Preclinical profile of stereoisomers of the anticonvulsant remacemide in mice

Stereoisomers of remacemide (racemate form) were compared for anticonvulsant efficacy and safety in mice. In the maximal electroshock seizure (MES) test for oral efficacy, the (-) stereoisomer, FPL 14145, was more potent than the racemate or the (+) stereoisomer, FPL 14144. Respective ED50 values (expressed as mg/kg) were: remacemide, 58; FPL 14145, 45; FPL 14144, 79. In 2 of 3 tests for neural impairment, FPL 14145 yielded significantly better therapeutic indices (toxic dose 50/ED50) than the racemate. The margin of safety (estimated median lethal dose ED50) was more favorable for FPL 14144: remacemide, 15.1; FPL 14144, 18.9; FPL 14145, 15.7. The duration of protection against MES indicated the stereoisomers were longer acting than the racemate. After intravenous administration the order of potency against MES was similar: FPL 14145 greater than remacemide greater than FPL 14144. Following daily administration of the oral ED98 for 4 days, with a dose response curve run on day 5, the MES ED50 values for all compounds were increased. The test indicates tolerance. In the pentylenetetrazol infusion test the racemate and FPL 14144 demonstrated more proconvulsant properties than FPL 14145. Intraperitoneal administration of 50 mg/kg or more produced changes in behavior with all compounds. At higher doses the racemate and FPL 14145 elicited more severe symptoms with death at 200 mg/kg.     

Tachykinin receptor cross-talk. Immunological cross-reactivity between the external domains of the substance K and substance P receptors.

In the present study, we have chemically synthesized peptides which correspond to the four putative extracellular domains of the predicted substance K (SK) receptor protein and raised specific polyclonal antibodies against these peptides. These antibodies were then tested for both structural and functional recognition of epitopes on the substance P (SP) receptor on rat AR42J pancreatic cells and human IM9 lymphoblasts, which express the SP receptor, but not the SK receptor. Antibodies directed against the first, second, and fourth external domains of the predicted SK receptor recognized a 58-kDa protein on AR42J cells. This protein has a molecular weight similar to the previously demonstrated SP receptor on both AR42J cells and IM9 cells. Furthermore, antibodies against the second and fourth extracellular domains significantly inhibited specific 125I-SP binding on both AR42J and IM9 cells, and also significantly inhibited SP-induced mobilization of [Ca2+]i on AR42J cells. These data suggest that the second and fourth extracellular domains of the SK and SP receptors may share common structural motifs for ligand binding and signaling mechanism.     

Partial purification and osteoinductive activity of swine bone morphogenetic protein.

Bone morphogenetic protein (BMP) was isolated from the bone matrix of swine and partially purified by means of differential precipitation and molecular sieve chromatography. The molecular weight of BMP estimated by SDS-gel electrophoresis was 19,000 dalton. Bioassay by implanting two milligrams of BMP fraction into thigh muscles of mice resulted in bone formation in 100% of the experimental animals.

     

Long-term treatment of ventricular tachycardia with amiodarone in presence of severe left ventricular dysfunction.

A group of 34 consecutive patients with coronary artery disease (n = 29) or dilated cardiomyopathy (n = 5) (3 women, 31 men, age 38-80 yr) who had severely impaired left ventricular function (left ventricular ejection fraction less than or equal to 40%) and high-grade ventricular ectopic activity (sustained or nonsustained ventricular tachycardia or ventricular fibrillation) were treated with amiodarone (mean dose: 206 mg/d) and followed for 1-117 (mean: 49) months. In the total group, there were seven sudden deaths, five deaths due to pump failure, one non-cardiac death, and two successful heart transplantations during follow-up. Thus the annual cardiac mortality in these carefully selected and followed patients was 8, 6%, the annual cardiac event rate was 10, 1%. The cumulative cardiac survival-rate was 62% after 5 years and 41% after 10 years. In five patients, treatment was interrupted after 10 to 43 months, three of the patients were alive at follow-up and two suffered cardiac death, resulting in an annual cardiac death rate of 12% in this subgroup of treatment. Based on the results of this retrospective analysis we conclude that in patients with low left ventricular ejection fraction and nonsustained or sustained ventricular tachycardia treated with low dose amiodarone, mortality was unexpectedly low. Thus, it may be the antiarrhythmic treatment to be considered in patients with ventricular tachycardia and severe left ventricular dysfunction.     

An improved method for determining 89Sr and 90Sr in urine

A method has been developed for the rapid isolation and quantitation of 89Sr and 90Sr in urine samples. The radiostrontium is concentrated from the bulk urine sample by coprecipitation with calcium phosphate. The precipitate is then wet ashed with nitric acid, and a solution of the resulting residue in 2 M HNO3-0.5 M Al(NO3)3 is passed through an extraction chromatographic column containing a supported crown ether that preferentially retains strontium. Sorbed strontium may then be eluted from the column with either dilute HNO3 or water and counted via liquid scintillation. A new counting scheme that permits quantitation of both 89Sr and 90Sr on the same day the separation is performed is described.     

Long-term survival after vinblastine, bleomycin, and cisplatin treatment in patients with germ cell tumors of the ovary: An update

Thirteen patients with a malignant germ cell tumor of the ovary have been treated with a combination of vinblastine, bleomycin, and cisplatin (VBP). In 12 patients a complete remission was reached, which was maintained in 10 of these patients. One patient with large tumor residues and a partial remission became CR after surgery. The tumor recurred in 2 patients after 6 and 27 months. Overall, 11 of these patients are in long-term remission, from 14 to 84 months after the start of treatment. VBP is an effective treatment for malignant germ cell tumors of the ovary, even in patients with large tumor residuals.