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Biomedical subjects

J R Martin

Publications and source records attributed to J R Martin.

At least 109 records · Page 6Linked to original sources
PubMed1992

Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders.

The classic benzodiazepines produce anxiolytic, anticonvulsant, sedative and myorelaxant effects at overlapping dose ranges. Efforts to reduce the sedative/myorelaxant component of this profile has a long history. Two rational approaches might theoretically lead to the desired drugs. One is based on the combination of partial (low efficacy) agonists of the benzodiazepine receptor with different receptor reserves in neurons subversing various functions. The other approach is based on the existence of GABAA-benzodiazepine receptor polymorphism and assumes that distinct receptor variants may be more prevalent on neurons involved in various CNS functions. Results are presented that were obtained with the partial agonist bretazenil and three other ligands in vitro as well as in vivo. Curves relating fractional receptor occupancy and various effects (potentiation of GABA-induced chloride flux, anticonvulsant, anticonflict and sedative effects) are fully consistent with the view that the particular profile of activity of bretazenil is the result of partial agonism. Comparison of fractional receptor occupancy required for the various effects of both full and partial agonists confirm earlier suggestions that receptor reserves for the individual effects differ with the same order. Clinical aspects of partial benzodiazepine receptor agonists are discussed on the basis of the preliminary information available to date.

Animals↗
PubMed1992

Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological profile of a potential anxiolytic.

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.

Acoustic Stimulation↗
PubMed1992

Acute simian varicella infection. Clinical, laboratory, pathologic, and virologic features.

Five African green monkeys inoculated intratracheally with 7.5 x 10(3) to 1.4 x 10(5) plaque-forming units of simian varicella virus (SVV) were subjected to clinical, laboratory, pathologic, and virologic analyses to study the pathogenesis of acute varicella. All animals developed viremia and rash and were sacrificed 8 to 11 days post-infection. No serum was available for postmortem serologic studies. Examination of multiple organs for pathologic changes and for SVV-specific antigen and nucleic acid revealed inflammation, hemorrhagic necrosis, and intranuclear Cowdry A inclusions in liver, lung, lymph node, and spleen; mild inflammation without necrosis in adrenal gland, kidney, and bone marrow, and SVV-specific antigen and nucleic acids in all viscera examined. No pathologic changes, SVV antigen or nucleic acids were detected in the spinal cord or in the brain from any of the monkeys. Ganglia revealed mild inflammation but no necrosis, and intranuclear inclusion bodies in non-neuronal cells of one trigeminal ganglion; SVV antigen and nucleic acids were detected in both non-neuronal and neuronal cells in ganglia. The pathologic and virologic findings in viscera are consistent with those described in viscera of humans with disseminated zoster, but the mild inflammatory changes in ganglia during acute simian varicella infection contrast with the extensive hemorrhagic necrosis and intranuclear inclusion bodies seen in human ganglia after disseminated varicella or zoster. Nevertheless, these studies show that ganglia become infected with varicella virus during primary infection, although the route of primary ganglionic infection remains to be determined, and indicate the possible usefulness of the SVV model to study varicella pathogenesis in humans.

Acute Disease↗
PubMed1991

Analysis of Krüppel control elements reveals that localized expression results from the interaction of multiple subelements.

The Drosophila gap gene Krüppel (Kr) displays a complex spatiotemporal pattern of expression during embryogenesis. Using P-element transformation experiments, we demonstrate that control elements guiding Kr expression in the central or in the anterior domain at the blastoderm stage are each composed of multiple subelements that interact synergistically. We provide evidence that bicoid (bcd) and hunch-back (hb) gene products, as well as at least one other activator, are needed to activate Kr expression in the central domain. We localize and describe regulatory elements within the 4.1-kilobase region proximal to the Kr promoter that are responsible for expression in the ectoderm, mesoderm, amnioserosa, and nervous system. Finally, a protein instability motif encoded in the second exon appears to be important for resetting the dynamic Kr pattern.

Animals↗
PubMed1991

Fatal varicella-zoster virus meningoradiculitis without skin involvement.

A 77-year-old man with T-cell lymphoma developed an acute fatal meningoradiculitis of cranial nerve roots and cauda equina, pathologically and virologically confirmed to be caused by varicella-zoster virus. This is the first report of fatal varicella-zoster virus-induced neurological disease in the absence of skin lesions. Varicella-zoster virus should be included in the differential diagnosis of acute radiculoneuropathy in the immunocompromised patient, particularly because antiviral treatment for varicella-zoster virus exists.

Aged↗
PubMed1991

Targets of herpes simplex virus type 1 infection in a mouse corneal model.

In animal models, spread of herpes simplex virus type 1 (HSV-1) from epithelial replication sites to the peripheral and central nervous system is known from analysis of individually dissected tissues. To examine virus spread in undissociated tissues, corneas of adult mice were inoculated with HSV-1. After 1 to 13 days groups of mice were perfused with formalin, and decalcified blocks of head and neck were embedded in paraffin. At intervals, serial sections were screened for HSV antigen. On days 1 and 2, viral antigen was restricted to cornea and conjunctiva but by days 3 and 4 was also seen in autonomic ganglia and the trigeminal system. On day 6, HSV antigen reached its maximum extent; infected sites included the trigeminal complex (ganglion, root, peripheral ophthalmic and maxillary branches and spinal nucleus and tract), ethmoid sinus and olfactory bulb, visual system, and autonomic ganglia (ciliary, pterygopalatine and superior cervical). Antigen progressively diminished on days 8 and 10, and was not detected on day 13. This method demonstrates a broader range of infected tissues and suggests a more complex pattern of HSV spread than has been previously recognized. Virus appears to reach the intracranial compartment by four different neural routes. When effects of higher and lower corneal inoculation doses were compared, a lower dose resulted in lower peak HSV titers in trigeminal ganglion and brain stem and later virus appearance in these tissues. Thus, dose may influence the kinetics of HSV spread from the peripheral inoculation site to the CNS.

Animals↗
PubMed1991

Herpes simplex virus infection in populations of mouse dorsal root ganglion neurons: effects of inoculation route and virus strain.

To investigate whether herpes simplex virus type-2 (HSV-2) infection of sensory ganglion neurons is restricted to a particular neuronal class, we unilaterally inoculated either the footpad, leg muscle or sciatic nerve of mice with strains of HSV-2 that differ in virulence and examined the soma sizes of lumbar dorsal root ganglion (DRG) neurons containing viral antigen near the peak of acute infection. Each inoculation route appeared relatively selective for a different portion of the neuronal size spectrum. Footpad inoculation primarily infected the smaller population of DRG neurons, by comparison, muscle inoculation tended to spare the smallest neurons while infecting medium and larger cells. Sciatic nerve inoculation infected the entire spectrum of DRG neurons. These results indicate that HSV-2 infection is not restricted to a specific subclass of sensory neurons. With any particular inoculation route, the least virulent strain infected fewer neurons than did those of greater virulence.

Animals↗
PubMed1991

Cerebral ischemia decreases the behavioral effects and mortality rate elicited by activation of NMDA receptors in mice.

The purpose of this study was to determine whether prior transient cerebral ischemia, in conscious mice, would alter the biological responses resulting from excessive activation of N-methyl-D-aspartate (NMDA) receptors, in an early stage. The responses to the activation of NMDA receptors by an intracerebroventricular injection of NMDA, such as wild running, tonic and clonic convulsions, absence of the visual placing reflex, loss of the righting reflex, impaired motor function and a high mortality rate, were to a large extent prevented if 30 min before treatment, either a 10-min period of global cerebral ischemia was induced or a 1 nmol intraventricular injection of NMDA was given but not if either of the above procedures was done one day before the test dose of NMDA. In contrast, behavioral symptoms, in response to activation of non-NMDA-type glutamate receptors elicited by intraventricular injection of either kainic acid or AMPA, were not clearly affected. Transient systemic hypercapnic anoxia (22-sec exposure to 100% CO2 gas), before treatment with NMDA did not significantly reduce the NMDA-induced behavior. The severity of these behavioral responses and high mortality rate observed after intraventricular injection of pentylenetetrazole (PTZ, 30 mumol) were not altered by either prior global ischemic insult or by a preexposure to NMDA given intraventricularly. The NMDA antagonist, MK801 (0.1 and 0.3 mg/kg i.p.) greatly reduced the behavioral effects and mortality rate, resulting from the intraventricular injection of NMDA and somewhat reduced the effects of the intraventricular injection of PTZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Type-specific identification of herpes simplex and varicella-zoster virus antigen in autopsy tissues.

To identify antigens of herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV) in human tissue, polyclonal antisera and an immunoperoxidase method were used to examine formalin-fixed, paraffin-embedded tissues from autopsy cases and experimentally infected animals. These antisera readily distinguished between HSV and VZV antigen, with no evident cross-reactivity. Antiser ato HSV-1 and HSV-2 were more strongly reactive with antigen of the homologous virus than with that of heterologous virus. This difference in immunoreactivity was used to discriminate between HSV-1 and HSV-2 antigens in experimentally infected animal tissues containing HSV antigens of known type and, by extrapolation, to distinguish between these antigens in human autopsy tissues. Thus, with appropriate antisera and tissue controls, HSV-1, HSV-2, and VZV can be identified in paraffin sections.

Adult↗
PubMed1991

Accidental firearm fatalities among New Mexico children.

STUDY HYPOTHESIS: Risk factors associated with unintentional gunshot fatalities among children include gender and race of the decedent, type of firearm used, and whether loaded guns are stored within the home. STUDY POPULATION: All New Mexico children 0 to 14 years old unintentionally killed by a firearm between 1984 and 1988. METHODS: The New Mexico Office of the Medical Investigator master mortality file was reviewed retrospectively to identify all unintentional firearm fatalities occurring in New Mexico children during a five-year period. Medical investigator, autopsy, and police reports were analyzed to identify epidemiologic factors associated with these deaths. Chi-square and Fisher's exact tests were used to analyze the data. RESULTS: Twenty-five unintentional firearm fatalities were identified. These deaths occurred most frequently among children playing with loaded firearms found within the home. A disproportionate number involved handguns. CONCLUSIONS: The study results provide a basis for preventive strategies that limit accessibility or decrease lethality of loaded firearms within the home.

Accident Prevention↗
PubMed1991

Hemodynamic effects of posterior hypothalamic injection of neuropeptide Y in awake rats.

Unilateral microinjection of neuropeptide Y (NPY) into the posterior hypothalamic nucleus was previously found to evoke a sympathoexcitatory-mediated increase in mean arterial pressure (MAP) in urethan-anesthetized rats. In this study, the effect of unilateral injection of NPY into the posterior hypothalamic nucleus on the cardiovascular system of conscious, freely moving rats was determined. Microinjection of NPY (0.2-2.4 nmol) or the cholinergic agonist carbachol (0.5-5.5 nmol) resulted in concentration-dependent increases in MAP. Pretreatment of animals with 7.5 mg/kg iv of the ganglionic blocker pentolinium resulted in a blockade of the increase in MAP evoked by microinjection of NPY (2.4 nmol) or carbachol (3.3 nmol). Despite their similarity of effects on MAP, NPY and carbachol evoked different changes in heart rate. NPY increased heart rate, whereas carbachol evoked a biphasic change in heart rate that consisted of an initial increase followed by a decrease. In addition, carbachol caused increases in both hindquarter and mesenteric vascular resistances, whereas NPY caused a short-lasting increase in mesenteric resistance and a tendency toward an increase in hindquarter resistance. Both NPY and carbachol increased total peripheral resistance while NPY decreased stroke volume. Cardiac output was not significantly affected by either NPY or carbachol, although NPY had a tendency to decrease cardiac output. These results suggest that microinjection of NPY or carbachol into the posterior hypothalamic nucleus of conscious rats evokes an increase in MAP primarily as a result of sympathoexcitation and that NPY and carbachol selectively affect autonomic nervous system control of the cardiovascular system.

Animals↗
PubMed1991

Preherpetic neuralgia.

We have encountered six zoster patients whose pain preceded rash by 7 to more than 100 days. Pain was severe, burning, and radicular, and located both in dermatomes different from, as well as in, the area of eventual rash. Two patients ultimately developed disseminated zoster with neurologic complications, one of zoster paresis, and the other, a fatal zoster encephalitis; both had been taking long-term, low-dose steroids. A third case of preherpetic neuralgia developed in a patient with prior metastatic carcinoma, and another case in a patient with an earlier episode of brachial neuritis. The final two cases of preherpetic neuralgia developed in individuals with no underlying disease. An extended period of pain before the onset of zoster rash has gone largely unrecognized.

Antigens, Viral↗
PubMed1990

Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028.

Continuous administration of triazolam, alprazolam or diazepam for a 7-day period by means of minipumps or chronic (17 days) p.o. treatment with alprazolam induced clear physical dependence in DBA/2J mice as assessed by precipitation of a withdrawal syndrome with an i.v. injection of the benzodiazepine receptor partial inverse agonist Ro 15-3505. In contrast, no precipitated withdrawal signs were observed following chronic exposure to high doses of the benzodiazepine receptor partial agonist Ro 16-6028. The use of minipumps and precipitation with a benzodiazepine receptor antagonist permits a simple and rapid evaluation of the physical dependence liability of potent compounds acting at the benzodiazepine receptor. Furthermore, these results support the hypothesis that benzodiazepine receptor partial agonists are less likely to induce physical dependence than full agonists.

Administration, Oral↗
PubMed1990

Serenics fluprazine (DU 27716) and eltoprazine (DU 28853) enhance neophobic and emotional behaviour in mice.

Two tests designed to elicit responses to novelty and to aversive stimuli were used to study the effects of the serenics fluprazine and eltoprazine on the behaviour of male Swiss mice: a free exploratory test (fluprazine; 2.5, 5 and 10 mg/kg; eltoprazine: 2.5, 5, 10 and 15 mg/kg) and a two-box choice procedure (fluprazine: 1.25, 2.5, 5 and 7.5 mg/kg; eltoprazine: 2.5, 5, 7.5 and 10 mg/kg). Both drugs increased the neophobic reaction, as well as the avoidance of a brightly illuminated box. These effects closely resemble those of psychostimulant drugs such as methamphetamine and caffeine. It is hypothesized that the behavioural changes induced by these drugs may be due to a nonspecific increase of the emotional reactivity of animals.

Animals↗
PubMed1990

Novel anxiolytics that act as partial agonists at benzodiazepine receptors.

Benzodiazepines in clinical use have a range of pharmacological activities. Some, e.g. sedation, tolerance and addiction, are not welcome. Undesirable side-effects of drugs are often controlled by developing compounds that bind more selectively to one particular receptor subtype. An alternative approach, discussed here by Willy Haefely and colleagues, is the development of partial agonists which exploit regional differences in receptor reserve to tease apart biological responses. Partial agonists for the benzodiazepine modulatory site on the GABAA complex have been developed and their pharmacological profiles can be interpreted to suggest that neurons mediating anticonvulsant and anti-anxiety effects do indeed have a higher receptor reserve than neurons mediating other unwanted effects. This suggests that benzodiazepine receptor partial agonists may have important therapeutic potential.

Animals↗
PubMed1990

The effect of local anesthetics on bacterial proliferation: TAC versus lidocaine.

We compared the effect of topical 0.5% tetracaine, 1:2,000 epinephrine, and 11.8% cocaine (TAC) with 1% lidocaine infiltration on bacterial proliferation in experimental lacerations. Forty-eight lacerations were made on the backs of Hampshire pigs, inoculated by injection with infectious doses of Staphylococcus aureus and randomly anesthetized with either topical TAC or lidocaine infiltration. Wounds were sutured, and quantitative cultures were obtained by excision after 48 hours. The mean log10 bacteria per gram of tissue for wounds anesthetized with TAC was 6.818 (95% confidence interval [CI], 6.07 to 7.54) compared with 6.820 (95% CI, 5.91 to 7.75) for those treated with lidocaine; this difference was not significant (P less than .05 by paired two-tailed t test). The probability of failing to detect an intergroup difference of 0.5 log10 bacteria per gram was less than .0001. TAC does not increase bacterial proliferation more than lidocaine infiltration in contaminated experimental porcine lacerations.

Administration, Topical↗
PubMed1990

Neurotropic herpesviruses, neural mechanisms and arteritis.

Cumulative evidence suggests that varicella-zoster virus (VZV) can infect walls of CNS arteries, causing stroke in man. We review observations relating infection with this neurotropic virus to the development of arteritis in the CNS and note evidence supporting the hypothesis that VZV spreads from ganglionic reactivation sites to the arterial wall by neural pathways. Problems relating to the pathogenesis of arteritis and experimental approaches to their solution are suggested.

Adult↗