PHARMACOKINETICS OF THE ENANTIOMERS OF VERAPAMIL AFTER INTRAVENOUS AND ORAL ADMINISTRATION OF RACEMIC VERAPAMIL IN A RAT MODEL

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg⁻¹) and oral (10 mg kg⁻¹) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R-verapamil was significantly greater than that of S-verapamil; 34·9 ± 7 against 2·7 ± 3·7 mL min⁻¹ kg⁻¹ (mean ± SD), respectively. After oral administration, the clearance of R-verapamil was significantly greater than that of S-verapamil, 889 ± 294 against 351 ± 109 mL min⁻¹ kg⁻¹, respectively. The apparent oral bioavailability of S-verapamil was greater than that of R-verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first-pass clearance after oral administration and the direction of stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.     

Intracoronary Infusion of Dilute Ethanol for Control of Ventricular Rate in Patients with Atrial Fibrillation

The effects of selective infusion of 25% ethanoi into the AV nodal artery was assessed in 1J putients with atriai fibrillation and uncontrollabiy rapid ventricular response rates. The primary study objective was to achieve permaneni modificafion of AV nodal function and control ventricular rate without drug therapy and mthout causing permanent complete AV block. "Clinical success" was defined as drug-free rate control by either AV nodal modification or the production of complete AV block. Selective catheterization and ethanol infusion into the AV nodal artery could be performed in nine patients. Jntracoronary ethanol infusion acutely caused second- or third-degree AV noda] block in seven palients and an increase in AV nodal refractory period and Wenckebach cycle length in two patients. Acute occlusion of the AV nodal artery or infarction of nontarget myocardium was not observed. During follow-up of 22.2 ± 2.2 months the primary study objective was attained in only four of nine patienfs treated, yielding an efficacy of 44%. However, the "clinical success" rate was 78%. The acute effects of ethanol on AV conduclion did not predict the chronic effects. Selective intracoronary infusion of dilute ethanol lo control the ventricular rate in atrial fibrillation should be considered when rodiofrequency ablation has been unsuccessful. This method of chemical ablation is as effective and probably safer than rapid administration of 96% ethanol.     

ACCURACY OF PREDICTING LONG-TERM PROSTATE SPECIFIC ANTIGEN OUTCOME BASED ON EARLY PROSTATE SPECIFIC ANTIGEN RECURRENCE RESULTS AFTER RADICAL PROSTATECTOMY

PURPOSE: We determined how prostate specific antigen (PSA) doubling time changed with time and whether an early measure of doubling time would accurately predict long-term PSA values and clinical outcome in a cohort of patients followed expectantly after radical prostatectomy. MATERIALS AND METHODS: We analyzed data on 121 patients with PSA recurrence after radical retropubic prostatectomy. Group and individual analyses were performed on 60 patients who met study inclusion criteria. PSA doubling time was calculated and a curve was plotted using logarithmic transformation with linear regression and least squares analysis. In analysis 1 patients were placed into 3 subgroups according to doubling time. Doubling time was calculated per subgroup and the slopes of the aggregate curves were compared to determine how doubling time changed with time. In analysis 2 we calculated early doubling time per patient using only the initial 2 detectable PSA values and compared it with eventual doubling time in each using all PSA values. In addition, we analyzed how doubling time correlated with the clinical course. RESULTS: Using the group methodology there was no statistically significant acceleration or deceleration with time in doubling time slope in any of the 3 subgroups. On individual analysis we noted a weak correlation of early with eventual doubling time (correlation coefficient 0.69, p = 0.01). In 88% of patients eventual doubling time was not within 10% of early doubling time. Metastasis developed in 60% of patients with an eventual DT of 0 to 6 months, while 80% with an eventual doubling time of 6 to 12 months had no evidence of local or metastatic disease. No patients with an eventual doubling time of greater than 12 months have had metastatic disease and only 4 (16%) had local recurrence, which was treated with radiation therapy. In 8 of the 14 patients (23%) with local recurrence or metastatic disease early doubling time predicted eventual doubling time. Early doubling time was more rapid and slower than eventual doubling time in 5 and 1, respectively, of the remaining cases, which would have placed them in a different subgroup. CONCLUSIONS: On group analysis PSA doubling time appeared to be constant with time and there was no evidence that it accelerated with time in our dataset of PSA recurrence after radical prostatectomy. On individual analysis early doubling time showed a weak but statistically significant correlation with eventual doubling time. However, there was significant inaccuracy when predicting PSA doubling time based on early PSA values in individuals. Generally early projections of doubling time tend to over predict tumor biological aggressiveness, that is local recurrence or metastasis. A need remains for more accurate predictors of the rate of disease progression at initial PSA recurrence to determine accurately early in the clinical course the patients who may benefit from additional therapy. Currently no patient in our study has died of prostate cancer.     

A comparative study of proliferation indices and ploidy in dysplastic naevi and malignant melanomas using flow cytometry

Cell proliferation indices and DNA content have been determined in 18 intradermal naevi, 40 dysplastic naevi and 16 superficial malignant melanomas (less than 0.76 mm depth of invasion) using flow cytometry. In this study, proliferation indices of intradermal naevi and dysplastic naevi were not significantly different from each other. Abnormalities of DNA ploidy were not identified in the intradermal naevi or dysplastic naevi; whereas three of the malignant melanomas were aneuploid. In addition, cellular proliferation was increased within the group of malignant melanomas, in comparison with the naevi. This study has found no evidence to indicate that sporadic dysplastic naevi were more likely than intradermal naevi to transform to malignant melanoma, when objective criteria were employed. However, dysplastic naevi could be distinguished from some early malignant melanomas by absence of aneuploidy and by low cell proliferation indices.     

Subxiphoid Approach for Implantable Cardioverter Defibrillator in Patients with Previous Coronary Bypass Surgery

From February 1988 until August 1991, 28 patients with prior coronary artery bypass grafting (CABG) received implantable Cardioverter defibrillator (ICD) therapy via a subxiphoid approach. Only one patient required conversion to a median sternotomy incision. The mean defibrillation threshold was 11.9 ± 4.4 J. The mean R wave was 8.2 ± 3.7 mV. One perioperative death occurred due to heart failure (mortality rate 1/28 [3.50%]). No patient required reexploration for bleeding. The subxiphoid method for ICD electrode implantation is safe and reliable in patients with prior CABG surgery.