Differing effects of alpha-difluoromethylornithine and CGP 40116 on polyamine levels and infarct volume in a rat model of focal cerebral ischaemia.

Focal cerebral ischaemia was induced in rats by occlusion of the left middle cerebral artery. Two days later, infarct volume was determined by magnetic resonance imaging and the concentrations of the polyamines putrescine (PU), spermine and spermidine by HPLC. In control (occluded) animals, PU levels were elevated in infarcted and non-infarcted areas of the left hemisphere. Treatment with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine, prevented the ischaemia-induced increase in tissue PU without affecting infarct volume. Conversely, administration of the N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116 decreased cortical infarction without changing the tissue content of PU. We conclude that there is no direct link between NMDA receptor activation and brain PU, or PU and post-ischaemic tissue damage, and that inhibitors of ODC are not cerebroprotective in this animal model of stroke.     

Evaluation of quinolinic acid induced excitotoxic neurodegeneration in rat striatum by quantitative magnetic resonance imaging in vivo.

Excitotoxic neurodegeneration in the rat striatum was induced by direct injection of quinolinic acid. The degree of damage was evaluated in vivo 1 day later by quantitative magnetic resonance imaging (MRI) and 7 days later in the same animals by measuring the activities of the neuronal marker enzymes choline acetyltransferase and glutamic acid decarboxylase. Striatal damage assessed using the two approaches was highly correlated. Moreover the cerebroprotective efficacy of the N-methyl-D-aspartate receptor antagonist CGP 40116 was indistinguishable based on all analytical parameters. MRI, however, was more reproducible than the enzymatic methods and was faster and simpler for routine analyses of excitotoxic damage and cerebroprotection in vivo.     

Electrophysiological characterization of a novel potent and orally active NMDA receptor antagonist: CGP 37849 and its ethylester CGP 39551

The selectivity and potency of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP 37849 and CGP 39551, were investigated in vitro and in vivo using electrophysiological approaches. Like the reference blocker DL-AP5, both compounds acted in vitro (hippocampus, substantia nigra, spinal cord) to antagonize the excitatory actions of exogenously administered NMDA as well as the synaptically elicited, physiological NMDA receptor responses in hippocampus and spinal cord. In all isolated preparations CGP 37849 was more potent than CGP 39551, and 5- to 10-fold more potent than DL-AP5. Neither compound showed any marked effect on responses evoked by quisqualate and kainate. NMDA excited dopaminergic cells in the pars compacta region of the substantia nigra in a concentration-dependent manner. This effect also could be selectively antagonized by CGP 37849 and CGP 39551. In the anaesthetized rat, excitatory responses of hippocampal pyramidal cells evoked by iontophoretic application of NMDA were antagonized by CGP 37849 and CGP 39551 following their oral administration without reducing quisqualate or kainate responses. In contrast to the in vitro situation, CGP 39551 was more potent than CGP 37849 in vivo. Effective doses were 30 mg/kg p.o. for CGP 39551 and 100 mg/kg p.o. for CGP 37849. In conclusion, it is demonstrated that CGP 37849 and CGP 39551 selectively antagonize NMDA evoked neuronal responses in vivo and in vitro and that the drugs are centrally active following their oral administration.     

CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity

1. The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2. Radioligand binding experiments demonstrated that CGP 37849 potently (Ki 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-((+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nM, and was 4, 5 and 7 fold more potent than the antagonists [+/-)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3. CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4. In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CA1 pyramidal cell firing rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Value of radionuclide ventriculography in the immediate characterization of patients with acute myocardial infarction

The ability of admission radionuclide ventriculography to discriminate among various clinical subsets was evaluated in patients with acute myocardial infarction. One hundred patients with acute myocardial infarction were evaluated within 8 ± 3.1 hours (mean ± standard deviation) after the onset of chest pain. Forty-one patients were in Killip functional class I, 52 in class II and 7 in class III. The mean radionuclide left ventricular ejection fraction was significantly lower in patients with higher Killip classification because of significant elevation of mean left ventricular end-systolic volume rather than significantly altered mean end-diastolic volume. Killip classification frequently failed to correlate with ejection fraction in individual cases. Admission chest X-ray findings were categorized according to the presence of findings suggestive of impaired left ventricular function. Mean left ventricular ejection fraction was significantly lower in patients with abnormal than in patients with normal chest X-ray findings because of significant elevations in both mean end-diastolic and end-systolic volumes. The chest X-ray findings frequently failed to correlate with ejection fraction in individual cases.Stepwise linear regression analysis was employed to analyze the ability of historical, physical, electrocardiographic and chest X-ray findings to predict radionuclide left ventricular ejection fraction. The most predictive variables in order of decreasing significance were anterior myocardial infarction, abnormal chest X-ray findings, rales to two thirds of the posterior thorax, previous myocardial infarction, transmural myocardial infarction and heart rate greater than 100 beats/min. However, even these six optimal predictive variables could explain only 42 percent of the observed variability in left ventricular ejection fraction. Thus, early radionuclide ventriculography adds significantly to the discriminant power of clinical and radiographic characterization of ventricular function in patients with acute myocardial infarction.     

Use of casts in the necropsy diagnosis of fetal congenital heart disease

Objective—To evaluate a casting technique in the interpretation of fetal cardiac anatomy.

Design—In 32 fetuses, the echocardiographic and cast features were compared and correlated.

Patients—Three normal fetal heart specimens from spontaneous abortuses and 32 specimens from spontaneous or induced abortions with congenital heart malformation.

Results—There was close correlation between the echocardiographic and anatomical features in 32 abnormal fetuses studied. In some, additional features of diagnosis could be displayed on the cast and the relative sizes of the cardiac structures could be appreciated and defined.

Conclusions—With increasing echocardiographic detection of congenital heart disease in early prenatal life, an increasing number of fetal heart specimens of small size are dissected for pathological confirmation. The use of silicone rubber casts to reproduce the internal anatomy proved a useful addition to dissection, providing a three dimensional model of the cardiac defect.

     

Deliberate self-harm in adolescents in Oxford, 1985-1995

Deliberate self-harm (DSH) has been one of the major health problems of adolescents in the U.K. for many years. Any changes in rates of DSH or the demographic characteristics of the patient population are likely to have important implications for clinical services and for future suicidal behaviour. Following a decline in rates in the late 1970s and mid 1980s, there were signs in the late 1980s that rates were beginning to increase again. We have used data collected by the Oxford Monitoring System for Attempted Suicide on the basis of patients presenting to the general hospital in Oxford to review trends in DSH in under 20-year-olds between 1985 and 1995. There was a substantial increase in the numbers of teenage DSH patients during the 11-year study period, with an increase between 1985-1986 and 1994-1995 of 27.7% in males, 28.3% in females, and 28.1% overall. There were no demographic changes within the catchment area to explain a change of this size. As rates of repetition of DSH also increased in both sexes during the study period the overall number of episodes of DSH rose even more between 1985-1986 and 1994-1995 (+56.9% in males, +46.3% in females, and +49.4% overall). As in previous studies the majority of adolescents had interpersonal problems and/or difficulties with studying or employment. Self-poisoning with paracetamol and paracetamol compounds became increasingly common such that by 1995 these were used in almost two-thirds of overdoses. The recent increase in DSH in adolescents has important implications for general hospital and adolescent psychiatric services. The greater frequency of repetition of DSH may herald increased future suicide rates. The case for restricting the amount of paracetamol available is overwhelming. Evaluative trials of specific interventions following adolescent DSH are urgently required.