Cyproheptadine hydrochloride

Cyproheptadine hydrochloride is an antagonist of serotonin receptor [1].

Cyproheptadine is a serotonin and histamine antagonist as well as an antimuscarinic reagent. It is used to treat for postgastrectomy-dumping syndrome, pruritic dermatoses, migraine, anorexia, and pituitary-dependent Cushing's syndrome. The major urinary product of cyproheptadine is cyproheptadine glucuronide, a quaternary ammonium compound. Cyproheptadine has some side effects including sedation, drowsiness, hypotension, tachycardia and blood dyscrasias. As a 5-HT2A receptor antagonist, cyproheptadine is found to reverse serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo suggesting its antiplatelet and thromboprotective effects. [1, 2]

References:
[1] Levine B, Green-Johnson D, Hogan S, Smialek JE.  A cyproheptadine fatality. J Anal Toxicol. 1998 Jan-Feb;22(1):72-4.
[2] Lin OA, Karim ZA, Vemana HP, Espinosa EV, Khasawneh FT.  The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function. PLoS One. 2014 Jan 23;9(1):e87026.

Preventive effect of cyproheptadine hydrochloride in refractory patients with frequent migraine.[Pubmed:24255866]

Springerplus. 2013 Oct 29;2:573.

Cyproheptadine hydrochloride (CH) is rarely used to treat adult patients with migraine in Japan because it causes sleepiness. In this study, we investigated the preventive effect of CH in 12 patients who had failed to respond to conventional preventive treatments among 103 migraine patients treated at our hospital. These 12 subjects had all received unsuccessful migraine prophylaxis with lomerizine, valproic acid and topiramate, or had discontinued these treatments due to adverse reactions. Initially, the subjects were given 4 mg CH before sleeping. In those who experienced no clinically significant sleepiness following the treatment, the drug was orally administered at 4 mg after breakfast as well (8 mg per day in total). Drug efficacy was evaluated by examining the frequency of migraine at one month and three months after the start of treatment. The frequency of migraine was dramatically reduced in all patients within 7 to 10 days after starting treatment. The average frequency of migraine during the three-month period was 2.6 episodes per month, representing a significant (p < 0.01) reduction from the pretreatment frequency of over 10 per month. Our results indicate that CH may be effective as a migraine-preventive treatment for patients in whom conventional drugs have been ineffective or have caused side effects. But this study is not a double blind randomized trial, and an open study with no control group.

Interaction of cyproheptadine hydrochloride with human serum albumin using spectroscopy and molecular modeling methods.[Pubmed:22605685]

Luminescence. 2013 Mar-Apr;28(2):244-52.

The interaction between Cyproheptadine hydrochloride (CYP) and human serum albumin (HSA) was investigated by fluorescence spectroscopy, UV-vis absorption spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and molecular modeling at a physiological pH (7.40). Fluorescence of HSA was quenched remarkably by CYP and the quenching mechanism was considered as static quenching since it formed a complex. The association constants Ka and number of binding sites n were calculated at different temperatures. According to Forster's theory of non-radiation energy transfer, the distance r between donor (human serum albumin) and acceptor (Cyproheptadine hydrochloride) was obtained. The effect of common ions on the binding constant was also investigated. The effect of CYP on the conformation of HSA was analyzed using FT-IR, synchronous fluorescence spectroscopy and 3D fluorescence spectra. The thermodynamic parameters DeltaH and DeltaS were calculated to be -14.37 kJ mol(-1) and 38.03 J mol(-1) K(-1), respectively, which suggested that hydrophobic forces played a major role in stabilizing the HSA-CYP complex. In addition, examination of molecular modeling indicated that CYP could bind to site I of HSA and that hydrophobic interaction was the major acting force, which was in agreement with binding mode studies.

The effect of cyproheptadine hydrochloride (periactin) and megestrol acetate (megace) on weight in children with cancer/treatment-related cachexia.[Pubmed:18989154]

J Pediatr Hematol Oncol. 2008 Nov;30(11):791-7.

BACKGROUND: Children with cancer frequently have associated cachexia and malnutrition. Failure to thrive affects nearly 40% of oncology patients with advanced or progressive disease. Malnutrition can erode quality of life and adversely impact disease prognosis. Appetite stimulation and increased food intake is 1 approach to combat cancer-related cachexia. MATERIALS AND METHODS: Cyproheptadine hydrochloride (CH), an appetite stimulant, was administered to children with cancer-associated cachexia to prevent further weight loss. All participants started CH and were evaluated for response after 4 weeks. Efficacy of megestrol acetate (MA) was evaluated in patients who did not respond to CH. Medical evaluation, weight measurements, prealbumin, and serum leptin levels were preformed at follow-up visits. RESULTS: Seventy patients were enrolled. Of the 66 evaluable patients, 50 demonstrated a response to CH (average weight gain 2.6 kg and mean weight-for-age z-score change of 0.35, P=0.001). Seven of the 16 nonresponders received MA. Six patients completed 4 weeks of MA, 5 responded (average weight gain of 2.5 kg). The most commonly reported side effect of CH was drowsiness. One patient on MA developed low cortisol levels and hyperlipidemia. CONCLUSIONS: This study demonstrates that CH is a safe and effective way to promote weight gain in children with cancer/treatment-related cachexia.

Micelle-enhanced spectrofluorimetric method for determination of cyproheptadine hydrochloride in tablets: application to in-vitro drug release and content uniformity test.[Pubmed:23900846]

J Fluoresc. 2014 Jan;24(1):85-91.

A highly sensitive and simple spectrofluorimetric method was developed for the determination of Cyproheptadine hydrochloride (CYP) in its pharmaceutical formulations. The proposed method is based on the investigation of the fluorescence spectral behaviour of CYP in a sodium dodecyl sulphate (SDS) micellar system. In aqueous solution, the fluorescence intensity of CYP was greatly enhanced (150 %) in the presence of SDS. The fluorescence intensity was measured at 410 nm after excitation at 280 nm. The fluorescence-concentration plot was rectilinear over the range 0.2-2.0 mug/mL, with lower detection limit of 0.06 mug/mL. The proposed method was successfully applied to the assay of commercial tablets as well as content uniformity testing. The application of the proposed method was extended to test the in-vitro drug release of CYP tablets, according to USP guidelines. The results were statistically compared with those obtained by official USP method and were found to be in good agreement.

Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription.[Pubmed:27088648]

J Med Chem. 2016 Apr 28;59(8):3650-60.

SET domain containing lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), also methylates non-histone proteins including estrogen receptor (ER) alpha. ERalpha methylation by Set7/9 stabilizes ERalpha and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. We identified cyproheptadine, a clinically approved antiallergy drug, as a Set7/9 inhibitor in a high-throughput screen using a fluorogenic substrate-based HMT assay. Kinetic and X-ray crystallographic analyses revealed that cyproheptadine binds in the substrate-binding pocket of Set7/9 and inhibits its enzymatic activity by competing with the methyl group acceptor. Treatment of human breast cancer cells (MCF7 cells) with cyproheptadine decreased the expression and transcriptional activity of ERalpha, thereby inhibiting estrogen-dependent cell growth. Our findings suggest that cyproheptadine can be repurposed for breast cancer treatment or used as a starting point for the discovery of an anti-hormone breast cancer drug through lead optimization.

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).[Pubmed:7938165]

Pharmacol Rev. 1994 Jun;46(2):157-203.

It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibitory 5-hydroxytryptamine receptors involved in pressor effects obtained by stimulation of sympathetic outflow from spinal cord in pithed rats.[Pubmed:7889292]

Br J Pharmacol. 1994 Dec;113(4):1358-62.

1. A study was made of the effects of 5-hydroxytryptamine (5-HT) on pressor response induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Intravenous infusion of 5-hydroxytryptamine at doses of 10 and 20 micrograms kg-1 min-1 reduced the pressor effects obtained by electrical stimulation at intervals of 10 min over the 1 h of infusion. 2. This inhibitory action of 5-HT was depressed by cyproheptadine and methiothepin but was not modified by ketanserin or MDL-72222. By contrast, the inhibitory action of 5-HT was lost in pithed rats that had been pretreated with exogenous noradrenaline. 3. The 5-HT1 receptor agonist 5-carboxamidotryptamine (5-CT) caused an inhibition of the pressor response, whereas the 5-HT3 receptor agonist, 1-phenylbiguanide, produced a variable but significant increase in the pressor response. The 5-HT2 receptor agonist, m-CPP, did not modify the pressor sympathetic response. 4. Our results suggest that 5-hydroxytryptamine interferes with sympathetic neurotransmission by inhibiting pressor effects as a result of stimulation of the complete sympathetic outflow, and that this inhibition is mainly through a presynaptic 5-HT1 mechanism.