Antibiotic therapy for foot infections in diabetics.
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Ampicillin↗
Biomedical subjects
M L Berger
Publications and source records attributed to M L Berger.
Comparison of the effects on quality of life and of the efficacy and tolerability of lovastatin versus pravastatin. The Quality of Life Multicenter Group.
This multicenter study compared the effects of lovastatin (40 mg) and pravastatin (40 mg) on quality of life. Men, aged 20 to 65 years old, with primary hypercholesterolemia (types IIa and IIb) were eligible for enrollment if baseline low-density lipoprotein cholesterol met the first National Cholesterol Education Program adult treatment guidelines. Eligible patients were enrolled into a 6-week diet baseline period, followed by a 6-week diet-plus-placebo period. Patients whose low-density lipoprotein cholesterol still met National Cholesterol Education Program guidelines for drug therapy were randomized into the double-blind, active-treatment period to receive either lovastatin 40 mg or pravastatin 40 mg/day for 12 weeks. Clinic visits were scheduled every 4 weeks and included complete serum lipid profiles, monitoring of adverse experiences, and patient completion of health-related quality-of-life questionnaires. The primary end point of the study was the change in quality of life, as measured by the Nottingham Health Profile (part 1) after 12 weeks of treatment. Secondary end points included responses to a general health question from the National Health and Nutrition Examination Survey, sexual function questions from the Medical Outcomes Study, and stress/life event questions from the National Institutes of Health Post-Coronary Artery Bypass Grafting Study. No significant differences between the 2 groups were observed in tolerability, health-related quality-of-life measures, or changes in lipid profiles.
Adult↗
Aminooxy-analogues of spermidine: new partial agonists and antagonists at the polyamine site of the rat hippocampal NMDA receptor complex.
The amino-1-oxy- and amino-8-oxy-analogues of spermidine (1-O-SPD and 8-O-SPD) were tested in vitro with rat hippocampal membranes as potential modulators of the N-methyl-D-aspartate (NMDA) receptor complex via the polyamine regulatory site. In the presence of 1 microM glutamate and glycine, the binding of the NMDA channel ligand [3H]MK-801 was stimulated by 8-O-SPD (EC50 = 50 microM); 1-O-SPD was without significant influence at concentrations up to 1 mM. Addition of 2 and 4 microM of the polyamine agonist spermine eliminated the stimulatory property of 8-O-SPD, whereas 1-O-SPD was inhibitory under these conditions (IC50 = 274 and 481 microM, respectively). At higher concentrations of spermine, both compounds were inhibitory. Inhibition of [3H]MK-801 binding by the inverse polyamine agonists 1,10-diaminodecane, 1,12-diaminododecane, and arcaine was attenuated by 1 mM 1-O-SPD. The data are compatible with the notion that 8-O-SPD is a partial polyamine agonist and that 1-O-SPD is an antagonist without intrinsic activity.
Animals↗
Benzimidazole-type glycine antagonists: the role of the ring nitrogen atoms.
Several derivatives of 1H-benzimidazole-2-carboxylic acid (BICA, 2a) were tested in vitro in comparison to 1H-indole-2-carboxylic acid (ICA, 1e) for their ability to displace [3H]glycine from rat hippocampal membranes. Compound 2a was 8 times more potent than 1e (Ki 5.3 microM, as compared to 42 microM). However, introduction of a carboxymethyl group or a corresponding ester at position 3 had no positive effect on the potency of 2a, while this type of structural modification increased the potency of 1e significantly. Nevertheless, 1-carboxymethyl-BICA (2b) displaced [3H]glycine with similar potency as the corresponding 3-carboxymethyl-ICA 1c, indicating that also a nitrogen atom lacking a hydrogen atom can be engaged in glycine receptor interaction. N-Methylation strongly reduced the potencies of both BICA and ICA derivatives.
Animals↗
Novel oral medication delivery system for famotidine.
A famotidine wafer that rapidly disperses on the tongue without water is a novel alternative to other histamine2 (H2)-antagonist dosage forms. Benefits associated with such a dosage form include convenience and potentially improved compliance for patients who dislike or have difficulty taking tablets and capsules. This report describes the research of three studies on the famotidine wafer dosage form. In the first trial, the bioequivalence and tolerability of the new 40-mg famotidine wafer and the marketed 40-mg famotidine tablet were studied in a 2-period crossover study (n = 18). The two formulations were bioequivalent as assessed by area under the plasma concentration versus time curve and maximum plasma concentration of famotidine. The plasma concentration of famotidine associated with 50% inhibition of pentagastrin stimulated gastric acid secretion (EC50; 10 ng/mL) was attained on average within 0.5 hours post-dose for the wafer and tablet. In a second trial, the tolerability of the famotidine 20-mg and 40-mg wafers or placebo given twice daily (bid) for 14 days were evaluated (n = 192). Both wafer strengths were well and equally tolerated. In a third trial of 450 subjects, the 40-mg wafer was preferred over tablets by 75% of the subjects, when they were asked to consider the method of administration and flavor. When used as an alternative to tablets and other conventional dosage forms, the wafers have the potential therapeutic benefit of improved compliance. It is concluded that similar systemic exposure, excellent tolerability, palatability, and preference make the famotidine wafer a clinically acceptable and convenient dosage from for patients on H2-antagonist therapy.
Administration, Oral↗
On the true affinity of glycine for its binding site at the NMDA receptor complex.
To determine the exact potency of inhibitors acting at the glycine site of the NMDA receptor complex using [3H]glycine as a radioligand, the true equilibrium constant (KD) of the radioligand has to be known. To achieve this goal, (1) the contamination of water by glycine was studied, (2) the true affinity of glycine for the NMDA receptor was estimated by different methods, and (3) the inhibition constant of a number of antagonists was determined. HPLC analysis of the deionized water used for the preparation of the assay buffers and solutions resulted in glycine concentrations below 6 nmol/L in four out of seven samples analyzed. The observable equilibrium constant of [3H]glycine binding (Kobs) was found to vary, in the presence of 10-mumol glutamate per liter, between 36 and 163 nmol/L (mean +/- SD: 69 +/- 21 nmol/L, 140 determinations). Based on the observation that the polyamine spermine increased the potency of glycine, but not that of glycine antagonists, an algorithm was developed to calculate KD from Kobs- and IC50-values obtained with and without 100-mumol spermine per liter. Using four different antagonists, KD-values between 24 and 57 nmol/L were obtained. Computer analysis of glycine-stimulated [3H]MK-801 binding resulted in EC50-values between 22 and 35 nmol/L. Based on these results, a true affinity constant for [3H]glycine of 40 nmol/L was assumed and used for the determination of Ki-values of 15 different inhibitors of [3H]glycine binding.
Algorithms↗
Role of glucocorticoids in the cholinergic degeneration in rat hippocampus induced by ethylcholine aziridinium (AF64A).
Glucocorticoids potentiate hippocampal damage induced by various noxious insults in vivo and in vitro and are implicated in age-related loss of neurons in the hippocampus of various species. The cholinergic innervation of the hippocampus appears to be especially prone to the endangering effect of glucocorticoids, since corticosterone, like acute stress or ACTH, induces a rapid activation of the cholinergic septo-hippocampal pathway. We now report the influence of glucocorticoids on the degeneration of this pathway induced by the cholinergic neurotoxin ethylcholine aziridinium (AF64A). The toxic effect of a submaximal dose of AF64A on cholinergic neurons was evaluated in rats during exposure to glucocorticoids or vehicle as well as in adrenalectomized or sham-operated rats. Daily treatment with either corticosterone or dexamethasone, starting 7 d before the bilateral intracerebroventricular injection of AF64A (1 nmol/ventricle), significantly increased the AF64A-induced loss of ChAT activity in the whole hippocampus, whereas bilateral adrenalectomy 7 d prior to AF64A-injection attenuated the effect of AF64A. Short-term exposure to corticosterone starting 24 hr before AF64A was as effective as the 7 d pretreatment. Dexamethasone exacerbated the AF64A-induced cholinergic lesion in the hippocampal subregions CA1, CA3, and dentate gyrus, and adrenalectomy protected all subregions against the action of AF64A. Along the longitudinal axis of the hippocampus a comparable influence was seen in the dorsal and ventral parts. The subregional pattern in the response to glucocorticoid suggests the involvement of mineralocorticoid type I receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Interaction of long chain n-alkyl diamines with the NMDA receptor complex.
Long chain 1, omega-diamines with 8, 10, 12, 14 and 16 carbon atoms reduced the binding of [3H]MK 801 to rat hippocampal membranes with IC50 values of 333, 72, 16.5, 4.7 and 4.3 microM, respectively. In the presence of medium-effective concentrations of the diamines, the concentration response curve of the stimulation by the polyamine spermine was shifted to higher spermine concentrations, reaching similar maximal stimulation as in the absence of the diamines. In the case of 1,12-diaminododecane (N-12-N) and 1,14-diaminotetradecane (N-14-N), the extent of this shift was compatible with competitive antagonism of spermine. Inhibition of [3H]MK 801 binding by long chain diamines was sensitive to spermine, inhibition by N-12-N and N-14-N exhibited the highest sensitivities. Of all diamines tested, N-12-N and N-14-N seem to be the most likely candidates for inverse polyamine agonists.
Amines↗
Cholinergic markers in ALS spinal cord.
We analyzed binding sites for quinuclidinyl benzilate (QNB) and hemicholinium-3 (HC-3) by quantitative slice autoradiography and the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in spinal cord of 5-7 patients with amyotrophic lateral sclerosis (ALS). In the ventral horn, QNB binding sites were markedly reduced (38% of controls; P less than 0.001), whereas HC-3 binding sites were only moderately affected (76%, P less than 0.01). Losses in cholinergic marker enzymes were inconsistent. The loss of muscarinic binding sites in the ventral horn was the most reliable cholinergic disease marker in ALS.
Acetylcholinesterase↗
Ranitidine does not have a uniquely lower affinity for cerebral H2-receptors.
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Animals↗
Membrane stabilization as a fundamental event in the mechanism of chemoprotection against chemical intoxication.
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Animals↗
Cholinergic deficit induced by ethylcholine aziridinium (AF64A) in rat hippocampus: effect on glutamatergic systems.
The reaction of the glutamatergic systems in the rat hippocampus to the withdrawal of cholinergic function after cholinergic degeneration induced by ethylcholine aziridinium (AF64A) was investigated. Furthermore, the question whether blockade of N-methyl-D-aspartate (NMDA) receptors by MK-801 has an impact on the extent of the cholinergic lesion was addressed. After bilateral intracerebroventricular injection of AF64A (2 nmol/ventricle) the activity of choline acetyltransferase (ChAT) started to decline in the hippocampus within 24 h. The reduction of ChAT activity reached its maximum within 4 days (65%) and persisted during the observation period of 65 days. The loss of ChAT activity was accompanied by a transient decline in the level of glutamate, which was most pronounced 1 to 2 days after AF64A (25% reduction). Within 65 days the glutamate level returned to normal. A detailed subdissection of the hippocampus revealed that the cholinergic system was most affected in the ventral part of the hippocampus and the CA3 subfield. On the other hand, the transient reduction in glutamate was restricted to the CA1 and CA3 area. In the dentate gyrus the marked loss of cholinergic function was not accompanied by any reduction in glutamate level. Treatment of the AF64A-injected rats with the muscarinic agonist pilocarpine prevented the decline in glutamate levels. The transient nature of the decline in glutamate as well as its reversal by treatment with pilocarpine are suggestive of an increased release of glutamate in response to the withdrawal of cholinergic function.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Mechanisms of chemical mediated cytotoxicity and chemoprotection in isolated rat hepatocytes.
Although N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and methylmethanesulfonate (MMS) cause injury and malondialdehyde formation in rat hepatocytes, MNNG toxicity is much more sensitive to inhibition by antioxidants. In order to quantify the relationship between toxicity and antioxidation potential, we compared 14 antioxidants that protected against MNNG and MMS toxicity. Chemoprotection was quantified as the concentration that delayed by 1 h the decline in trypan blue exclusion to less than or equal to 50%. While chemoprotection against MNNG and antioxidant efficacy were directly related (R = 0.86), chemoprotection against MMS and antioxidant efficacy were unrelated (R = 0.37). Since we hypothesized that protection against MMS involved stabilization of membranes, the capacity of the 14 compounds to stabilize membranes in an unrelated system (i.e. prevention of erythrocyte osmotic rupture) was assayed. Chemoprotection against both MNNG and MMS correlated with reduced RBC fragility (R = 0.97 and 0.70, respectively). One of the better protecting compounds, 4b,5,9b,10-tetrahydroindeno[1,2-b]indole, was also protective against hepatocellular toxicity mediated by acetaminophen, carbon tetrachloride and tert-butyl hydroperoxide, suggesting a fundamental basis in the mechanism of chemoprotection. We propose that methylating agents and perhaps other chemical toxicants destabilize cellular membranes resulting in hepatocellular injury. For MNNG, radical mediated events may result in membrane destabilization; for MMS, membranes are destabilized without concurrent radical events. The current studies provide a basis for future work to determine structure-activity relationships of chemoprotective agents, examine protection mechanisms, and develop better protective compounds.
Animals↗
Regional heterogeneity in the distribution of neurotransmitter markers in the rat hippocampus.
A detailed neurochemical analysis of the distribution of markers for the most relevant neurotransmitter systems within the rat hippocampal formation has been performed. The hippocampi, obtained from unfrozen brains of male Sprague-Dawley rats were subdissected into tissue parts containing mainly CA1, CA3 or the dentate gyrus, respectively. Each part was further divided into ventral and dorsal halves. In these six hippocampal subregions the concentrations of noradrenaline, dopamine, serotonin, 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid and the putative neurotransmitter amino acids glutamate, aspartate, GABA, glycine and taurine, and the levels of somatostatin and neuropeptide Y and the activities of choline acetyltransferase, acetylcholinesterase and glutamate decarboxylase were measured. A marked heterogeneity in the subregional distribution of markers for various neurotransmitter systems within the hippocampal formation was observed. Each neuronal marker was characterized by an individual pattern of distribution. Most of the markers showed a concentration-gradient, increasing from dorsal to ventral; only taurine was more abundant in the dorsal than in the ventral parts and no dorsoventral difference was seen for aspartate, glycine and neuropeptide Y. The highest molar ratios of total 3-methoxy-4-hydroxyphenylglycol to noradrenaline and 5-hydroxyindoleacetic acid to serotonin were found in the dorsal hippocampus. The levels of noradrenaline, GABA and glutamate decarboxylase activity were highest in the dentate gyrus and lowest in CA1. The concentrations of somatostatin were highest in CA1; those of serotonin were highest in CA3. Highest activities of choline acetyltransferase and acetylcholinesterase were found in the dentate gyrus; lowest activities were found in CA3. In CA3 the lowest values of glutamate, aspartate, taurine and somatostatin were also found. The heterogeneity in the distribution of individual neurochemical markers allows insights into possible functional differences of hippocampal subregions and provides a relevant basis for future neurochemical investigations in this brain area.
Animals↗
Pre-mortem diagnosis of Creutzfeldt-Jakob disease by detection of abnormal cerebrospinal fluid proteins.
Creutzfeldt-Jakob disease (CJD) may be difficult to diagnose early or when it has an atypical presentation. We describe two patients with progressive dementia in whom the results of diagnostic brain biopsies were unhelpful. Spinal fluid from these patients, analyzed by two-dimensional electrophoresis, contained two abnormal proteins (Nos. 130 and 131, with relative molecular masses of 26,000 and 29,000 daltons and isoelectric points of 5.2 and 5.1). These findings suggested a provisional diagnosis of Creutzfeldt-Jakob disease, which was confirmed in both patients at autopsy. Detection of these abnormal cerebrospinal fluid proteins appears to be a valuable laboratory adjunct in evaluating patients with an unexplained progressive dementia.
Aged↗
Importance of protein thiols during N-methyl-N'-nitro-N-nitrosoguanidine toxicity in primary rat hepatocytes.
N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), a potent toxicant in isolated rat hepatocytes, was evaluated for its mechanism of cytotoxicity. This direct acting toxicant generates an alkylating carbonium ion that covalently binds to cell macromolecules, depletes nonprotein thiols (NPT), and subsequently kills cells. In this study MNNG depleted protein thiols (PT) in a two-phase process. The first phase (about 30% depletion) occurred rapidly, in parallel with the depletion of NPT. After a plateau, a second phase of PT depletion occurred 5-8 min prior to cell death. Indole-3-carbinol (I-3-C), added prior to MNNG, did not alter the depletion of NPT nor the first phase of PT depletion. However, cell killing was substantially retarded and was still immediately preceded by the second phase of PT depletion. The addition of o-phenanthroline or 5,10-dihydroindeno[1,2-b]indole (DHII) prior to MNNG did not alter the first phase of PT depletion, but partially protected (about 30%) against the depletion of NPT. However, o-phenanthroline or DHII completely protected against the MNNG-induced loss of cell viability and the second-phase depletion of PT. When DHII was added after MNNG and prior to the expected second phase of PT depletion, that depletion was markedly depressed, as was the subsequent loss of cell viability. We conclude that MNNG covalent binding, depletion of NPT, and first-phase depletion of PT may be necessary, but insufficient to kill cells. We propose that rapid depletion of cellular antioxidants predisposes the cell to oxidative stress and that oxygen toxicity is responsible for the second-phase depletion of PT and the final cytotoxic events. The fact that the second-phase depletion of PT is required for and immediately precedes cell death suggests the importance of critical but as yet unidentified target thiol proteins in MNNG hepatotoxicity.
Animals↗
Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats.
Kainic acid (KA, 8-15 ng) was injected into the amygdala of conscious freely moving rats via chronically implanted fused silica cannulas. At 15-25 min after the injection, most rats suffered a limbic seizure attack of short duration, consisting of mastication, forelimb clonus, and raising on hind limbs, behaviorally indistinguishable from kindled seizures. Typically, the attack was followed by stereotypies, intense exploration, and by 1 or 2 more attacks. About 60 min after the injection, most rats appeared normal again and histopathological changes in their brains did not exceed those seen in vehicle-injected rats. In 3 cases, however, recurrent seizures culminated in behavioral status epilepticus 60-90 min after the injection. The status epilepticus was stopped by i.p. injection of diazepam (10 mg/kg) after a duration of 10 min (1 case) and 30 min (2 cases), respectively. After 10 min status epilepticus, we observed marginal neuronal damage with slight gliosis in both hippocampi (CA3 and CA1); after 30 min, hippocampal histopathology was more pronounced, with additional necrosis of the ipsilateral piriform cortex. After 0.8 microgram KA, a hundredfold higher dose, the incidence of limbic seizures during the first 40 min was not significantly higher (9/12) than after the lower KA doses (13/19). However, a significantly higher proportion of rats exhibited long-lasting seizure activity, associated with confluent destruction of CA3 pyramidal cells and additional seizure-related brain damage. Our results show that limbic motor seizures do not inevitably lead to histopathological changes in the brain, provided they do not culminate in a state of permanent seizure activity.
Amygdala↗