[S]-AR-R 15896AR-A novel anticonvulsant: acute safety, pharmacokinetic and pharmacodynamic properties.

A rational, chemical, synthetic effort to identify promising low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists for use as antiepileptic drugs led to the discovery of AR-R 15035AR, or [RS]-alpha-phenyl-2-pyridine-ethanamine.2HCl. Chiral separation followed by intensive in vivo screening resulted in the selection of the [S] enantiomer, AR-R 15896AR, as the best compound for further preclinical development. AR-R 15896AR prevented tonic seizures in rodents for up to 6 to 8 h in response to maximal electroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as characteristic seizures following injections of N-methyl-DL-aspartic or kainic acids. AR-R 15896AR was ineffective in two kindling models of epilepsy, did not produce tolerance to MES, and was devoid of proconvulsant and phencyclidine-like properties in mice and rats, respectively. Therapeutic indices for AR-R 15896AR were comparable to or exceeded those for standard anticonvulsants. Orally administered AR-R 15896AR rapidly entered the rat brain and was eliminated in parallel from the plasma and plasma-free compartment. A dose-response relationship between plasma and brain levels after p.o. or i.v. administration of AR-R 15896AR and protection against MES was highly correlative. The time course for loss of protection against MES mirrored the elimination of the compound from brain and plasma. The total brain concentration (25 microM) of drug at the ED50 value (approximately 3 mg/kg) for protection against MES seizures was consistent with the reported affinity of AR-R 15896AR at the N-methyl-D- aspartic acid binding site (IC50 value = 1.3 microM). The present findings demonstrated the attractiveness of AR-R 15896AR as a candidate for further development to treat epilepsy.

The New York High-Risk Project: attention, anhedonia and social outcome.

In the New York High-Risk Project we have followed two samples of subjects (Sample A and Sample B) at risk for schizophrenic or affective disorders and low-risk controls from childhood to adulthood, in an attempt to identify early predictors of later psychopathology. We administered a large number of cognitive, psychometric and other types of measures to both samples as possible psychopathology predictors, including an index of attentional deviance assessed in childhood, the Physical Anhedonia Scale in adolescence, and three measures of social outcome in adulthood ('Suspicious Solitude', 'Social Insecurity', and 'Lack of Empathy'), derived from the Personality Disorders Examination. In the analysis of the combined samples, parental diagnostic group, gender, attentional deviance in childhood, and physical anhedonia in adolescence were used to predict three measures of social outcome in adulthood. While only physical anhedonia was directly related to all three social outcome measures, with the strongest relationship to Suspicious Solitude, attention deviance successfully predicted two of the three outcomes. Subjects at risk for affective disorder did not show increased levels of attention deviance, physical anhedonia, or social dysfunction, relative to the normal control subjects. Attention deviance appears to be a key neurobiological indicator and physical anhedonia appears to be a potentiating factor mediating the relationship between risk for schizophrenia and later social dysfunction.

Evaluation of new anti-infective drugs for the treatment of infective endocarditis. Infectious Diseases Society of America and the Food and Drug Administration.

These guidelines describe the design and implementation of clinical trials to assess the safety and efficacy of anti-infective drugs for the treatment of infective endocarditis. Identification and enrollment of patients in clinical trials is based on a modification of traditional criteria. To accrue a sufficient number of patients, only those with streptococcal or staphylococcal endocarditis should be included in studies. Results of treatment with approved drugs allow for projection of expected bacteriologic cure rates and survival rates. Prospective randomized, double-blind studies are recommended. These guidelines are based on the premise that future protocols may include shorter courses of therapy, combinations of drugs, or progression from parenteral to oral therapy. Clinical response is judged as cure, failure, or indeterminate; there is no "improved" category. Microbiologic response is categorized as eradication, persistence, or relapse. When a patient has shown no clinical evidence of active disease for a protracted period, there may be no need to perform a posttreatment blood culture; for such patients, the microbiologic response is termed presumptive eradication. Several months of follow-up may be necessary to detect late relapses.

Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat.

Studies conducted by Fisons Pharmaceuticals and the Antiepileptic Drug Development Program (ADD Program) of the Epilepsy Branch (NINDS, NIH) revealed that 'remacemide' (FPL 12924, formerly PR 934-423) was effective orally in the prevention of maximal electroshock seizures (MES) in rats. In this context (-)stereoisomer (FPL 14145) was of equal potency to the racemate (remacemide), while the (+)stereoisomer (FPL 14144) was 54% less potent. With respect to neurotoxicity, remacemide and its enantiomers possessed more favorable therapeutic indices than phenobarbital and valproate and less favorable indices than phenytoin and carbamazepine. The duration of protection of rats in the MES test at the ED50 or 3 x ED50 of remacemide and the (+)isomer was better or on par with the best reference compounds, phenytoin and phenobarbital. After subchronic administration of either the ED50 or the ED97 of remacemide, no tolerance developed in the hexobarbital sleep test, however, the activities of 3 hepatic microsomal enzymes were elevated. In naive rats high doses of remacemide or its (-)isomer and low doses of phenobarbital caused an increase in spontaneous motor activity. Alternatively, motor activity was depressed subsequent to high doses of phenobarbital and phenytoin. Remacemide was inactive against pentylenetetrazol and 'kindling' seizures. It was without effect in 5 electrophysiological tests (evoked responses, recurrent inhibition, long-term potentiation, penicillin-induced discharge rate and veratridine-induced depolarization) employing the in vitro hippocampal slice technique. Moreover, remacemide failed to demonstrate potent binding in vitro to neuronal L-glutamate, gamma-amino-butyrate A, adenosine A1, benzodiazepine, N-methyl-D-aspartate (strychnine-insensitive glycine and ion channel subsites) or muscarinic receptors. In conclusion, remacemide specifically prevents seizures elicited by MES, an action predicting utility in patients with generalized tonic/clonic convulsions.

Experimental Escherichia coli endocarditis in rats: roles of serum bactericidal activity and duration of catheter placement.

Studies were undertaken to investigate the relationship of the sensitivity of Escherichia coli to the bactericidal properties of serum and the ability of different strains to induce and sustain endocardial infection in rats. Strains of E. coli demonstrated different degrees of serum sensitivity, as determined by a method which employed concentrations of serum from 10 to 95% and periods of incubation as long as 24 h. The greater the serum sensitivity of the E. coli strain, the less able it was to initiate infection and the more rapidly it was spontaneously eliminated from established infections. Endocardial infection with E. coli was established by intravenous challenge in rats with polyethylene catheters passing through the aortic valve into the left ventricle. An E. coli strain of low serum sensitivity was used; the initiation of infection depended upon the length of time the catheter had been in place and, in addition, whether the catheter was in place at the time of bacterial challenge. Removal of the catheter permitted spontaneous sterilization of the endocardial vegetations. The time necessary for sterilization was in direct proportion to the length of time the catheter remained in place following bacterial challenge. If the catheter was not removed, sterilization of the endocardial vegetations did not take place. These studies suggest that serum bactericidal activity is an important host defense mechanism, acting to prevent the initiation of endocarditis in the case of highly serum-sensitive E. coli and to sterilize experimentally induced endocarditis in the case of less-serum-sensitive bacteria. The catheter used to induce nonbacterial endocardial vegetations favored the colonization of vegetations by E. coli, and it delayed the spontaneous sterilization of infected vegetations which occurred in relation to the susceptibility of the strain to the bactericidal properties of the serum. This effect of the catheter was not attributable to bacteria remaining viable in its lumen, nor was it attributable to inhibition of the bactericidal capacity of the serum as measured in vitro. Whatever the mechanism responsible for the catheter effect, experimental studies of the evolution of infections established with this technique must take into consideration the duration of catheter placement and whether and for how long it was present before or after inoculation with test bacteria.

The pathogenesis of infective endocarditis.

Three aspects of our current understanding of the pathogenesis of infective endocarditis are reviewed: the size of the infected vegetation, host defence mechanisms and conditions which determine the outcome of experimental infection. Animal studies have been conducted with anticoagulants in which fatal infective endocarditis was produced without macroscopic evidence of endocardial vegetations. Detection of such lesions in man would change our perception of the epidemiology and clinical course of the disorder. It is probable that polymorphonuclear leucocytes are important in limiting the development of infected vegetations throughout the vascular system and, because of their ineffectiveness in the left side of the heart, are probably responsible for the preponderance of infections within that particular part of the circulation. Furthermore, polymorphonuclear leucocytes may also contribute to the pathogenesis of valve perforation. Finally, the size of the bacterial challenge, and the duration of catheterization of the heart to induce infection, have been shown to significantly influence the natural history of experimental infection and also the effectiveness of prophylactic antibiotics. Any comparison of the effectiveness of different prophylactic measures will require careful standardization of these conditions. It is difficult to determine the optimal size of the bacterial inoculum in animal studies since so little is known about this factor in man. Peripheral infections in animals may disseminate sufficient bacteria to produce endocardial infection and yet not be easily, if at all, detectable in the circulating blood.

Treatment of staphylococcal pyelonephritis in rats with N-formimidoyl thienamycin.

The therapeutic efficacy of N-formimidoyl thienamycin alone or coadministered with MK0791, an inhibitor of renal dehydropeptidase-I, compared to methicillin in experimental pyelonephritis in rats was investigated. Pyelonephritis was produced with a methicillin-sensitive strain (2776) and a methicillin-resistant strain (Berman) of Staphylococcus aureus. N-formimidoyl thienamycin alone or coadministered with the inhibitor was significantly better than methicillin when treating methicillin-sensitive or methicillin-resistant infection. There was a trend suggesting that N-formimidoyl thienamycin coadministered with MK0791 was overall the best agent. These studies show that N-formimidoyl thienamycin is efficacious in the treatment of S. aureus pyelonephritis in the rat regardless of methicillin sensitivity, and this agent plus the dehydropeptidase inhibitor should be considered in the treatment of such infections.

Antibiotic prophylaxis against streptomycin-resistant and -susceptible Streptococcus faecalis endocarditis in rabbits.

This report describes the capacities of ampicillin, vancomycin, streptomycin, gentamicin, and combinations thereof to prevent endocarditis in rabbits challenged with either streptomycin-resistant (three strains) or streptomycin-susceptible (one strain) Streptococcus faecalis. Vancomycin (15 mg/kg) alone was effective in preventing infection with three of four strains, including two which were streptomycin resistant. Vancomycin (30 mg/kg) alone was effective against the other streptomycin-resistant strain. The vancomycin-gentamicin combination was the only therapeutic regimen to demonstrate complete prophylaxis for all strains regardless of streptomycin susceptibility. The ampicillin-gentamicin combination was variably effective despite in vitro synergism.

Natural history of aortic valve endocarditis in rats.

Sterile aortic vegetations were produced in rats by introducing a polyethylene catheter through the right carotid artery. The catheter was either left in place throughout the experiments or removed before bacterial challenge. Bacterial endocarditis was uniformly produced by intravenous injection of 10(7) colony-forming units of Staphylococcus aureus or Streptococcus intermedius, whether the catheter was left in place or removed. However, in rats with the catheter left in place, bacterial multiplication within the vegetations with both strains was accelerated, and mortality from Staphylococcus aureus infection was increased. Using 10(7) colony-forming units of serum-resistant Escherichia coli as a test microorganism, we found a marked difference in the production of endocarditis depending upon whether the catheter was left in place or removed before injection; only those animals infected with the catheter in place developed infection. From these experiments in rats, it was evident that the presence of a foreign body has a considerable influence on the ability of bacteria to grow within an intravascular vegetation. In addition, a striking difference in the virulence of the three strains studied was established; Staphylococcus aureus was the most, and E. coli the least, pathogenic.

Effect of nitrogen mustard on natural history of right-sided streptococcal endocarditis in rabbits: role for cellular host defenses.

Cellular host defenses are considered to be ineffective in bacterial endocarditis; the microorganisms in infected vegetations are protected from phagocytic cells by dense layers of fibrin. To test this hypothesis, nitrogen mustard-induced agranulocytosis and leukopenia were produced in rabbits with right-sided streptococcal endocarditis. The spontaneous sterilization of tricuspid infection observed in the control animals was not present in the granulocytopenic, leukopenic animals. Since the bacterium Streptococcus intermedius is not sensitive to the complement-mediated bactericidal effect of serum and since the animals were not bacteremic during the time of agranulocytosis, an inhibitory effect of the drug on local cellular host defense mechanisms is postulated. We suggest that the spontaneous sterilization of infective endocarditis in the right side of the heart in rabbits is mediated by cellular host defenses.

Experimental endocarditis: prophylaxis of Candida albicans infections by 5-fluorocytosine in rabbits.

The prevention of Candida endocarditis in the rabbit was easily accomplished with a single intramuscular injection of 75 mg of 5-FC (A predominantly fungistatic agent) per kg either 40 min before, or at the same time as, the intravenous challenge with Candida albicans. Renal infarcts were observed more often in rabbits with infected valvular vegetations than in control rabbits with sterile endocarditis. The prophylactic effect of 5-FC is greater in aortic vegetations than in the kidneys. This may be related to differences in the pathophysiology of infection and the pharmacokinetics of 5-FC in the two areas.