Cyproheptadine Research Articles

Cyproheptadine ion-selective electrodes and their applications in some pharmaceutical formulations

Cyproheptadine hydrochloride (C) shows an antihistaminic as well as antimuscarine, antiserotonic and sedative activity. The present work describes sensitive and reasonably selective poly(vinyl chloride) membrane electrodes for Cyproheptadine. They are based on the use of cyproheptadine-tetrakis(4-chlorophenyl)borate (C-TC1PB) and cyproheptadine-dipicrylamine (C-DPA) as a novel electroactive compound. Cyproheptadine ion-selective poly(vinyl chloride) membrane electrodes contain an ion-pair complex of Cyproheptadine with 2-nitrophenyloctyl ether (ENPO), 2-nitrodiphenyl ether (ENdP), bis(2-ethylhexyl)sebacate (DOS) and l-isopropyl-4-nitrobenzene (IPNB) as solvent mediators. The performance of the electrodes was investigated by measuring the e.m.f. values of 10−2–10−7 mol 1−1 Cyproheptadine hydrochloride. The effect of pH on the potential readings of the Cyproheptadine electrodes was checked by the recording on the e.m.f. of 10−3 mol 1−1 Cyproheptadine hydrochloride with pH values from 2.5 to 7.0. Potentiometric selectivity coefficient were measured by the separate solution method using a 10−3 mol 1−1 concentration of Cyproheptadine and the some concentration of interferent cations. The electrode obtained with C-TC1PB with DOS and electrode with C-DPA with IpNB were used in the potentiometric determination of Cyproheptadine in bulk substance and tablets PERITOL 4 mg as indicator electrodes. The results are in good agreement with those obtained by UV spectrophotometric method. Keywords: Cyproheptadine hydrochloride; Ion-selective electrode; Potentiometric titration; Cyproheptadine determination; Drag analysis

Studies on physico-chemical properties of cyproheptadine in water and water-methanol mixtures

Solubility of cyproheptadine and cyproheptadine hydrochloride in water and partition coefficients of cyproheptadine between n-octanol and water at different pHs were determined at 298 K. Ionisation constants of cyproheptadine in water-methanol mixtures were determined pH-metrically and extrapolated to zero methanol concentration to have the pK value of cyproheptadine in water. The result was confirmed spectrophotometrically utilising phosphate buffers. The pK value suggests molecular cyproheptadine to be more effective physiologically.

Cyproheptadine as Growth Promoter In Broiler Chickens

Cyproheptadine hydrochloride is a very high potent histamine and serotonine antagonist. This study was conducted to investigate the role of cyproheptadine on feed intake, body weight gain, feed conversion ratio, serum total protein, cholesterol and glucose. Red blood cells (RBC), Hemoglobin (Hb), Packed Cell Volume (PCV) and differential leukocytic count in blood of chickens were also estimated. A total of 60 one-day-old Fabro chicks were randomly divided into 2 groups. One group was received cyproheptadine at a rate of 10 ug / 100g body weight daily for eight weeks and the second group was used as a control. 
 The results revealed that cyproheptadine could stimulate feed intake and improve body weight gain in chickens. Erythrocyte count, hemoglobin content and PCV where increased significantly in these chickens accompanied by an increase in percentage of lymphocytes with a significant decrease in percentage of heterophiles and H / L ratio. This drug also reduces the total protein, cholesterol and glucose in serum.

Non-adrenergic non-cholinergic excitatory innervation in the airways: role of neurokinin-2 receptors.

1 The hypothesis that the non-adrenergic, non-cholinergic excitatory (NANC-e) innervation is involved in the induction of asthma and that antagonists of NANC-e neurotransmitter could reduce bronchoconstriction during asthma was tested. 2 The first objective was to identify the neurotransmitter(s) of NANC-e innervation from a group of selected putative neurotransmitters. The second objective was to use the antagonist of the identified neurotransmitter(s) to determine its effectiveness against bronchoconstriction to ovalbumin (OVA) in sensitized guinea-pigs. 3 Neurotransmitter identification was performed using the "tracheal pouch"', a surgical preparation established for demonstrating NANC innervation, in anaesthetized guinea-pig airways. A segment of trachea was cannulated and clamped at one end and the other end was connected to a pressure transducer. The stump of the trachea was connected to a ventilator to keep the blood gas values within the normal range. The vagus nerve and the sympathetic nerves were isolated bilaterally and cut. The left carotid artery was cannulated to monitor blood pressure and for sampling blood for blood gas analysis. The jugular vein was cannulated for administration of test agents. 4 Both NANC-e and NANC-i (inhibitory) control responses of airways were obtained by bilateral vagal stimulation after complete autonomic blockade with atropine, propranolol and prazosin. The relaxation of the tracheal pouch was indicative of the NANC-i response and the increase in insufflation pressure of the ventilated peripheral airways was due to NANC-e stimulation. 5 The involvement of the putative neurotransmitters such as neurokinin-A (NK-A), histamine, serotonin and endothelin (ET) was investigated by using the respective antagonists, MEN-10376, pyrilamine maleate, cyproheptadine hydrochloride, and two ET receptor antagonists (BQ-123 and IRL-1038), respectively. The antagonists were administered at the dose rate of 4 mg kg-1 i.v. which was determined from preliminary studies by testing against the respective agonists. 6 MEN-10376 (neurokinin-2 receptor antagonist) significantly inhibited the insufflation pressure (peripheral airway pressure) increase caused by NANC-e stimulation. MEN-10376 also inhibited the fall in blood pressure caused by bilateral vagal stimulation. The 5-HT antagonist, cyproheptadine, significantly enhanced the NANC-e response. 7 After identifying the NANC-e neurotransmitter as NK-A, the effectiveness of its antagonist, MEN-10376, was evaluated for its ability to attenuate the increase in insufflation pressure (bronchoconstriction) induced in guinea-pigs sensitized by OVA. Guinea-pigs were sensitized to OVA (200 mg i.p.) and 10 days later prepared for the determination of tracheal pouch and insufflation responses to 100 microg of OVA administered i.v. (challenge dose). This caused an increase in insufflation pressure in the presence of adrenergic and cholinergic blockade, which was significantly attenuated by MEN-10376. 8 These studies indicated that neurokinin-2 receptors were involved in the vagally mediated efferent neurotransmission of NANC-e and that NANC-e plays a role in allergen-induced bronchoconstriction.

The chemotherapy of rodent malaria. LIX. Drug combinations to impede the selection of drug resistance, Part 3: Observations on cyproheptadine, an antihistaminic agent, with chloroquine.

Several compounds in current clinical use as antihistaminic agents, among them cyproheptadine (CYP), have been shown, in experimental models, to reverse resistance of the asexual, intra-erythrocytic stages of rodent or human malarial parasites to chloroquine (CQ). Although preliminary clinical trials with CYP failed to confirm such activity in subjects with naturally acquired infection with Plasmodium falciparum, Nigerian investigators have reported that another antihistaminic, chlorpheniramine, significantly restores the blood schizontocidal action of CQ in semi-immune patients with CQ-resistant P. falciparum, when the two compounds are administered together. The rates at which resistance to CYP can be produced, in mice infected either with CQ-resistant P. yoelii ssp. NS or CQ-resistant P. yoelii nigeriensis, when drug-selection pressure is exerted with this compound alone have now been compared with the rate and extent to which resistance develops in infected animals that are treated with various combinations of CYP and CQ. The data indicate that, in both parasites, stable resistance develops slowly to CYP alone and that exposure to a combination of CYP plus CQ significantly impedes the selection of resistance to CYP. Although the antimalarial action of CYP is reported to extend to the pre-erythrocytic hepatic stages, there was no evidence of gametocytocidal activity in the present study. The future implications of these observations are discussed in relation to the clinical potential of CYP + CQ and similar combinations and possible future research.

Cyproheptadine-Induced Central Anticholinergic Syndrome

Cyproheptadine hydrochloride is a potent antihistamine with antiserotonin, anticholinergic, and possibly calcium channel - blocking activities. It is

Relationship between the skin permeation movement of propranolol and skin inflammatory reactions.

We studied inflammatory reactions induced by dermal application of the beta-blocker propranolol (PRL) in ethanol to guinea pigs in order to elucidate the relation of the reactions with the cumulative PRL permeating amount through the stratum corneum or the PRL content in the stripped skin, and to investigate the chemical mediators responsible for the reactions. The cumulative PRL permeating amount through the stratum corneum increased rapidly up to 2 h after dermal application, then increased linearly with time up to 24 h after application. Visual observation revealed formation of erythema and edema at the applied site of PRL, and histopathological examination revealed infiltration of pseudoeosinophiles of dermis and epidermis and degeneration/necrosis of epidermis. In general, it was considered that the duration and the extent of these reactions were dependent on the PRL dosage and application time. It was expected that the cumulative PRL permeating amount through the stratum corneum could be used to predict possible inflammatory reactions during development of transdermal drug delivery systems. On the other hand, contact of PRL with guinea pig skin tissues released histamine, and intradermal injection of PRL caused an increase of capillary permeability at the site of application. Also, the inhibitory effects of anti-inflammatory agents (diphenhydramine, dexamethasone, indomethacin, cyproheptadine hydrochloride, CV3988 and AA-861) to PRL-induced erythema formation demonstrated that histamine and prostaglandins were responsible for the inflammatory reactions induced by PRL.

Disposition of cyproheptadine in cats after intravenous or oral administration of a single dose

SUMMARY Objective To determine disposition of cyproheptadine hydrochloride in cats after intravenous or oral administration of a single dose. Animals 6 healthy cats. Procedure A randomized crossover design was used, and each cat was studied after intravenous (2 mg) and oral (8 mg) administration of cyproheptadine. Blood samples were collected at fixed time intervals after drug administration, and serum cyproheptadine concentration was determined by means of polarized immunofluorescence. Results Mean (± SD) residence time was significantly longer after oral (823 ± 191 minutes) than after intravenous (339 ±217 minutes) administration, but no significant differences were detected between other pharmacokinetic parameters after oral and intravenous administration. Mean ± SD oral bioavailability was 1.01 ± 0.36. Mean elimination half-life after oral administration was 12.8 ± 9.9 hours. Peak extrapolated cyproheptadine concentration was 669 ± 206 ng/ml. Only 1 cat developed adverse effects (transient vocalization). Conclusions Cyproheptadine appeared to be well tolerated in cats and had high bioavailability after oral administration. The mean elimination half-life of 12 hours indicated that approximately 2.5 days must elapse to achieve steady-state concentrations of cyproheptadine after oral administration of multiple doses. A 12-hour dosing interval is acceptable, but an 8-hour interval may be indicated for some cats. Clinical Relevance On the basis of pharmacokinetic parameters determined in this study, the oral form of cyproheptadine appears to be suitable for use in clinical trials to treat anorexia in cats. Its half-life is compatible with once or twice daily dosing. (Am J Vet Res 1998;59:79–81)

Effect of the appetite stimulant cyproheptadine on deoxynivalenol ‐ induced reductions in feed consumption and weight gain in the mouse1

Deoxynivalenol (DON, vomitoxin), a Fusarium mycotoxin, is suspected of inducing its anorectic/feed refusal activity through a serotoninergic (5HT) mechanism, possible via 5HT2‐receptors. In this study the efficiency of cyproheptadine (CYP), a serotonin antagonist and known appetite stimulant, to attenuate the adverse effect of DON was investigated in mice. CYP was administered in the feed for two days before animals began receiving the DON, which was also added to the feed. Both agents were administered concurrently thereafter for a 12‐day period. Dosing levels included various combinations of the two compounds, ranging from 0–16 ppm DON and 0–20 ppm CYP. Results showed that CYP could effectively offset the reduction in feed intake caused by dietary DON, but only when dose levels were optimized (CYP appeared to have a narrow effective dose range, which was also dependent on the DON concentration). In fact, optimum CYP doses were able to enhance feed intake in DON‐fed mice above control levels, indicating that more than just a direct block of the toxin's effect was occurring. Conversely though, the effect of CYP on weight gain (WG) was ambiguous. At the lower CYP doses (≤ 5 ppm), alone or in combination with the lowest DON level tested (4 ppm), a modest positive effect was noted, but at the higher DON concentrations (≥ 8 ppm) the overall WG generally remained depressed, and tended to be reduced further by increasing doses of CYP. These results provide additional support that serotoninergic mechanisms probably play a role in mediating DON‐induced reduction in feed intake. Where and how DON actually initiates its anorectic effect, however, has not been resolved.

Is Cyproheptadine Effective in the Treatment of Subjects With Epidermolysis Bullosa Simplex-Dowling-Meara?

Epidermolysis bullosa simplex—Dowling-Meara (EBS-DM) is a severe form of EBS, with oral and nail involvement as well as severe skin blistering. Reports1,2of treatment with 5-hydroxytryptamine—2 antagonists reducing the severity of blisters in subjects with EBS-DM prompted us to study cyproheptadine hydrochloride therapy in 13 individuals with a diagnosis of EBS-DM confirmed by electron microscopic examination. Participants served as their own controls. There was a 2-week observational period, an initial 6-week period during which cyproheptadine was taken daily, a 4-week period with no treatment, and a second 6-week regimen of daily administration of cyproheptadine. Standard dosages of cyproheptadine were used.3The study was designed in this manner in an attempt to compensate for temporal variation in blister formation as well as variations in season, weather, and activity levels of the participants. Subjects were asked to record the number of blisters lanced each day rather than the

Luteinizing hormone and ovarian response of early postpartum Debouillet ewes treated with cyproheptadine and(or) melatonin.

Two trials were conducted to evaluate the effects of cyproheptadine (serotonin receptor antagonist, Trial 1) along with administering melatonin (Trial 2) to early postpartum (PP) ewes on LH profiles and follicular development. In Trial 1, 12 mature ewes received either control (CON) or cyproheptadine (CYP) treatments (six ewes/treatment). Beginning on d 5 PP, each ewe received i.v. either 0 (vehicle) or .1 mg of CYP/kg BW twice daily for 5 d. Cyproheptadine tended to stimulate (P < .10) release of LH on d 5 PP (1.3 and .8 +/- .2 ng LH/mL for CYP-treated and CON ewes, respectively) with a similar trend (P < .10) of LH release occurring on d 9. Cyproheptadine also had a positive effect on follicular development, but no luteal activity was detected. In Trial 2, 16 mature ewes received CON, i.v. CYP (.1 mg/kg BW twice daily), i.m. melatonin (MEL, 5 mg x ewe(-1) x d(-1)), or CYP+MEL. Treatments were administered from d 5 through 14 PP. Cyproheptadine tended to increase (P < .10) LH pulsatility on d 5 and 14, but MEL had no effect (P > .20). Follicular development was not affected (P > .40) by CYP or MEL treatments. Neither MEL nor CYP affected progesterone (P > .60). Cyproheptadine tended to increase LH concentration and pulse frequency in early PP ewes, but MEL had no effect on LH profiles. Both treatments failed to initiate ovarian cyclicity in early PP ewes.

Fungal transformations of antihistamines : metabolism of cyproheptadine hydrochloride by Cunninghamella elegans

1. Metabolites formed during incubation of the antihistamine cyproheptadine hydrochloride with the zygomycete fungus Cunninghamella elegans in liquid culture were determined. The metabolites were isolated by hplc and identified by mass spectrometric and proton nmr spectroscopic analysis. Two C. elegans strains, ATCC 9245 and ATCC 36112, were screened and both produced essentially identical metabolites. 2. Within 72 h cyproheptadine was extensively biotransformed to at least eight oxidative phase-1 metabolites primarily via aromatic hydroxylation metabolic pathways. Cyproheptadine was biotransformed predominantly to 2-hydroxycyprohep tadine. Other metabolites identified were 1- and 3-hydroxycyprohep tadine, cyproheptadine 10,11epoxide, N-desmethylcyproh eptadine, N-desmethyl- 2-hydroxycyprohep tadine, cyproheptadine N-oxide, and 2-hydroxycyprohep tadine N-oxide. Although a minor fungal metabolite, cyproheptadine 10,11- epoxide represents the first stable epoxide isolated from the microbial biotransformation of drugs. 3. The enzymatic mechanism for the formation of the major fungal metabolite, 2hydroxycyprohep tadine, was investigated. The oxygen atom was derived from molecular oxygen as determined from 18O-labelling experiments. The formation of 2-hydroxycyproheptadine was inhibited 35, 70 and 97% by cytochrome P450 inhibitors metyrapone, proadifen and 1-aminobenzotriazole respectively. Cytochrome P450 was detected in the microsomal fractions of C. elegans. In addition, 2-hydroxylase activity was found in cellfree extracts of C. elegans. This activity was inhibited by proadifen and CO, and was inducible by naphthalene. These results are consistent with the fungal epoxidation and hydroxylation reactions being catalysed by cytochrome P450 monooxygenases. 4. The effects of types of media on the biotransformation of cyproheptadine were investigated. It appears that the glucose level significantly affects the biotransformation rates of cyproheptadine; however, it did not change the relative ratios between metabolites produced.

Effect of cyproheptadine treatment on conditioned avoidance response in female rats

1. 1. The percentage of conditioned avoidance response was higher during proestrus compared to diestrus. 2. 2. Cyproheptadine (CPH) significantly enhanced avoidance behavior during diestrus. 3. 3. On the other hand, CPH treatment did not alter avoidance behavior during proestrus. 4. 4. Serum progesterone and testosterone levels were determined at the end of 60 trials for acquisition of conditioned avoidance response after prolonged (12–15 days) CPH treatment (0.5 mg/kg for 24 h per os (p.o.). 5. 5. Prolonged CPH treatment lowered adrenal testosterone levels, and rats with impaired avoidance had higher testosterone and progesterone levels. 6. 6. The results of this study indicate a positive role for CPH in the acquisition of avoidance response during diestrus, and a negative effect of progesterone and adrenal testosterone on the avoidance response.

ANALYTICAL STUDY OF SOME ANTIHISTAMINES WITH HAEMATOXYLIN REAGENT

The reaction between haematoxylin reagent and eight antihistaminic drugs (chlorpheniramine maleate, pheniramine maleate, cyproheptadine hydrochloride; astemizole, terfenadine, ranitidine hydrochloride, famotidine and cimitidine) was investigated and utilized as the basis for a new, simple and sensitive spectrophotometric procedure for their determinations. The procedure is based on the reaction of the methanolic solution of the anti-histaminic compounds with haematoxylin reagent in 3x10-3 M boric acid to give a reddish-violet colour (lmax 555 nm). The absorbance was linear with all compounds over the 5-200 µg/ml general concentration range of the final measured antihistamine base solution. A good correlation was found between log A (1%, 1 cm) and pka values for six of the studied drugs. The method can be applied successfully to the analysis of commercially available tablet formulations. No interference was observed due to additives which are commonly present in tablet formulations or coformulated compounds such as phenazone, phenazone salicylate, sodium salicylate paracetamol, propyphenazone and caffeine.

Serotonin-induced short- and long-term sensitization in the crab Chasmagnathus

On sudden presentation of a passing shadow (a visual danger stimulus), the crab Chasmagnathus granulatus responds with a running reaction that we term an escape response (ER). A single administration of 5-HT in a dose range between 0.005 and 0.1 μg/g enhances the ER at 30 min, and a dose of 10–15 μg/g has a similar effect for at least 24 h. The classical 5-HT antagonist cyproheptadine (CYP) given within a dose range 0.01–2.0 μg/g has no effect on ER at 30 min, but 0.5 μg/g blocks the 5-HT-induced short-term sensitization. An enhancing effect of CYP on the ER is shown at 24 h with 1.0–2.0 μg/g doses. An explanation of this results in terms of a model similar to that proposed for Aplysia, that is two sensitizing processes linked in parallel and mediated by two different types of 5-HT receptors is discussed. Results indicate that the sensitizing effect of 5-HT is confined to high responders, thus suggesting that crabs of a same population have different degrees of sensitivity to the drug according to their different degrees of reactivity to the visual danger stimulus.

EFFECT OF CYPROHEPTADINE HYDROCHLORIDE ON INGESTIVE BEHAVIORS

Cyproheptadine (CY) has been used therapeutically as an appetite stimulant at a dose which appears to have antiserotoninergic activity. However, the role which CY may play in appetite regulation remains unclear. This study was designed to examine the effect of CY on ingestive behaviours in female Wistar rats. CY administered orally (0.52mgkg −1b.w., dissolved in the daily water) for up to six oestrus cycles did not affect 24h food intake. On the other hand, CY reduced both 24h liquid intake and 24h urine output. Furthermore, 24h liquid consumption and 24h urine output, were found to fluctuate according to the oestrus cycle.

Poisoning due to an over-the-counter hypnotic, Sleep-Qik (hyoscine, cyproheptadine, valerian).

The clinical features and risk of hepatotoxicity of 'Sleep-Qik' (valerian dry extract 75 mg, hyoscine hydrobromide 0.25 mg, cyproheptadine hydrochloride 2 mg) were determined in 23 patients treated in our hospital between 1988 and 1991. The main clinical problems were central nervous system depression and anticholinergic poisoning. There was no clinical evidence of acute hepatitis in the 23 patients after taking an average of 2.5 g of valerian (range 0.5 to 12 g). There was no evidence of subclinical liver damage in 12 patients who had routine liver function tests performed approximately 6-12 hours after ingestion. Delayed onset of severe liver damage was excluded in 10 patients in whom a telephone follow-up was possible. However, subclinical liver dysfunction in the acute stage (onset after 12-24 hours) and in the intervening period after discharge from hospital could not be excluded. To establish the risk of hepatotoxicity in long-term users and in those taking an overdosage of valerian, a much larger study of longer duration with serial liver function tests is clearly needed.

Cyproheptadine analogues, sar from structural and electrostatic fittings

Cyproheptadine analogues, sar from structural and electrostatic fittings

Inhibition of insulin production by cyproheptadine in RINm5F rat insulinoma cells.

The clonal insulin producing cell line RINm5F was evaluated as a model for the action of cyproheptadine (CPH)-like diabetogenic compounds in the rat pancreas. Treatment with 10 microM CPH and selected structural analogs under culture conditions produced a progressive loss of cellular insulin which reached 30% of control within 24 hours. Comparison of the activities of the analogs 4-diphenylmethylpiperidine (4-DPMP) and 2-diphenylmethylpiperidine (2-DPMP) to produce cellular insulin depletion showed that 4-DPMP was as active as CPH but 2-DPMP had no activity at the highest concentration employed (10 microM). The CPH metabolite desmethyl CPH-epoxide was five times more active than the parent compound in producing loss of insulin in RINm5F cells. These results are consistent with previously published results of CPH actions in vivo. An inhibition of insulin biosynthesis with no loss of preproinsulin mRNA occurred in RINm5F cells treated with CPH or DMCPH-epoxide. This suggests that an effect on transcription may not be the primary action by which CPH and its analogs inhibit insulin synthesis in vivo.

VOLITIONAL ADJUNCTIVE THERAPY FOR THE SHORT BOY

Short boys, referred without pathologic etiology but with social maladjustment present or anticipated, were offered a choice of ameliorative therapy. 168 boys, over a period of more than 15 years, ranging in age from less than 10 to 16 were originally referred; 37 were seen twice or less and 23 were less than 11 years old, leaving 108. Of the 108, 35 chose no treatment; 6 grew well enough to cross growth lines and 29 continued to grow within growth lines. 58 of the treated boys received only testosterone enanthate at 50 mg/month or less, considered to be less than the dose that would induce pubescence. 30 of the 58 crossed growth lines; 28 did not. A total of 72 boys were treated with combined therapies, receiving cyproheptadine (CY), clonidine (CL), fluoxymesterone (FL) and oxandrolone, singly or in combination with testosterone (TT). About 1/2 of this group also crossed growth lines. Neuroseeretory growth hormone dysfunction was not absolutely ruled oui in either group although none was truly growth hormone deficient. The results of such choice therapy with testosterone in low dose for the treatment of delayed (or anticipated delayed) adolescence and short stature in boys, may recommend its selected use.