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M L Cohen

Publications and source records attributed to M L Cohen.

At least 91 records · Page 5Linked to original sources
PubMed1996

LY353433, a potent, orally effective, long-acting 5-HT(4) receptor antagonist: comparison to cisapride and RS23597-190.

Although many 5-HT (serotonin, 5-hydroxytryptamine)(4) receptor antagonists have been described, none possess the requisite oral activity and duration of action for a clinically effective therapeutic agent. The present report identifies LY353433 (1-(1-methylethyl)-N-[2-[4-[tricyclo[3.3.1.1(3,7)]dec-1-ylcarbo nyl) amino]-1-piperidinyl]ethyl]-1H-indazole-3-carboxamide), an indazole amide, as a high affinity antagonist at the 5-HT(4) receptor in the rat esophagus. LY353433 (10(-8), 3 x 10(-8), 10(-7) M) inhibited 5-HT-induced relaxation of carbamylcholine-contracted esophagus with greater potency than cisapride or RS23597-190, a known 5-HT(4) receptor ligand. Furthermore, RS23597-190 possessed marked agonist activity as did cisapride, whereas LY353433 did not relax the rat esophagus in concentrations up to 10(-5) M. LY353433 (up to 10(-5) M) did not possess appreciable affinity for adrenergic, dopaminergic, histaminergic, muscarinic or GABAergic receptors and, thus, was a highly selective 5-HT(4) receptor antagonist. In addition, LY353433 only slowly associated with an dissociated from the 5-HT(4) receptor, an attribute that conferred long-lasting 5-HT(4) receptor antagonist activity, in contrast to RS23597-190, which rapidly dissociated from the 5-HT(4) receptor. LY353433 dose-dependently inhibited the 5-HT(4) receptor-mediated ex vivo relaxation in the rat esophagus after either i.v. (0.1, 0.3 and 1.0 mg/kg) or p.o. (0.1, 0.3, 1.0 and 3.0 mg/kg) administration. Furthermore, the p.o. to i.v. dose ratio was approximately one, suggesting that LY353433 was well absorbed with excellent pharmacodynamics in the rat. LY353433 (0.3 mg/kg p.o.) blocked esophageal 5-HT(4) receptors ex vivo through 6 hr after p.o. dosing with responses returning to control by 16 hr, indicative of long duration receptor blockade. Lastly, in rats LY353433 was exceptionally safe because acute doses up to 300 mg/kg p.o. did not result in either symptoms or deaths. Thus, LY353433 is a potent, selective, orally effective, long-acting and safe 5-HT(4) receptor antagonist that is highly suitable for clinical use.

Adamantane↗
PubMed1996

Neomycin selectively inhibits 5-hydroxytryptamine-induced contraction in the guinea pig trachea.

Neomycin (3 mM) inhibited maximal 5-HT-induced contraction by approximately 50% without inhibiting [3H]5-HT binding to 5-HT2A receptors. In contrast, neomycin had no effect on carbamylcholine- or histamine-induced contraction. Carbamylcholine (10 microM) and histamine (10 microM) both stimulated phosphatidylinositol (PI) hydrolysis but neomycin had no effect on the increase in PI hydrolysis. 5-HT (10 microM) did not stimulate PI hydrolysis in the absence or presence of neomycin, suggesting that neomycin inhibited 5-HT contraction in the guinea pig trachea independent of PI turnover. Although bradykinin stimulated phospholipase D (PLD) activity, 5-HT did not activate PLD, suggesting that the 5-HT2A receptor is not coupled to this enzyme in the guinea pig trachea. Neomycin (3 mM) and nitrendipine (1 microM) inhibited 5-HT-induced contraction to a similar extent, and neomycin did not further inhibit contraction in the presence of nitrendipine. These data indicate that neomycin inhibited 5-HT-induced contraction, like nitrendipine, via an effect on calcium influx through L-type calcium channels and did not affect intracellular calcium release. However, unlike nitrendipine which completely blocked KCl-induced contraction, neomycin only marginally reduced the maximal KCl-induced contraction. Taken together, these data suggest that neomycin may indirectly inhibit calcium influx through L-type calcium channels in guinea pig tracheal smooth muscle. The mechanism by which neomycin inhibited calcium influx in the guinea pig trachea may provide insight into the novel signaling pathway of the 5-HT2A receptor in this tissue.

Animals↗
PubMed1996

LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery.

The canine coronary artery possesses a smooth muscle relaxant serotonin (5-HT) receptor distinct from previously characterized 5-HT receptors. On the basis of the ability of LY53857 to block weakly coronary smooth muscle relaxation to 5-HT, we examined several structurally related ergolines in endothelium denuded rings of canine coronary artery precontracted with PGF2 alpha (10 microM). 5-HT (10 nM-100 microM)-induced relaxation was antagonized competitively by the ergoline esters LY53857 (-log KB = 6.5) and sergolexole (-log KB = 6.4) and by the ergoline amide amersergide, (-log KB = 6.7). In contrast to the relatively low affinity of these ergolines, LY215840, another ergoline amide, antagonized 5-HT-induced relaxation in a competitive manner with the highest affinity (-log KB = 8.3). This effect was independent of the 5-HT2 receptor affinity of these ergolines, because LY215840, LY53857, sergolexole and amesergide all possessed similar 5-HT2 receptor affinity. Further, all four ergolines possessed affinity for the human 5-HT7 receptor, and LY215840 had the highest 5-HT7 receptor affinity (Ki = 14.7 nM). Finally, in vascular smooth muscle under basal tone, LY215840 (1 microM) blocked the relaxant response to high concentrations of 5-HT and 5-MeOT without altering their contractile potency. LY215840 (1 microM) did not alter contraction to sumatriptan, an agent that lacks relaxant activity. In contrast, LY215840 (1 microM) markedly potentiated contraction to 5-carboxamidotryptamine, the most potent coronary relaxant agonist and the agonist with the highest 5-HT7 receptor affinity. The ability of LY215840 to block the relaxant 5-HT receptor in canine coronary artery may reflect its 5-HT7 receptor antagonist activity and make it a useful tool to probe the relationship between the 5-HT7 receptor and the coronary vasoactive properties of 5-HT.

Animals↗
PubMed1996

Effects of oxidized low-density lipoprotein on vascular contraction and relaxation: clinical and pharmacological implications in atherosclerosis.

Oxidized LDL exerts profound effects on the vasomotor response of isolated blood vessels to various stimuli that closely mimic the vascular dysfunction associated with hypercholesterolemia and atherosclerosis in humans. The beneficial effect of lipid-lowering therapy in normalizing vascular function and greatly decreasing the frequency of clinical events associated with atherosclerosis, combined with the ability of antioxidants to alleviate vasomotor disturbances in hypercholesterolemia and slow the progression of atherosclerosis, strongly support a causative role of oxidized LDL in mediating vascular dysfunction in vivo and contributing to the clinical sequalae of coronary artery disease. Further research to understand more fully the mechanisms of oxidized LDL formation and actions in vivo may reveal novel strategies to inhibit these events, and may prove beneficial in the therapeutic management of atherosclerotic disease.

Arteriosclerosis↗
PubMed1996

Selective enhancement of 5-hydroxytryptamine-induced contraction of porcine coronary artery by oxidized low-density lipoprotein.

Oxidatively modified low-density lipoprotein(LDL) may be involved in the vasomotor disturbances associated with hypercholesterolemia and atherosclerosis, but effects of this lipoprotein on agonist-induced coronary vasoconstriction have not been reported. This study determined the effects of oxidized LDL on contraction of isolated porcine coronary arteries to several contractile agonists and investigated the mechanism of these effects. Oxidized LDL (10-100 microgram/ml) enhanced 5-hydroxytryptamine (5-HT)-induced contraction in a concentration-dependent manner, whereas native LDL (100 microgram/ml) had no effect. Enhancement of 5-HT-induced contraction was dependent on the presence of endothelium and blocked by L-NG-monomethyl-arginine (100 microM). Oxidized LDL (100 microgram/ml) similarly inhibited endothelium- and nitric oxide-dependent relaxation induced by 5-HT, but had no effect of relaxation induced by sodium nitroprusside. Furthermore, contraction to U46619 and acetylcholine, agonists that did not mediate endothelium-dependent relaxation, was unaffected by oxidized LDL (100 microgram/ml). Lysophosphatidylcholine (10-30 mumol/liter) also enhanced 5-HT-induced contraction and inhibited 5-HT-induced, endothelium-dependent relaxation. Endothelium-dependent relaxation to bradykinin was unaffected by lysophosphatidylcholine (20 muM). Thus, oxidized LDL enhanced 5_HT-induced coronary vasoconstriction in an endothelium dependent manner, actions that were mimicked by relevant concentrations of lysophosphatidylcholine. These in vitro effects of oxidized LDL mimicked effects of hypercholesterolemia and atherosclerosis on 5-HT vasoactivity in human coronary arteries in vivo, suggesting that oxidized LDL may play an important role in the development of vasomotor disturbances in these pathologies.

Acetylcholine↗
PubMed1995

Is nitric oxide involved in 5-HT2B receptor-mediated contraction in the rat stomach fundus?

Although contraction of the rat stomach fundus by 5-HT is known to be mediated by the 5-HT2B receptor, the second messenger pathways involved in this response remain unclear. Since nitric oxide (NO) has been associated with contraction of certain gastrointestinal smooth muscle, the purpose of this study was to determine if NO is involved in 5-HT-induced contraction in the rat stomach fundus. The arginine analogs L-NAME and L-NMMA, at a concentration (100 microM) established to inhibit NO synthase in the rat stomach fundus by inhibiting depolarization-induced relaxation in this tissue, had no effect on 5-HT contraction. Furthermore, the NO donors sodium nitroprusside and SNAP did not contract rat stomach fundus under basal tone, whereas 5-HT was a potent contractile agonist. These data do not support a role for NO in 5-HT2B receptor-mediated contraction in the rat stomach fundus.

Animals↗
PubMed1995

Role of alpha 1-adrenoceptors and 5-HT2 receptors in serotonin-induced contraction of rat prostate: autoradiographical and functional studies.

Urinary obstruction from benign prostatic hyperplasia is a common clinical problem possibly associated with excessive prostatic constriction around the urethra. These studies compared adrenergic and serotonergic functional activity to specific alpha 1 and serotonin (5-hydroxytryptamine; 5-HT) binding sites in the rat prostate. Isolated, left ventral lobes of the rat prostate were removed and examined for in vitro contraction. Norepinephrine-induced contraction of the rat prostate was competitively blocked by prazosin with an apparent antagonist dissociation constant (pKB) of 8.13. 5-HT also contracted the rat prostate. However, in the presence of prazosin, maximum 5-HT contraction was reduced by half suggesting that high concentrations of 5-HT can activate alpha 1 receptors in the prostate. The concentration-response curve to 5-HT in the presence of 1 microM prazosin was competitively inhibited by the 5-HT2 receptor antagonist LY53857 (6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid 2-hydroxyl-1-methylpropylester (Z)-2-butenedioate (1:1)) (pKB = 9.02). Autoradiographic studies with [125I]LSD (2-iodo-lysergic acid diethylamide) documented the presence of 5-HT2 receptors since significant displacement of the radioligand occurred with 5-HT and LY53857, but not with prazosin. The alpha 1-adrenoceptor ligand [125I]HEAT ([beta-(4-hydroxy-3-iodophenyl)ethylaminomethyl]-tetralone) confirmed the presence of alpha 1-adrenoceptors in the rat prostate since significant displacement of the radioligand occurred with prazosin, but not 5-HT or LY53857. The inability of prazosin to displace [125I]LSD and the inability of 5-HT to displace [125I]HEAT suggest that 5-HT cannot directly interact with alpha 1-adrenoceptors in the prostate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

Hemolytic uremic syndrome with particular involvement of basal ganglia and favorable outcome.

Two children with hemolytic uremic syndrome and extrapyramidal complications are presented. Neuroimaging studies demonstrated bilateral basal ganglia (striatal) involvement with favorable recovery in both patients. The pathophysiology of the neurologic complications in hemolytic uremic syndrome are probably multifactorial. Our patients suggest a reversible process because both patients recovered clinically and radiographically. Neurologic complications do not always portend a poor prognosis and, in general, involvement of the basal ganglia is associated with favorable outcome.

Basal Ganglia↗
PubMed1995

American National Standard for nonautomated sphygmomanometers. Summary report.

The Association for the Advancement of Medical Instrumentation develops voluntary standards for medical devices so that manufacturers might provide information on their product and basic safety and performance criteria that should be considered in qualifying the instrument for clinical use. American National Standards are generated through a consensus process by committees of experts in research, development, and design from user, industry, and government communities. Draft standards are made available for public review and become American National Standards after review by the American National Standards Institute. This report is a summary of the American National Standard that establishes both the safety and performance requirements of pneumatic and other nonautomated sphygmomanometers (especially mercury gravity and aneroid sphygmomanometers) used in the indirect measurement of blood pressure. This standard was developed by a consensus panel from academia, industry, and government; it updates the previous standard approved by the American National Standards Institute in 1986. This summary report does not cover all of the provisions of the revised 1994 American National Standard, thus users, researchers, and instrument designers should refer to the standard for detailed requirements.

Blood Pressure Determination↗
PubMed1995

NF2 gene analysis distinguishes hemangiopericytoma from meningioma.

The histogenesis of dural-based or "central" hemangiopericytomas (cHPCs) remains controversial. Some authors consider these tumors variants of meningiomas while others consider them akin to peripheral hemangiopericytomas (pHPCs). Meningiomas frequently have mutations in the neurofibromatosis 2 (NF2) gene, providing a molecular marker for meningiomas and other NF2-related tumors. We therefore analyzed the NF2 gene in cHPCs, pHPCs, and meningiomas to determine whether cHPCs are more similar at the molecular genetic level to meningiomas or pHPCs. Using paraffin-embedded archival material from 28 cHPCs (including three primary and recurrent tumors), 10 pHPCs, and 26 meningiomas, we scanned all 17 exons of the NF2 gene and flanking intronic sequences for mutations with single strand conformation polymorphism analysis and DNA sequencing. No NF2 mutations were found in either cHPCs or pHPCs, whereas 35% of meningiomas had NF2 gene alterations (P < 0.001). The NF2 gene mutations in meningiomas were all truncating mutations, consistent with previous studies. Our findings suggest that cHPCs are distinct from meningiomas at the molecular genetic level and support prior clinico-pathological data that distinguish these tumor-entities.

Adult↗
PubMed1995

Antagonism of serotonin3 (5-HT3) receptors within the blood-brain barrier prevents cisplatin-induced emesis in dogs.

Recently discovered serotonin3 (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site where 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antiemetic effect of 5-HT3 receptor antagonists is exerted in the brain areas that reside inside or outside of the blood-brain barrier. Tropisetron, zatosetron (LY277359 maleate) and its quaternary analog zatosetron-QUAT were used in this study. Zatosetron and zatosetron-QUAT showed high affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats with an approximate ID50 of 0.7 and 0.2 microgram/kg i.v., respectively. Zatosetron and tropisetron significantly inhibited cisplatin-evoked emesis in dogs (estimated ID50 values of 34.4 +/- 2.3 micrograms/kg and 108.3 +/- 4.8 micrograms/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v.) had no effect. [14C]-zatosetron-QUAT (100 micrograms/kg) was not detected in the brain after i.v. administration to rats, consistent with the inability of charged compounds to achieve significant brain concentrations. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT reduced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). These studies suggest that, in dogs, antagonism of 5-HT3 receptors located within the blood-brain barrier is important to block cisplatin-induced emesis.

Animals↗
PubMed1995

5-Hydroxytryptamine2B receptor signaling in rat stomach fundus: role of voltage-dependent calcium channels, intracellular calcium release and protein kinase C.

The rat stomach fundus is enriched with the 5-hydroxytryptamine (5-HT)2B receptor, the newest subtype of the 5-HT2 receptor family to be cloned. Although the 5-HT2A and 5-HT2C receptor subtypes couple to phosphatidylinositol hydrolysis, such a coupling has not been established for the 5-HT2B receptor in tissues. Thus, the purpose of this study was to characterize further the signal transduction mechanism of the 5-HT2B receptor in rat stomach fundus. Nitrendipine (1 microM) inhibited the maximal contraction to 5-HT (1 microM) by approximately 50%. Removal of extracellular calcium did not inhibit 5-HT contraction to a greater extent than that produced by nitrendipine, indicating that calcium influx through voltage-dependent calcium channels was predominantly responsible for the dependence of the 5-HT contraction on extracellular calcium. Depletion of both extracellular calcium and intracellular calcium stores abolished 5-HT contraction. Ryanodine (30 microM), a compound which inhibits calcium release from intracellular stores, significantly inhibited the maximal contraction to carbamylcholine (3 microM). In contrast, ryanodine (30 microM) did not inhibit the maximal contraction to 5-HT (1 microM) in the absence of nitrendipine. However, ryanodine (30 microM) did significantly inhibit the nitrendipine-insensitive 5-HT contraction, suggesting that this component of the contraction was due in part to calcium release from a ryanodine-sensitive store. Bisindolylmaleimide (5 microM), a specific inhibitor of protein kinase C (PKC), inhibited 5-HT contraction in either the absence or presence of nitrendipine, suggesting that activation of PKC is also involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Is the "atypical" beta-receptor in the rat stomach fundus the rat beta 3 receptor?

The rat gastric fundus is known to possess an "atypical" beta-adrenergic receptor that mediates relaxation to isoproterenol. The purpose of this study was to characterize the relationship between this "atypical" beta receptor in the rat stomach and the cloned rat beta 3 receptor by taking advantage of highly selective pharmacological and molecular biological probes of the beta 3 receptor. Nuclease protection analysis of RNA from the rat gastric fundus identified beta 3 receptor mRNA whose levels in the stomach were exceeded only by those in adipose tissue. Pharmacological analysis of the recombinant rat beta 3 receptor expressed in Chinese hamster ovary cells indicated low affinity of propranolol with a Ki value of 2.3 microM. Therefore, 0.3 microM propranolol was chosen as a concentration that would completely block beta 1 and beta 2 receptors (Ki = 1-5 nM) but would leave beta 3 receptors largely intact in the rat stomach fundus. In the presence of propranolol, several beta-adrenergic receptor agonists relaxed the rat stomach fundus with a rank potency order of (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3- benzodioxole-2,2-dicarboxylate (CL316,243) > isoproterenol > norepinephrine = epinephrine = dl-4-3[(1,1-dimethylethyl)amino]-2- hydroxylproproy]1,3 dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) > clenbuterol > terbutaline > pindolol. Isoproterenol, norepinephrine and epinephrine were full agonists, whereas (R,R)-5-[2-[[2-(3-chlorophenyl)-2- hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate was only a partial agonist with 66% intrinsic activity relative to isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1995

Medicine and the Canadian state: from the politics of conflict to the politics of accommodation?

This paper analyzes data from three large-scale surveys of Canadian physicians conducted over the past decade to examine the politics of a cohort of recently established family physicians in Ontario, and to assess the extent to which these politics represent a "softening" of professional resistance to government health insurance. Politically, this is an important cohort because the physicians in it have grown up without any firsthand knowledge of the pre-Medicare period, and because they are among the first to establish practices in the wake of the month-long 1986 Ontario physicians' strike, a high point of profession-government conflict. Factors which may have contributed to a moderation of medical politics include the progressive entry of women into medicine. Our data suggest that professional opposition to Medicare is declining and that fewer physicians support a return to voluntary and commercial control of the health system, a shift which could assist in breaking the historical cycle of profession-government conflict and moving to the politics of accommodation. In the conclusions we discuss implications for medical politics in Canada and other countries such as the United States.

Attitude of Health Personnel↗
PubMed1994

Age-related alterations in sensitivity of muscarinic and serotonergic responses of guinea pig trachea to removal of extracellular Ca2+.

Contractile responses to carbamylcholine and 5-hydroxytryptamine (5-HT) in the presence and absence of extracellular Ca2+ were compared in tracheal rings from 3-4-week-old and 7-8-week-old guinea pigs. Contraction to carbamylcholine and 5-HT did not differ in potency or maximal response between age groups in the presence of extracellular Ca2+. However, removal of extracellular Ca2+ inhibited maximal contraction mediated by both agonists to a greater extent in younger versus older guinea pigs. These data suggest that carbamylcholine- and 5-HT-induced contraction of guinea pig trachea from younger animals is more dependent on extracellular Ca2+ as compared to mature animals, and may be related to an age-dependent maturation of sarcoplasmic reticulum function in smooth muscle.

Aging↗
PubMed1994

Mononeuritis multiplex. A harbinger of acute leukemia in relapse.

OBJECTIVE: To report the findings in a patient who developed severe mononeuritis multiplex in the setting of hematologic remission from acute myeloid leukemia. DESIGN: Single case report of the patient, hospital course, and autopsy findings. PATIENT: A 63-year-old woman with a history of acute myeloid leukemia in hematologic remission experienced a succession of acute clinical neuropathies (left median, right radial, and left sciatica) several months before hematologic relapse of leukemia. Electrophysiologic tests localized the abnormalities of the left median and right radial nerves to the arms, and a magnetic resonance imaging scan of the right arm revealed focal swelling of the radial nerve proximal to the elbow. The patient refused treatment for leukemic relapse and died about 6 months after the onset of the neuropathies. An autopsy revealed leukemic infiltrates in multiple nerves without appreciable involvement of the cauda equina or many of the proximal nerves. CONCLUSION: Mononeuritis multiplex, without polyradiculopathy or diffuse peripheral neuropathy, can be a presenting feature of leukemia.

Female↗