Life-threatening bilateral aorto-ostial coronary artery disease in an octogenarian.

Aorto-ostial disease is difficult to approach percutaneously; therefore, a surgical option may be more desirable. We describe a case of an octogenarian in which the clinical arguments and technical approach have been summarised for a successful percutaneous therapeutic strategy. (Neth Heart J 2009;17:30-2.).

[Diagnostic image (209). A man after submersion in water]. / Diagnose in beeld (209). Een te water geraakte man.

A 32-year-old man was presented with severe hypothermia and respiratory insufficiency after submersion in water. The ECG showed Osborn waves and a prolonged QRS and QT duration which normalized after correction of the hypothermia.

VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation.

INTRODUCTION: Many relapses of atrial fibrillation (AF) occur, especially during the first week(s) after electrical cardioversion (ECV). The aim of the present study was to compare in a randomized design the efficacy of verapamil (intracellular calcium lowering) versus digoxin (calcium increasing) for maintenance of sinus rhythm after ECV. METHODS AND RESULTS: Ninety-seven patients with persistent AF were randomized to verapamil (n = 49) or digoxin (n = 48) for 1 month before and 1 month after ECV. The first month after ECV, patients recorded heart rhythm using daily transtelephonic monitoring. No additional antiarrhythmic drugs were given. Of the 97 patients, 43 patients (20 verapamil) underwent ECV per protocol. Median previous AF duration was 18 and 26 days for verapamil and digoxin, respectively. There were no differences in atrial dimensions and underlying heart disease between the two groups. The success rate of ECV was 75% versus 83% (P = NS). After 1 month, 47% versus 53% (P = NS) had recurrence of AF. Median time to recurrence was 5 days (range 0 to 26) versus 8 days (range 2 to 28) (P = NS), respectively. CONCLUSION: Stand-alone intracellular calcium lowering by verapamil around ECV does not enhance cardioversion outcome.

Immediate reinitiation of atrial fibrillation after electrical cardioversion predicts subsequent pharmacologic and electrical conversion to sinus rhythm and amiodarone.

Ninety-one percent of patients with atrial fibrillation (AF) resisting electrical cardioversion because of immediate reinitiation of AF after the shock maintain long-term sinus rhythm with amiodarone and repeat cardioversion. Thus, immediate reinitiation of AF is an important sign that should guide further treatment in patients with electrical cardioversion-resistant AF.

Sample pooling to enhance throughput of brain penetration study.

The advent of combinatorial synthesis and high throughput screening in pharmaceutical research has inevitably given rise to a large number of interesting prelead compounds that requires rapid analytical throughput for kinetic characterization. The traditional approach of one-compound-at-a-time bioanalysis has not been able to meet the demand for high productivity of pharmacokinetic screening. This report demonstrates the application of sample pooling in expediting the pharmacokinetic screening, including assessment of brain penetration, of six NK1 receptor antagonists in rats: CAM 6108 (C1), CAM 6122 (C2), CAM 6178 (C3), CAM 5825 (C4), CAM 6182 (C5), and CAM 6121 (C6). The approach was adopted to avoid complications associated with cocktail dosing where multiple compounds are administered to one animal. The present investigation features individualized dosing (one compound per animal), followed by sample pooling of brain and plasma and bioanalysis via a conventional LC-fluorescence method. Rats were dosed intravenously with each of the six NK1 receptor antagonists and blood and brain samples were harvested at suitable post-dose time intervals. Plasma or brain homogenate samples from the same time points were pooled into two groups (C1-C3 and C4-C6) for assay. Drug compounds in plasma or brain were extracted by protein precipitation and quantitated using a validated gradient HPLC/fluorescence method, which was made feasible for both groups of compounds with a modification in gradient scheme. Plasma assay precision and accuracy for C1-C6 were < or =4.7% and within +/-9.8%, respectively. Brain homogenate assay accuracy for C1-C6 was within +/-7.0%. Brain penetration of these compounds was evaluated as the AUC of brain and plasma and their respective brain/plasma AUC ratio. The sample pooling approach helped to quickly identify C1 as the NK1 receptor antagonist with the greatest extent of brain penetration, followed by C2, C6, C4, C5, and C3 in that order. By employing sample pooling approach, pharmacokinetic parameters and brain penetration of all six compounds were obtained in a fraction of the time required by conventional single compound dosing and analysis.

Sample pooling to expedite bioanalysis and pharmacokinetic research.

In the progression from drug discovery to development, not only pharmacokinetic (PK) characterization needed for lead compound selection often becomes a rate-limiting step, but also high volume of routine sample analysis ensued from numerous required biodisposition studies for the lead compounds and their back-ups often place a burdensome hurdle to the throughput of IND and NDA development phases. Higher throughput of PK screening via cocktail dosing has been reported to accelerate PK screening in the discovery phase. However, concerns on drug-drug interactions and other limitations associated with the cocktail M-in-One dosing (multiple compounds per dose per animal) has prompted the present investigation of sample pooling alongside One-in-One dosing strategy (one compound per dose per animal) as an alternative to the cocktail dosing approach. Using traditional HPLC for bioanalysis as an example, the present study illustrate the concept and usefulness of sample pooling that could facilitate the throughput of PK screening and characterization in both discovery and development phases. Six proprietary dopamine D4 receptor antagonist preleads representing three different chemical classes, used as model compounds (C1-C6), were administered orally to rats. One rat received one compound and three rats were used for each compound. Six unknown plasma samples from six different rats at each time point were pooled. The pooled plasma samples were extracted by a one-step liquid-liquid extraction and concentrations of the six preleads were quantitated simultaneously. By sample pooling, a substantial amount of PK information was obtained at the same time for the six preleads, which requires much less workload than when bioanalysis is dealt with one compound at a time. For the first time in one aspect of innovative bioanalysis, the present investigation has demonstrated that sample pooling following One-in-One dosing can be utilized to enhance the throughput rate in PK screening in discovery phase. The sample pooling approach is likely to be useful in enhancing the throughput of PK characterization in development phase. With the advent of LC-MS and its becoming user-friendly, where separation of drug compounds is no longer an issue, the uniqueness of sample pooling may also pose a new way of thinking in regard to the old ways of handling bioanalysis for traditional PK research.

Development of HPLC plasma assays for CAM 4515 and CAM 4750, two new nonpeptide tachykinin antagonists, and application to bioavailability studies.

CAM 4515 and CAM 4750 are new nonpeptide tachykinin NK1 receptor antagonists with different lipophilicities. Two separate, simple, and sensitive HPLC methods for the quantitation of these two compounds in plasma and the evaluation of their oral bioavailability in rats were developed and validated. Extraction of CAM 4515 from plasma involved protein precipitation with acetonitrile, while that for CAM 4750 involved a one-step liquid-liquid extraction with methylene chloride. The analytes in extracts were chromatographed on a C18 column using two different separation buffers, 47% 0.02 M sodium citrate (pH 3.5)-53% acetonitrile for CAM 4515 and 59% 0.02 M potassium phosphate dibasic (pH 7.0)-41% acetonitrile for CAM 4750, and both compounds were detected by fluorescence (excitation 278 nm; emission 342 nm). Stability profiles of both drugs at -20 degrees C or room temperature in plasma and in reconstituted buffers were good. The limit of quantitation for both drugs was 5 ng ml-1 with good linearity from 5 to 1000 ng ml-1 using 100-200 microliters of plasma. Excellent precision (relative standard deviation < 8.3%) and accuracy (relative error +/- 9.2%) were observed for both CAM 4515 and CAM 4750. Oral bioavailability studies were conducted for each compound in rats receiving a p.o. dose of 20 mg kg-1 and an i.v. dose of 5 mg kg-1. The absolute oral bioavailability of CAM 4750 (80%) was estimated to be 40-fold greater than that of CAM 4515 (2%). The experimental results suggest that incorporation of a pyridine group into the structural backbone may greatly improve bioavailability.