Reference: Hum Exp Toxicol 2000 Mar;19(3):178-84

 Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 microM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 microM) and the CYP2C19 inhibitor omeprazole (10 microM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2=0.68, P < 0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 microM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

Vasorelaxing properties of carteolol in isolated porcine ciliary arteries. 

Reference: Klin Monatsbl Augenheilkd 2000 May;216(5):318-20
 

INTRODUCTION: Carteolol is a topical beta-blocker used in ophthalmology to decrease the intraocular pressure. This study investigates the vasoactive effect of carteolol in isolated porcine ciliary processes.

 MATERIAL AND METHODS: With a myograph system isometric force measurements, quiescent vessels or vessels either precontracted with endothelin-1 (0.03 microM) or the thromboxane A2 analog U 46619 (0.3 microM) were exposed, in cumulative manner, to increasing concentrations of carteolol (10 microM-3 mM). Vessels that had a functional endothelium were compared with vessels that had a non functional endothelium (intentionally and mechanically damaged). 

RESULTS: In quiescent vessels carteolol did not induce contractions. In contrast, in precontracted arteries, carteolol evoked marked relaxations which were endothelium-independent.

CONCLUSIONS: In vitro, carteolol has a marked vasorelaxing effect on porcine ciliary arteries, however the clinical relevance of this observation for the care of glaucoma patients requires further evaluation.

Ischemic stroke risk with oral contraceptives: A meta-analysis. 

Reference: JAMA 2000 Jul 5;284(1):72-8.

CONTEXT: The relationship between ischemic stroke and oral contraceptive (OC) use has been studied for 40 years, but disagreement about an association persists. 

OBJECTIVE: To review available literature to determine whether OC use is associated with increased stroke risk. 

DATA SOURCES: Studies published from January 1960 through November 1999 were identified from electronic databases (MEDLINE, BIOSIS, and Dissertation Abstracts Online), Index Medicus, bibliographies of pertinent review articles and pertinent original articles, textbooks, and expert consultation. 

STUDY SELECTION: From 804 potentially relevant references retrieved, 73 were studies investigating risk of ischemic stroke with OC use. Two reviewers independently applied the following inclusion criteria: more than 10 stroke cases sampled, clear stroke subtype differentiation, concurrent controls included, adequate data included to determine relative risks (RRs) and confidence intervals (CIs), analysis controlled for age, and no later publication of identical data. A third investigator adjudicated disagreements. Sixteen studies met all inclusion criteria and were included in the meta-analysis. 

DATA EXTRACTION: Two investigators independently extracted data, with disagreements resolved through discussion. 

DATA SYNTHESIS: The 16 studies were analyzed using random effects modeling. Current OC use was associated with increased risk of ischemic stroke (RR, 2.75; 95% CI, 2.24-3.38). Smaller estrogen dosages were associated with lower risk (P=.01 for trend), but risk was significantly elevated for all dosages. Studies that did not control for smoking (P=.01) and those using hospital-based controls (P<.001) found higher RRs, but no other
patient characteristics or elements of study design were important. The summary RR was 1.93 (95% CI, 1.35-2.74) for low-estrogen preparations in population-based studies that controlled for smoking and hypertension. This translates to an additional 4.1 ischemic strokes per 100,000 nonsmoking, normotensive women using low-estrogen OCs, or 1 additional ischemic stroke per year per 24,000 such women. The RR of stroke due to OC use was not different in women who smoked, had migraines, or had hypertension. 

CONCLUSIONS: Summary results indicate that risk of ischemic stroke is increased in current OC users, even with newer low-estrogen preparations. However, the absolute increase in stroke risk is expected to be small since incidence is very low in this population.

Exercise Therapy or Angioplasty ? A Summation Analysis

Reference: Eur J Vasc Endovasc Surg 2000 Jul;20(1):4-12
 
OBJECTIVES: To compare the outcome of exercise therapy or angioplasty for the treatment of patients with intermittent claudication. 

DESIGN: A summation analysis. Methods a search using MEDLINE and PUBMED between 1966 and April 1999 followed by a review of the manuscripts yielded 54 studies involving angioplasty and 27 studies involving exercise therapy for intermittent claudication. Studies were only included (12 angioplasty and nine exercise series) when results were available for patients with intermittent claudication alone, and when outcome was assessed in terms of symptoms at a minimum of 6 months. 

RESULTS: The total number of claudicants undergoing exercise therapy was 294 patients, with a mean symptomatic success rate of 38.4% and a mean improvement in maximum walking distance of 189.7% at 6 months. The total number of claudicants undergoing angioplasty was 2071, with a mean overall symptomatic success rate of 76.6%. The mean overall complication rate was 9% and mean major complication rate was 2.7% for the angioplasty studies. 

CONCLUSION:Although the result demonstrates an advantage of angioplasty over exercise therapy at 6 months,
there is a small risk of major complications. However, comparison of studies was impaired due to disparity in patient numbers, limited follow-up time and lack of uniformity in outcome assessment. In order to achieve a valid comparison of these therapies in a future randomised study, a validated disease-specific instrument for the assessment of symptomatic outcome for claudicants is required.