patient's prior estimate of

ISSN:0277-0008    

DOI:10.1002/j.1875-9114.1988.tb04075.x

出版商:Blackwell Publishing Ltd    

年代:1988

数据来源: WILEY