La presente invention concerne une methode qui permet de traiter ou de prevenir chez un patient des episodes mixtes et/ou maniaques lies au trouble bipolaire, ainsi qu'au trouble de la memoire et/ou a la deficience qui lui sont... more
La presente invention concerne une methode qui permet de traiter ou de prevenir chez un patient des episodes mixtes et/ou maniaques lies au trouble bipolaire, ainsi qu'au trouble de la memoire et/ou a la deficience qui lui sont associes. La methode consiste a administrer audit patient une quantite efficace d'au moins un modulateur du canal calcique selectionne dans le groupe constitue par: (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, ou nitrendipine; ou 2) l'enantiomere R d'un compose de 1,4-dihydropyridine autre que (+)-isopropyl-2-methoxyethyl-4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.
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... Based Screening as an Approach to Polypharmacological Ligands DANI BRUNNER, VADIM ALEXANDROV, BARBARA CALDARONE, TALEEN HANANIA, DAVID ... we used the forced swim and marble burying test; and for anxiolytics, we used the... more
... Based Screening as an Approach to Polypharmacological Ligands DANI BRUNNER, VADIM ALEXANDROV, BARBARA CALDARONE, TALEEN HANANIA, DAVID ... we used the forced swim and marble burying test; and for anxiolytics, we used the stress-induced hyperthermia ...
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A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake... more
A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake by the large neutral amino acid carrier in vitro and in vivo; active transport may thus confer a good bioavailability to this class of compounds. CNS effects were demonstrated by significant changes in 2-deoxyglucose-uptake in various brain regions at doses from 1 to 10 mg/kg i.p. With the most active agent, SDZ 220-581, full protection against maximal electroshock seizures (MES) was obtained at oral doses of 10 mg/kg in rats and in mice. The compound had a fast onset (< or = 1 hr) and a long duration (> or = 24 hr) of action. Motor-debilitating effects (impairment of rotarod performance) occurred at doses about 10 times higher than those required for protection against MES. Neuroprotective activity was demonstrated by the ability of the compounds to reduce the extent of quinolinic acid-induced striatal lesions in rats, in the dose range of 3-15 mg/kg (i.p.) or 10-50 mg/kg (p.o.). In the middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats, the test compounds reduced the infarct size by 40-50% when given i.v. before or by 20-30% when given i.v. 1 hr after MCAO. SDZ 220-581 provided 20-30% protection at > or = 2 x 10 mg/kg p.o. This compound also showed analgesic activity at low oral doses in a model of neuropathic pain, although higher doses were required in model of mechanical inflammatory hyperalgesia. Unexpectedly, SDZ 220-581 at low s.c. doses counteracted the antiparkinsonian effects of L-DOPA in MPTP-treated marmosets. (Sub)chronic administration of SDZ 220-581 did not reduce its ability to protect against quinolinic acid neurotoxicity, and no upregulation of NMDA receptors was detected using a [3H]CGP-39653 binding assay. In conclusion, from a series of biphenyl-AP7-derivatives, SDZ 220-581 is clearly the most active compound in vivo. Its pharmacological profile with a good, long-lasting oral activity might open up novel therapeutic applications for competitive NMDA receptor antagonists.
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properly; as they age, or are affected by toxins such as beta amyloid peptides, neurons lose this ability. An increase in Ca entry into the cell alters activity of Ca -dependent proteins such as ion channels and proteolytic enzymes which... more
properly; as they age, or are affected by toxins such as beta amyloid peptides, neurons lose this ability. An increase in Ca entry into the cell alters activity of Ca -dependent proteins such as ion channels and proteolytic enzymes which may adversely affect many cell functions. Excessive Ca entry may be exacerbated by an increase in density of L-type Ca -channels reported to occur in aging and in Alzheimer’s disease. Blocking voltage-regulated calcium channels may facilitate the ability of neurons to maintain appropriate calcium levels and function properly. Memory Pharmaceuticals is developing MEM1003, a dihydropyridine (DHP) Ca channel modulator, for Alzheimer’s disease. MEM1003 is equipotent to nimodipine, another DHP, in blocking L-type Ca currents in CA1 hippocampal neurons, but it is 4 to 15-fold less potent in relaxing rat thoracic smooth muscle when compared to other DHPs like nimodipine, nitrendipine or felodipine. This suggests that MEM1003 may have a superior safety profile. MEM1003 is a single enantiomer, unlike nimodipine and many other DHP drugs, and may lack potential off-target pharmacological activities present in racemic mixtures. We will present data showing the effectiveness of MEM1003 in improving cognitive performance in multiple preclinical behavior models at plasma exposure levels consistent with its affinity for the DHP binding site. One proposed mechanism for the procognitive effects of MEM1003 is that it mediates a reduction in the slow afterhypolarization (sAHP) of CA1 pyramidal neurons. An enlarged sAHP, functionally linked to L-type Ca channels, may interfere with cognitive behaviors. Our recent findings have demonstrated that sAHP amplitude co-varies with spatial learning ability in aged rats (Tombaugh et al., 2005). The pharmacokinetic and safety profiles of MEM1003 were recently studied in double-blind, randomized, placebocontrolled Phase 1A and Phase 1B clinical trials. MEM1003 was well tolerated up to the highest dose tested of 180 mg twice daily. The safety data and pharmacokinetics of MEM1003 in these studies will be presented and the relevance of the exposure levels to preclinical animal efficacy models and toxicology studies will be discussed. MEM1003 is currently in a Phase 2A clinical trial for Alzheimer’s disease.
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Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 2, Issue 3, Pages S646-S647, July 2006, Authors:David Lowe; Michael De Vivo; Crista Tripodi; Tom Kornecook; Jeff Kogan; Geoff Tombaugh;... more
Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 2, Issue 3, Pages S646-S647, July 2006, Authors:David Lowe; Michael De Vivo; Crista Tripodi; Tom Kornecook; Jeff Kogan; Geoff Tombaugh; Daguang Wang; Chengjun Deng; Marc Dizon; Michael ...
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Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (EC 4.1.3.5) was purified to homogeneity from ox liver and obtained essentially free from acetoacetyl-CoA thiolase activity. The purification procedure included substrate elution from... more
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (EC 4.1.3.5) was purified to homogeneity from ox liver and obtained essentially free from acetoacetyl-CoA thiolase activity. The purification procedure included substrate elution from cellulose phosphate and chromatofocusing. The relative molecular mas was about 100 000 and S20,w0 was 6.36S. The enzyme appears to be a dimer of identical subunits (Mr 47 900). The Km for acetoacetyl-CoA is extremely low (less than 0.5 microM), and acetoacetyl-CoA (Acac-CoA) gives marked substrate inhibition (KiAcac-CoA = 3.5 microM) that is competitive with respect to acetyl-CoA. Both CoA and DL-3-hydroxy-3-methylglutaryl-CoA give mixed product inhibition with respect to acetyl-CoA, which is compatible with a Ping Pong mechanism in which both products can form kinetically significant complexes with two forms of the enzyme. The two forms are most likely to be free enzyme and an acetyl-enzyme intermediate.
Research Interests: Chemistry, Kinetics, Biology, Mitochondria, Medicine, and 13 moreBiological Sciences, Animals, Biochemical, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Enzyme, CHEMICAL SCIENCES, Cattle, Amino Acids, Analytical Ultracentrifugation, Molecular weight, Dimer, Medical and Health Sciences, and Chromatofocusing
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Increasing evidence suggests that neutrophils play a role in the host response to Mycobacterium tuberculosis. We determined whether neutrophil counts in peripheral blood are associated with tuberculosis (TB) and with mycobacterial load in... more
Increasing evidence suggests that neutrophils play a role in the host response to Mycobacterium tuberculosis. We determined whether neutrophil counts in peripheral blood are associated with tuberculosis (TB) and with mycobacterial load in sputum in HIV-infected patients. Adults enrolling in an antiretroviral treatment (ART) clinic in a Cape Town township were screened for TB regardless of symptoms. Paired sputum samples were examined using liquid culture, fluorescence microscopy, and the Xpert MTB/RIF assay. Absolute neutrophil counts (ANC) were measured in blood samples. Of 602 HIV-infected patients screened, 523 produced one or more sputum samples and had complete results available for analysis. Among these 523 patients, the median CD4 count was 169×10(9)/L (IQR, 96-232) and median ANC was 2.6×10(9)/L (IQR, 1.9-3.6). Culture-positive pulmonary tuberculosis was diagnosed in 89 patients. Patients with TB had a median ANC of 3.4×10(9)/L (IQR, 2.4-5.1) compared to 2.5×10(9)/L (IQR, 1....
Research Interests: Mathematics, Hematology, Biostatistics, Gastroenterology, Infectious Diseases, and 15 moreBacterial Diseases, Immunopathology, HIV, Clinical immunology, Medical Immunology, Humans, Internal Medicine, Female, Male, Coinfection, Adult, Counts, Absolute Neutrophil Count, leukocyte Count, and HIV infections
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BACKGROUND: Patients with prolonged cardiac arrest that is not responsive to conventional cardiopulmonary resuscitation have poor outcomes. The use of extracorporeal membrane oxygenation (ECMO) in refractory cardiac arrest has shown... more
BACKGROUND: Patients with prolonged cardiac arrest that is not responsive to conventional cardiopulmonary resuscitation have poor outcomes. The use of extracorporeal membrane oxygenation (ECMO) in refractory cardiac arrest has shown promising results in carefully selected cases. We sought to validate the results from an earlier extracorporeal cardiopulmonary resuscitation (ECPR) study (the CHEER trial). METHODS: Prospective, consecutive patients with refractory in-hospital (IHCA) or out-of-hospital cardiac arrest (OHCA) who met predefined inclusion criteria received protocolised care, including mechanical cardiopulmonary resuscitation, initiation of ECMO, and early coronary angiography (if an acute coronary syndrome was suspected). RESULTS: Twenty-five patients were enrolled in the study (11 OHCA, 14 IHCA); the median age was 57 years (interquartile range [IQR], 39–65 years), and 17 patients (68%) were male. ECMO was established in all patients, with a median time from arrest to ECM...
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Research Interests: Chemistry, Mass Spectrometry, Medicine, Circular Dichroism, Peptide, and 11 moreClinical Sciences, Infrared, Secondary Structure, Liquid Chromatography, Fourier transform infrared spectroscopy, Circular Dichroism Spectroscopy, Aqueous Solution, Biochemistry and cell biology, Phosphate Buffer Saline, random coil, and Medical biochemistry and metabolomics
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Marijuana is known to have psychotropic effects in humans. In this study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to explore whether CB(1) receptor stimulation or blockade induces behavioral changes... more
Marijuana is known to have psychotropic effects in humans. In this study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to explore whether CB(1) receptor stimulation or blockade induces behavioral changes consistent with psychotomimetic or antipsychotic agents, respectively. We determined whether (a) the cannabinoid agonist CP 55940 decreased pre-pulse inhibition (PPI) as might be expected from a psychotomimetic agent, and (b) the selective CB(1) receptor antagonist, SR 141716A, had any effect on PPI on its own or following disruptions by psychotomimetic agents. In addition, we investigated the effects of SR 141716A on elevated levels of hyperactivity and stereotypy elicited by d-amphetamine. These studies were conducted in rats using standard methodologies for determination of PPI following acoustic stimuli, and d-amphetamine-induced hyperactivity and stereotypies. Decreased startle responses to 120 dB stimuli were observed in rats treated with CP 55940 (0...