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R Levy

Publications and source records attributed to R Levy.

At least 163 records · Page 9Linked to original sources
PubMed1999

Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group.

OBJECTIVE: To determine the efficacy and safety of the cyclooxygenase 2 (COX-2) specific inhibitor, rofecoxib in patients with osteoarthritis (OA) of the knee. METHODS: Rofecoxib, 25 mg or 125 mg once daily, was compared with placebo in a 6 week, double blind, parallel group, randomized, multicenter study of 219 patients with knee OA. RESULTS: Both doses of rofecoxib produced clinically significant improvement as assessed by primary (e.g., WOMAC Pain Subscale 0-100 mm, decrease from baseline: placebo: 7.1 mm; rofecoxib 25 mg: 28.1 mm, rofecoxib 125 mg: 28.0 mm; p < 0.001 rofecoxib vs placebo) and secondary efficacy (p < 0.05) criteria compared with placebo. Clinical improvement with the 25 mg dose was similar to that with the 125 mg dose. Both rofecoxib doses were generally well tolerated. CONCLUSION: Specific inhibition of COX-2 by 25 and 125 mg rofecoxib, administered once daily, resulted in clinically meaningful improvements in patients with OA. This study confirms that COX-2 derived prostanoids are important clinical mediators of pain and other symptoms of knee OA and that inhibition of COX-1 is not required to provide clinical benefit.

Adult↗
PubMed1999

Hydrolysis of long-chain, n-3 fatty acid enriched chylomicrons by cardiac lipoprotein lipase.

The hydrolysis of chylomicrons enriched in long-chain n-3 fatty acids by cardiac lipoprotein lipase was studied. In 60 min, 24.8% of the triacylglycerol fatty acids were released as free fatty acids. The fatty acids were hydrolyzed at different rates. DHA (docosahexaenoic acid, 22:6n-3) and EPA (eicosapentaenoic acid, 20:5n-3) were released at rates significantly less than average. Stearic acid (18:0), 20:1n-9, and alpha-linolenic acid (18:3n-3) were released significantly faster than average. There was no relationship between the rate of release of a fatty acid and the number of carbons or the number of double bonds. Lipoprotein lipase selectively hydrolyzes the fatty acids of chylomicron triacylglycerols. This selectively will result in remnants that are relatively depleted in 18:0, 20:1, and 18:3 and relatively enriched in 20:5 and 22:6.

Animals↗
PubMed1999

In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent.

Levetiracetam and its carboxylic metabolite (AcL) were tested for their potential inhibitory effect on 11 different drug metabolizing enzyme activities using human liver microsomes. The following specific assays were investigated: testosterone 6beta-hydroxylation [cytochrome P-450 3A4 (CYP3A4)], coumarin hydroxylation (CYP2A6), (R)-warfarin hydroxylation (CYP1A2), (S)-mephenytoin hydroxylation (CYP2C19), p-nitrophenol hydroxylation (CYP2E1) tolbutamide hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), epoxide hydrolase and UDP-glucuronyltransferase (UGT) toward paracetamol (UGT1*6), ethinyloestradiol (UGT1*1), p-nitrophenol (UGT(pl 6.2)), and valproic acid. None of these activities were affected by levetiracetam or AcL added at concentrations up to 1 mM. Additionally, primary cultures of rat hepatocytes were used to assess a potential inducing effect of levetiracetam on CYPs. Phenobarbital (2 mM), beta-naphtoflavone (40 microM), dexamethasone (1 microM), and phenytoin (up to 300 microM) were tested as positive controls. When added to cells for 48 h, all the positive controls increased 7-ethoxycoumarin O-deethylase activity demonstrating the inducibility of CYPs in the present culture conditions. By contrast, levetiracetam did not affect the activity up to 1 mM. The highest levetiracetam concentrations examined in the above in vitro studies are well in excess of those measured in the plasma of patients receiving therapeutic doses. It is thus concluded that levetiracetam is unlikely to produce pharmacokinetic interactions through inhibition of CYPs, UGTs, and epoxide hydrolase. Furthermore, based on the in vitro assays with rat hepatocytes, it could be speculated that levetiracetam does not act as a CYP inducer.

Animals↗
PubMed1998

A general mechanism for regulation of access to the translocon: competition for a membrane attachment site on ribosomes.

For proteins to enter the secretory pathway, the membrane attachment site (M-site) on ribosomes must bind cotranslationally to the Sec61 complex present in the endoplasmic reticulum membrane. The signal recognition particle (SRP) and its receptor (SR) are required for targeting, and the nascent polypeptide associated complex (NAC) prevents inappropriate targeting of nonsecretory nascent chains. In the absence of NAC, any ribosome, regardless of the polypeptide being synthesized, binds to the endoplasmic reticulum membrane, and even nonsecretory proteins are translocated across the endoplasmic reticulum membrane. By occupying the M-site, NAC prevents all ribosome binding unless a signal peptide and SRP are present. The mechanism by which SRP overcomes the NAC block is unknown. We show that signal peptide-bound SRP occupies the M-site and therefore keeps it free of NAC. To expose the M-site and permit ribosome binding, SR can pull SRP away from the M-site without prior release of SRP from the signal peptide.

Animals↗
PubMed1998

Anti-idiotype antibodies can induce long-term complete remissions in non-Hodgkin's lymphoma without eradicating the malignant clone.

The immunoglobulin on the surface of B-cell lymphomas can be a tumor-specific target for monoclonal antibody therapy. Between 1981 and 1993, 45 individuals with low grade B-cell lymphoma were treated with 52 courses of custom-made anti-idiotype antibodies. The antibodies were used either alone or in combination with alpha-interferon, chlorambucil, or interleukin-2 (IL-2). The majority of these patients responded to treatment, with a 66% overall and 18% complete response rate. Six patients (13%) experienced prolonged complete remissions, five of which are ongoing from 4 to 10 years after therapy and are the subject of this report. We asked whether residual lymphoma could be found in these patients with prolonged remissions. We performed enzyme-linked immunosorbent assay (ELISA) assays for idiotype protein or anti-idiotype antibodies in serum. Blood and bone marrow samples were examined by flow cytometry for idiotype positive cells, and by polymerase chain reaction (PCR) for clonal gene rearrangements of immunoglobulin CDR3 sequences or t(14;18) translocations. Using these sensitive and specific tests it was possible to detect very low levels of residual lymphoma in five of these patients who had been in clinical remission for 3 to 8 years before this evaluation. These five have continued without recurrence for up to 3 years since. Thus, we have found a pattern of residual inactive disease in patients treated with anti-idiotype antibodies. The biology of follicular lymphoma evidently includes the potential for tumor dormancy after therapies with varied mechanisms of action, resulting in clinical inactivity for many years. Thus, long-term control of the disease is possible at a clinical level despite persistence of the malignant clone.

Animals↗
PubMed1998

Determination of anti-idiotype antibodies by surface plasmon resonance.

A method based on surface plasmon resonance has been used to detect and to quantitate antibodies against other antibodies. This method has been applied to the detection of syngeneic antibodies. Concentrations as low as 0.3 microg/ml could be detected even when the antibodies were present in undiluted serum. Quantitation of both monoclonal and polyclonal antibodies could be performed. Anti-idiotype antibodies could be detected equally well against an IgM molecule derived directly from the B cell tumour or against a chimeric protein composed of the same idiotypic determinants embedded in a human IgG molecule. Surface plasmon resonance will be the method of choice for the detection of antibody responses in humans vaccinated against idiotypic determinants of their own tumour.

Animals↗
PubMed1998

Specificity of an anti-aluminium monoclonal antibody toward free and protein-bound aluminium.

Anti-aluminium monoclonal antibodies (mAbs) were prepared using aluminium chloride-bovine serum albumin complex (Al-BSA) as immunogen. Competitive enzyme-linked immunosorbant assay (ELISA), using an Al-BSA coated immunoplate, demonstrated that mice immune sera showed stronger reactivity to AlCl3 than to BSA. Supernatants from hybridomas prepared from cloned anti-Al antibody-producing cells reacted in ELISA assays whether the metal was bound to proteins like calmodulin (CaM) and S100b protein or to immunogen BSA. Moreover, addition of citrate, a potent ligand for trivalent cations, resulted in a significant withdrawal in mAb recognition of aluminium which was previously bound to either CaM or S100b proteins. The anti-Al mAbs also reacted with aluminosilicate complexes formed from aluminium chloride and silicic acid. The results indicate that the monoclonal antibodies recognized aluminium alone, aluminium bound to silicate, or aluminium bound to a protein core and thus may be used as an immunologic tool for identifying aluminium in both in vitro and in vivo systems.

Aluminum↗
PubMed1998

Differential modulation of adenylyl cyclases I and II by various G beta subunits.

The accepted dogma concerning the regulation of adenylyl cyclase (AC) activity by G beta gamma dimers states that the various isoforms of AC respond differently to the presence of free G beta gamma. It has been demonstrated that AC I activity is inhibited and AC II activity is stimulated by G beta gamma subunits. This result does not address the possible differences in modulation that may exist among the different G beta gamma heterodimers. Six isoforms of G beta and 12 isoforms of G gamma have been cloned to date. We have established a cell transfection system in which G beta and G gamma cDNAs were cotransfected with either AC isoform I or II and the activity of these isoforms was determined. We found that while AC I activity was inhibited by both G beta 1/gamma 2 and G beta 5/gamma 2 combinations, AC II responded differentially and was stimulated by G beta 1/gamma 2 and inhibited by G beta 5/gamma 2. This finding demonstrates differential modulatory activity by different combinations of G beta gamma on the same AC isoform and demonstrates another level of complexity within the AC signaling system.

Adenylyl Cyclases↗
PubMed1998

Essential requirement of cytosolic phospholipase A2 for activation of the phagocyte NADPH oxidase.

Arachidonic acid (AA) can trigger activation of the phagocyte NADPH oxidase in a cell-free assay. However, a role for AA in activation of the oxidase in intact cells has not been established, nor has the AA generating enzyme critical to this process been identified. The human myeloid cell line PLB-985 was transfected to express p85 cytosolic phospholipase A2 (cPLA2) antisense mRNA and stable clones were selected that lack detectable cPLA2. cPLA2-deficient PLB-985 cells differentiate similarly to control PLB-985 cells in response to retinoic acid or 1,25-dihydroxyvitamin D3, indicating that cPLA2 is not involved in the differentiation process. Neither cPLA2 nor stimulated [3H]AA release were detectable in differentiated cPLA2-deficient PLB-985 cells, demonstrating that cPLA2 is the major type of PLA2 activated in phagocytic-like cells. Despite the normal synthesis of NADPH oxidase subunits during differentiation of cPLA2-deficient PLB-985 cells, these cells fail to activate NADPH oxidase in response to a variety of soluble and particulate stimuli, but the addition of exogenous AA fully restores oxidase activity. This establishes an essential requirement of cPLA2-generated AA for activation of phagocyte NADPH oxidase.

Biological Transport↗
PubMed1998

Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease.

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37+/-17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71+/-23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1-2 seconds) of electrical microstimulation of STN could produce tremor arrest but were not found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.

Adult↗
PubMed1998

Developing musculoskeletal education programs for physicians and the general public: findings from a needs assessment.

OBJECTIVE: To assess the educational needs and learning preferences of primary care physicians and the general public in receiving musculoskeletal health education. METHODS: Prospective surveys were mailed simultaneously to 2,250 primary care physicians and 2,250 members of the general public. The surveys included questions about demographics, motivation for attending programs, and preferred education program formats. RESULTS: The 68 responding physicians attend continuing medical education programs mainly based on topics, speakers, and timing. They prefer lectures and find question and answer sessions least helpful in supporting learning. The 96 responding members of the general public attend programs mainly based on topics, speakers, and fees. The general public stated that question and answer sessions best support learning in programs. A large percentage of responding physicians provide health education to their patients, but a small percentage of the general public respondents stated that they receive health education from physicians. DISCUSSION: Responses from physicians and the general public were generally not surprising but revealed interesting contrasts between learning preferences. While physicians and the general public both value speakers and topics, the physicians want to increase their knowledge about disease, whereas the general public wants practical information. Physicians and the general public also appear to take different approaches to learning. The contrast between availability and provision of health education is also striking. We cannot generalize our results with absolute confidence because the return rates for the surveys were so low. Nonetheless, we support the need to educate physicians and the general public in ways that match their preferred learning methods and educational needs.

Adult↗
PubMed1998

A review of the effects of moderate alcohol intake on psychiatric and sleep disorders.

In this chapter we discuss the effects of moderate ethanol consumption on the treatment of psychiatric and sleep disorders. A review of the literature on the interactions of ethanol with neurotransmitters and psychotropic medications suggests that although ethanol affects the clinical course of psychiatric and sleep disorders by different mechanisms, it does so principally through perturbations it causes in the balance of central nervous system neurotransmitter systems, which may modify the clinical course of primary psychiatric and sleep disorders and undermine the therapeutic response to psychotropic medications. Neurotransmitter responses may also be manifested clinically by rebound phenomena, akin to a subsyndromal withdrawal, which affect sleep and precipitate anxiety and mood symptoms. In addition, ethanol also modifies the clearance and disposition of a variety of psychotropic metabolites and interferes with their clinical effectiveness. We recommend that most psychiatric patients, and all patients with sleep disorders, should abstain from even moderate ethanol use, as this may adversely affect their clinical course and response to treatment.

Alcohol Drinking↗
PubMed1998

Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders.

N-propargyl-1-(R)aminoindan (rasagiline) is a new and selective irreversible MAO-B inhibitor, currently being considered as the mesylate salt for potential therapy in certain neurological disorders. It has been studied in animal models of cognition and motor dysfunction. Its ability to restore normal motor activity was determined in models of acute drug-induced dopaminergic dysfunction: Its effects in improving cognition and memory deficits was studied in adult and senescent rats that had been exposed to prolonged hypoxia, then subjected to the passive and active avoidance tests. In alpha-methyl-p-tyrosine (alpha-MpT)-induced hypokinesia (100-120 mg/kg, i.p.) pretreatment with rasagiline at 2.5 mg/kg i.p. restored motor activity to control level. But pretreatment with reserpine abolished the protective effect of rasagiline. Rasagiline at 0.5 mg/kg/day was protective against alpha-MpT also in hypoxia-lesioned rats. In haloperidol-induced catalepsy in rats (1.5 mg/kg, s.c.) or mice (4-6 mg/kg s.c.), rasagiline improved recovery of normal locomotion, gait and coordination at 0.4-2.4 mg/kg i.p. and 1.8-1.5 mg/kg i.p., respectively. In amphetamine-induced stereotypy (0.6 mg/kg s.c., rasagiline potentiated this effect at 1.5 mg/kg i.p. In hypoxia-induced impairment of memory and learning, rasagiline at 0.32-0.5 mg/kg/day per os improved performance of adult rats in passive and active avoidance, and of senescent rats in active avoidance. Selegiline was either ineffective or less effective at equivalent doses. Racemic N-propargyl-1-aminoindan (AGN-1135), besides being of lower potency, had a different dose-dependency than rasagiline in antagonizing haloperidol-induced catalepsy or alpha-MpT-induced hypokinesia. 1-(R)aminoindan ((R)AI), a metabolite of rasagiline, in relatively high doses produced effects that were distinct in certain respects from those of rasagiline.

Aging↗
PubMed1998

(R)(+)-N-propargyl-1-aminoindan (rasagiline) and derivatives: highly selective and potent inhibitors of monoamine oxidase B.

(+)-N-Propargyl-1-aminoindan (rasagiline) and a series of derivatives have been synthesized and screened for monoamine oxidase inhibitory activity. Rasagiline and several analogues were found be highly selective and potent inhibitors of the B form of the enzyme in contrast to the levorotatory enantiomer which was not active. The results indicate that rasagiline has potential for the treatment of Parkinson's Disease. This compound is currently under development for that indication.

Animals↗