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Biomedical subjects

R N Wright

Publications and source records attributed to R N Wright.

At least 19 recordsLinked to original sources
PubMed1995

Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug.

Nefazodone is a new antidepressant drug with a pharmacologic profile distinct from that of the tricyclic, monoamine oxidase inhibitor, and serotonin selective reuptake inhibitor antidepressants. Nefazodone was initially discovered for its ability to block 5-HT2A receptors and its reduced potency as an alpha 1-adrenergic blocker. It was later shown to inhibit both serotonin and norepinephrine uptake in vitro, attributes which most likely impart its clinical efficacy and which differentiate nefazodone from its chemical predecessor trazodone. The combination of these two mechanisms may ultimately result in a facilitation of 5-HT1A-mediated neurotransmission, which may be beneficial for treating symptoms of depression as evidenced by recent clinical findings. In addition, the preclinical profile of nefazodone demonstrates that it has decreased anticholinergic and antihistaminic activity relative to traditional agents. Clinical findings to date are consistent with these observations.

Animals↗
PubMed1995

Melatonin agonists modulate 5-HT2A receptor-mediated neurotransmission: behavioral and biochemical studies in the rat.

Interactions between melatonin and serotonin type 2A (5-HT2A) receptors in the regulation of the sleep-wakefulness cycle in the rat have been reported. We studied the acute effects of melatonin and related agonists on 5-HT2A neurotransmission as reflected in behavioral (head shake) and biochemical [phosphoinositide (PI) hydrolysis] responses to 5-HT2A receptor stimulation. Like 5-HT1A agonists and antidepressants, acute administration of melatonin and related agonists inhibited the 5-HT2A-mediated (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced head shake in a dose-dependent manner. Consistent with these behavioral findings, in vitro incubation of cortical slices with melatonin agonists robustly inhibited 5-HT2A receptor-mediated PI hydrolysis in a noncompetitive manner. 2-Iodomelatonin-induced reductions in 5-HT2A-stimulated PI hydrolysis were blocked by preincubation with the melatonin antagonist N-acetyltryptamine. Further, pretreatment of rats in vivo with melatonin and related agonists reduced the cortical PI hydrolysis response to the 5-HT2A agonist alpha methyl-5-HT but did not alter cortical 5-HT2A receptor density. The present data support an interaction between melatonin and 5-HT2A receptors in the central nervous system.

Amphetamines↗
PubMed1993

5-HT-dependent myoclonus in guinea pigs: mediation through 5-HT1A-5-HT2 receptor interaction.

Investigations utilizing agonists for 5-HT receptor subtypes have been conducted to determine which 5-HT receptor subtype(s) subserve myoclonus in the guinea pig. Administration of a nonselective 5-HT agonist such as 5-MeODMT (5-HT1A/5-HT2 agonist) induces a dose-dependent behavior characterized by head jerking at low doses (1-2 mg/kg, SC) and full-blown myoclonus (continuous rhythmic whole-body jerking) at higher doses (2.5-5 mg/kg, SC). In contrast, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2 receptor agonist DOI do not induce myoclonus, and elicit only limited head jerking across an otherwise behaviorally active range of doses (1-5 mg/kg, SC). Importantly, the coadministration of both 8-OH-DPAT and DOI results in the emergence of dose-dependent myoclonic behavior. These data suggest that coactivation of 5-HT1A and 5-HT2 receptors may be required for the induction of myoclonus in the guinea pig.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Peripheral 5-carboxamidotryptamine induces hindlimb scratching by stimulating 5-HT1A receptors in rats.

Treatment of rats with 5-carboxamidotryptamine (5-CT) or 5-methoxy-tryptamine (5-MeOT) induces a hindlimb scratch response. These compounds have high affinity for 5-HT1A and 5-HT1D receptors. The selective 5-HT1A receptor agonist N,N-dipropyl-5-CT (DP-5-CT) also induced hindlimb scratching while the selective 5-HT1D receptor agonist, sumatriptan, did not. 5-CT-induced hindlimb scratching was inhibited dose-dependently by several 5-HT1A antagonists (BMY 7378, NAN-190, MDL 73005EF and pindobind-5-HT1A) as well as the non-selective 5-HT antagonist, methiothepin. Pretreatment of rats with the serotonin (5-HT) synthesis inhibitor, p-chlorophenylalanine (PCPA) or the 5-HT depleting agent, reserpine, markedly attenuated 5-CT-induced hindlimb scratching. These data suggest that hindlimb scratching induced by 5-HT agonists may not be centrally mediated but rather may be mediated by a neuronal 5-HT1A receptor localized outside the blood-brain barrier.

5-Methoxytryptamine↗
PubMed1992

5-HT1A and 5-HT2 receptors mediate discrete behaviors in the Mongolian gerbil.

Although the ability of agonists at specific serotonin (5-HT) receptor subtypes to induce distinct behaviors has been well documented in the rat, similar studies have not been reported in the Mongolian gerbil. We have found that the 5-HT1A/5-HT2 agonist 5-methoxy,N-N dimethyltryptamine (5-MeODMT) (0.5-8 mg/kg, SC), the specific 5-HT1A agonist 8-hydroxy(di-n-propylamino)tetralin (8-OH-DPAT) (0.125-16 mg/kg, SC), and the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) (100-250 mg/kg, SC) all elicit a 5-HT syndrome in the gerbil. This syndrome, analogous to the 5-HT syndrome in the rat, consists of reciprocal forepaw treading (RFT), hindleg abduction (HA), body tremors (BT), and Straub tail (ST). The putative 5-HT1A antagonist NAN-190 (0.25-8 mg/kg, SC) when dosed 15 min prior to either 5-MeODMT (4 mg/kg, SC) or 8-OH-DPAT (16 mg/kg, SC) blocked both RFT and HA in a dose-dependent manner, suggesting these 5-HT syndrome behaviors are mediated via 5-HT1A receptor activation. We also identified a unique, dose-responsive behavior in the gerbil, induced selectively by 5-HT1A agonists such as quipazine (2-16 mg/kg, SC) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-8 mg/kg, SC). This reciprocal hindleg body scratch (RHBS) behavior is dose dependently inhibited by pretreatment with the selective 5-HT2 antagonist ritanserin (0.0125-0.2 mg/kg, SC). RHBS behavior is also potently inhibited by pretreatment with the selective 5-HT1A agonist 8-OH-DPAT (0.005-0.04 mg/kg, SC), demonstrating a 5-HT1A/5-HT2 receptor subtype interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1990

8-OH-DPAT and buspirone analogs inhibit the ketanserin-sensitive quipazine-induced head shake response in rats.

Behavioral syndromes mediated by serotonergic mechanisms may reflect interactions between distinct effects initiated by specific 5-HT receptors, such as the 5-HT1A and the 5-HT2 receptor. This hypothesis was tested by examining the effect of various 5-HT1A agonists on the 5-HT2 receptor-mediated quipazine-induced head shake response in rats. Subcutaneous administration of 8-OH-DPAT, buspirone, gepirone, and ipsapirone produced a dose-dependent inhibition of the ketanserin-sensitive quipazine-induced head shake response. These effects were produced by doses of agonists which did not induce reciprocal forepaw treading. Furthermore, pretreatment with a partial 5-HT1A agonist (+/-)pindolol blocked the inhibitory effects of 8-OH-DPAT to the level of inhibition produced by (+/-)pindolol itself. These results suggest that stimulation of central 5-HT1A receptors can modulate the expression of a central 5-HT2 receptor-mediated behavior.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Nefazodone: preclinical pharmacology of a new antidepressant.

Recent pharmacologic studies suggest that nefazodone may possess antidepressant activity. Nefazodone is active in behavioral models predictive of antidepressant potential. It is active in reversing learned helplessness, prevents reserpine-induced ptosis, and enhances response efficiency in the differential reinforcement for low rates of response paradigm. In in vitro studies, nefazodone inhibits the binding of [3H]ketanserin to cortical serotonin2 (5-HT2) binding sites, whereas in vivo, it antagonizes the 5-HT2-mediated quipazine-induced head shake in rats. In ex vivo studies, acute oral administration of nefazodone inhibits cortical serotonin uptake and occupies frontal cortical 5-HT2 receptor binding sites. Chronic administration of nefazodone produces a reduction in 5-HT2-mediated behavior and decreases cortical 5-HT2 receptor binding site density. Further, a chronic high-dose nefazodone regimen significantly potentiates 5-HT1A-mediated behavioral responses in rats. Nefazodone exhibits decreased anticholinergic, alpha-adrenolytic, and sedative activity relative to other antidepressants.

Animals↗
PubMed1988

BMY-25801, an antiemetic agent free of D2-dopamine receptor antagonist properties.

BMY-25801, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]2-(1-methyl-2-oxopropoxy ) benzamide, a new antiemetic agent free of D2-dopamine receptor antagonist properties, was effective against emesis induced by cytostatic agents (cisplatin, cyclophosphamide and doxorubicin) and total body radiation in the ferret. It also was effective against cisplatin-induced emesis in the dog; however, it was inactive against emesis caused by apomorphine and hydergine in the same species. In terms of activity profile, BMY-25801 could be differentiated both from metoclopramide and domperidone. Metoclopramide was nonselectively active against emesis induced by cytostatic agents, radiation and D2-dopamine receptor agonists, whereas domperidone was selectively effective against emesis induced by apomorphine and hydergine only. BMY-25801 failed to reveal any D2-dopamine receptor antagonist properties in several pharmacological tests (catalepsy, apomorphine stereotypy, serum prolactin, striatal dihydroxyphenylacetic acid and [3H]spiperone displacement) whereas metoclopramide was uniformly active in these tests. The activity profile of domperidone was compatible with its classification as a peripherally acting D2-dopamine receptor antagonist. BMY-25801 and metoclopramide antagonized serotonin-induced bradycardia (Bezold-Jarisch reflex) in the anesthetized rat, a response involving peripheral neuronal 5-HT3 receptors. Thus, BMY-25801 represents a novel antiemetic acting independently of D2-dopamine receptor mechanisms; however, its exact mode of action remains unknown.

Animals↗
PubMed1987

Disease modifying activity of HWA 486 in rat adjuvant-induced arthritis.

HWA 486 was investigated for its ability to modify the development of adjuvant-induced polyarthritis in Lewis rats. HWA 486 (20 mg/kg/day p.o.), dosed for 8 or 16 days beginning with the day of adjuvant administration, significantly reduced edema, fibrinogen levels, and erythrocyte sedimentation rates (ESR) 42 days later. When HWA 486 (20 mg/kg/day, p.o.) and cyclosporin A (CsA 15 mg/kg/day, p.o.) were tested in the 8-day treatment regimen, the antiarthritic effects of HWA 486 were more sustained. Both compounds reduced the delayed hypersensitivity (DTH) response on day 9 followed by a rebound to an enhanced DTH response on day 21. The PHA-induced mitogenic response of splenocytes from arthritic rats was suppressed on day 9. Treatment with HWA 486 but not CsA restored the splenocyte response to the level of the negative controls.

Animals↗
PubMed1982

Acute endocarditis in drug addicts: surgical treatment for gram-negative sepsis.

We studied 37 consecutive patients, all drug addicts, who underwent 48 valve operations from 1976 through 1981. GN bacteria were the major organisms in 25 patients (64%), compared with a previous reported incidence of 10%. Operative indications were uncontrolled sepsis in 49%, embolism in 27% and heart failure in 24% of the patients. Primary operations included nine tricuspid valvectomies and 14 aortic, 10 mitral and four aortic/mitral valve replacements. Early (30-day) mortality was 2.7% (one of 37 patients); five of nine patients who had 11 reoperations survived. Long-term follow-up revealed a late mortality of 39% (11 of 28) in patients with left-sided disease; eight of the 11 patients who died had GN infection with perivalvular abscess. Thus, the subgroup with GN sepsis and left-sided disease had a combined early and late mortality of 50%, with all deaths occurring within 8 months postoperatively. We conclude that valve replacement in the presence of active sepsis can be safely performed, but GN sepsis in addicts increases the risk of early reinfection and late mortality.

Acute Disease↗
PubMed1980

Pulmonary mucormycosis (Phycomycetes) successfully treated by resection.

Pulmonary mucormycosis (Phycomycetes) is an uncommon fungus infection complicating diabetes mellitus, leukemia, lymphoma, and other debilitating diseases. A review of the literature revealed that of 21 diabetic patients in whom Phycomycetes occurred without underlying malignancy, only 7 survived. These 7 underwent operation. This report concerns another patient with pulmonary mucormycosis who was successfully treated by pulmonary resection.

Diabetes Complications↗
PubMed1978

Potassium cardioplegia. An alternate method of intraoperative myocardial protection.

Potassium-induced cardioplegia was studied in 38 mongrel dogs supported by normothermic cardiopulmonary bypass and subjected to 60 minutes of aortic cross clamping followed by 30 minutes of reperfusion. A study of preischemic and postischemic ventricular function and myocardial high-energy phosphate compounds, lactate, and glycogen showed substantial preservation of high-energy phosphates and ventricular performance when potassium cardioplegia was used. However, the substantial depression in contractility observed following ischemia nad reperfusion suggests that potassium cardioplegia alone does not provide adequate intraoperative protection of the myocardium.

Adenosine Diphosphate↗
PubMed1977

Does intermittent coronary perfusion offer greater myocardial protection than continuous aortic cross-clamping?

There has been considerable controversy concerning the relative merits of intermittent coronary perfusion vs. continuous aortic cross-clamping for cardiac procedures requiring ischemic arrest. Using the isovolumic ventricular balloon model and "stop-freeze" biopsy techniques, myocardial contractility (LV dp/dt max, length-tension, and force-velocity relationships) and metabolism (adenine nucleotides, creatine phosphate, and glycogen) were studied in 46 intact dogs supported by normothermic cardiopulmonary bypass and subjected to either 60 minutes of continuous ischemic arrest or to four 15-minute intervals of ischemia each followed by 5 minutes of reperfusion. Following ischemia the hearts were reperfused for 30 minutes and defibrillated after the first 10 minutes. There were no significant differences in either metabolic parameters or contractile function between the groups. Although partial regeneration of adenosine triphosphate and glycogen occurred during reperfusion, only creatine phosphate achieved normal values and the end result was no difference between the two techniques. These data indicate that 5 minutes of coronary reperfusion between consecutive episodes of ischemic arrest affords no greater intraoperative protection of the myocardium than does continuous aortic cross-clamping.

Adenine Nucleotides↗
PubMed1977

Hernia reduction en masse.

A case of hernia reduction en masse is reviewed. Discussion of the pathogenesis, diagnosis, and operative approach suggests that the use of taxis in the reduction of incarcerated hernia should be tempered by awareness of potential complications including mass reduction. Diagnosis is by history with the persistence of intestinal obstruction after reduction is a key feature. A preperitoneal approach is recommended for facility of reduction, resection, and anatomic hernia repair.

Aged↗