Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome

Nisijima, Koichi; Shioda, Katsutoshi; Yoshino, Tatsuki; Takano, Kenji; Kato, Satoshi

doi:10.1016/s0197-0186(02)00213-9

Cited by 59 publications

(28 citation statements)

References 26 publications

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“…Changes in body-core temperature (claudqcT cor ), attributable to 5-HT-mediated thermoregulation in the central nervous system (Lin et al, 1998), are a most obvious indication for the toxidrome (Isbister and Buckley, 2005). Several studies conducted in animals have revealed both hyperthermia and hypothermia in the toxidrome (Abdel-Fattah et al, 1995, 1997Nisijima et al, 2001Nisijima et al, , 2003. However, little is known about changes in body-core temperature in the context of different degrees of toxicity although in the severe state their relationship has been examined by others using a single dose protocol (Grahame-Smith, 1971b;Jacobs and Klemfuss, 1975;Nisijima et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Ma¹,

Zhang²,

Jenney³

et al. 2008

European Journal of Pharmacology

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Patients are at high risk of developing serotonin-toxicity syndrome (toxidrome) when they take multiple serotonergic drugs, particularly co-administered with monoamine oxidase inhibitors or 5-hydroxytryptamine (5-HT) reuptake blockers. The toxidrome can vary from mild to severe. The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5-hydroxy-L-tryptophan (5-HTP) in clorgylinized rats. The severity was obtained by scoring behavioral signs including head shakes, penile erection, forepaw treading, hind limb abduction, Straub tail and tremor. It was found that 5-HTP produced a dosedependent increase in degrees of the toxidrome. Furthermore, correlation between the toxidrome and changes in body-core temperature (claudqcT cor ) was determined. There was hypothermia in the mild toxidrome (claudqcT cor < −1 °C), high hyperthermia in the severe toxidrome (claudqcT cor > +2 °C) and a small change in T cor in the moderate toxidrome (−1 °C < claudqcT cor < +2 °C). Thus, claudqcT cor in response to drugs can be used to estimate the severity of the toxidrome. The second attempt was to identify the receptors mediating those changes. 5-HT 1A receptors were involved in the hypothermic response while 5-HT 2A and NMDA receptors mediated head shakes, hyperthermia, forepaw treading and Straub tail. Lastly, antidotal effect of cyproheptadine and (+)-MK-801 was examined. Both drugs blocked hyperthermia and death. However, the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced. These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5-HT toxidrome.

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Section: Introductionmentioning

confidence: 99%

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Ma¹,

Zhang²,

Jenney³

et al. 2008

European Journal of Pharmacology

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“…It is suggested to prescribe Cyproheptadine for patients in moderate and severe cases, although there are no randomized controlled trials about severe cases (47,48). Diazepam is a GABA mimetic, which has been studied more and blunts the hyper-adrenergic symptoms of serotonin syndrome (42,49,50). Diazepam not only sedates the patient, but also improves mild hypertension and tachycardia, and reduces fever (1,51).…”

Section: Discussionmentioning

confidence: 99%

Concurrent Serotonin Syndrome and Hyponatremia: A Case Report and Review

Elyasi

Azizi

2017

Iran J Psychiatry Behav Sci

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Introduction: These days, selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed and used antidepressants. Serotonin syndrome is a potentially fatal complication with hyper-serotonergic situation. Its symptoms result from over activation of the central and peripheral receptors caused by high serotonin levels. The use of SSRIs is associated with the frequency of syndrome. Hyponatremia is one of the side effects of SSRIs, especially in elderly patients. The mechanism by which SSRIs cause hyponatremia is thought to be secondary to the development of the syndrome of inappropriate antidiuretic hormone (SIADH). Patients with hyponatremia secondary to SIADH have been reported with fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram. There are very few reports about the concurrent incidence of serotonin syndrome and hyponatremia. Case Presentation: The patient was a 66-year-old woman with rheumatoid arthritis. She was treated with a fixed dose of fluoxetine and buspirone added with the amount of 15 mg per day. The patient was hospitalized 8 weeks with symptoms of confusion, lack of insight into time and space, inability to stand and walk, continuous involuntary tremor, uncoordinated and uncontrolled movements of arms and legs, hyperreflexia, and mydriasis. She also showed severe hyponatremia in the experiments. She was admitted to an academic general hospital in Iran on 2014. Based on the clinical findings, taking buspirone aside fluoxetine, as well as old age of the patient, she was diagnosed with serotonin syndrome. Treatment was carried out after discontinuation of fluoxetine and buspirone, restriction of fluid therapy, as well as prescription of sodium chloride 5%, cyproheptadine, and diazepam. Conclusions: Consumers of SSRIs are at a higher risk of hyponatremia compared to those taking other antidepressants, especially if they are simultaneously treated by diuretics. Hyponatremia and SIADH need to be considered if a patient experiences disorientation receiving SSRIs. Physicians should be aware of the probability of acute hyponatremia and serotonin syndrome secondary to SSRIs in simultaneous use of fluoxetine and buspirone with diuretics. Moreover, physicians should note that serotonin toxicity is dose-dependent rather than idiosyncratic.

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“…The avoidance of neurological effects would need to be addressed in the design and evaluation of related compounds. For example, compounds that are predicted to have neurological effects could be screened in animal models of the serotonin syndrome (24,28). These data indicate that 8-OH-DPAT may target a 5HT1A-like receptor present in P. falciparum and thus may be used to identify this membrane channel by affinity purification or as a biotinylated probe for quantitative proteomic analysis (36).…”

Section: Discussionmentioning

confidence: 99%

5HT1A Serotonin Receptor Agonists InhibitPlasmodium falciparumby Blocking a MembraneChannel

Locher

Ruben²,

Gut

et al. 2003

Antimicrob Agents Chemother

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To identify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 M, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels.Discovery of drugs for the treatment of malaria is essential because of the widespread resistance of Plasmodium falciparum to chloroquine and other drugs. Drug resistance contributes importantly to the 1 to 2 million deaths caused by malaria every year (25, 37). Natural products from traditional medicinal plants have formed the basis of new synthetic antimalarial analogues with potent activity, and numerous other lead compounds have been identified, including alkaloids, quinones, terpenes, and flavonoids (17,26). During the screening of plant extracts used in traditional Polynesian medicine and other natural products for antiviral and antimicrobial activity (19), we found that some serotonin (5-hydroxytryptamine [5HT]) receptor agonists have antimalarial properties. The activity of these agonists was accompanied by the blocking of a membrane channel on parasitized erythrocytes. Serotonin agonists may therefore be useful for the characterization of the membrane transport properties of the malaria parasite and may provide new lead candidates for the treatment of malaria. MATERIALS AND METHODSGrowth inhibition assays. The P. falciparum isolates used were Uganda-Palo Alto (FUP; mefloquine resistant) (10), Falciparum Vietnam Oak Knoll (FVO; chloroquine resistant) (29),...

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Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome

Cited by 59 publications

References 26 publications

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Concurrent Serotonin Syndrome and Hyponatremia: A Case Report and Review

5HT1A Serotonin Receptor Agonists InhibitPlasmodium falciparumby Blocking a MembraneChannel

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