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At least 19 recordsLinked to original sources
PubMed1976

Effect of cyproheptadine and combinations of cyproheptadine and amphetamine on intermittently reinforced lever-pressing in rats.

Effects of the tryptamine antagonist, cyproheptadine, as well as of amphetamine, chlordiazepoxide, and combinations of cyproheptadine with amphetamine on lever-pressing behavior of rats were determined. A multiple, fixed-interval, 2 min fixed-ratio, 15 response schedule of water presentation was used. The three drugs affected fixed-interval fixed-ratio responding in a rate-dependent way, lower rates being more increased whereas higher rates were relatively more decreased. Cyproheptadine increased low response rates to a lesser extent than amphetamine, but increased high response rates that were little affected or only decreased by amphetamine. The combination of cyproheptadine and amphetamine increased response rates to a higher extent than either of the drugs alone. In addition, the rate-suppressant effects of the highest doses of amphetamine were also enhanced by cyproheptadine. These results show that cyproheptadine can increase nonpunished responding and suggest that cyproheptadine and amphetamine act synergistically, but through different mechanisms, upon multiple fixed-interval fixed-ratio performance.

Amphetamine↗
PubMed1997

Cyproheptadine produced modest increases in total caloric intake by humans.

Four male and three female normal-weight research volunteers, participating in an 18-day residential study, received oral cyproheptadine (4 mg) or placebo at 0930, 1245, and 1730 hours daily. Food intake, performance, and subjective ratings were measured throughout the day. The interaction between cyproheptadine and carbohydrate consumption was examined by providing subjects diets that engendered varied levels of carbohydrate intake. Three diet conditions were tested for 6 days each: a regular diet, a low-carbohydrate (high-fat) diet, and a high-carbohydrate diet. Placebo was given on days 1, 2, 3, and 6, while cyproheptadine was given on days 4 and 5 of each diet condition. When subjects received placebo and had access to a regular diet, they consumed 2500 kcal/day (59% carbohydrate 28% fat, 13% protein). Total caloric intake decreased (p < 0.007) when subjects received placebo and had access to the low-carbohydrate diet (40% carbohydrate, 43% fat, 17% protein) and increased (p < 0.056) when subjects received placebo and had access to a high-carbohydrate diet (70% carbohydrate, 19% fat, 11% protein). Cyproheptadine significantly increased total daily caloric intake by 20%, to 3000 kcal, only under the regular diet condition. The increase in caloric intake was due to an increase in the number of eating occasions without a change in eating occasion size. Although subjects consumed more food under the regular diet and cyproheptadine condition, cyproheptadine had no effect on the relative contribution of macronutrients to total daily caloric intake. There was no evidence for a modulation of the food-intake increasing effects of cyproheptadine by the macronutrient mix of the available diet. Cyproheptadine also significantly altered self-reported mood: compared to placebo, cyproheptadine produced significant increases in ratings of "Tired", "Sleepy", "Headache", "Can't Concentrate", and "Bad Drug Effect" and decreases in "Alert". Furthermore, cyproheptadine produced small decrements in psychomotor task performance.

Adult↗
PubMed1997

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 hple 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-I metabolites primarily via aromatic hydroxylation metabolic pathways. Cyproheptadine was biotransformed predominantly to 2-hydroxycyproheptadine. Other metabolites identified were 1- and 3-hydroxycyproheptadine, cyproheptadine 10,11-epoxide, N-desmethylcyproheptadine, N-desmethyl-2-hydroxycyproheptadine, cyproheptadine N-oxide, and 2-hydroxycyproheptadine 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, 2-hydroxycyproheptadine, 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 cell-free 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.

Biotransformation↗
PubMed1985

Cyproheptadine-mediated inhibition of growth hormone and prolactin release from pituitary adenoma cells of acromegaly and gigantism in culture.

The effect of cyproheptadine on growth hormone (GH) and prolactin (Prl) secretion from cultured pituitary adenoma cells of acromegaly and pituitary gigantism was studied. When varying doses of cyproheptadine ranging from 0.01 to 1 microM were added to the incubation media, GH secretion was consistently inhibited and a dose-response relationship was observed between the cyproheptadine concentrations and the amounts of GH released into the media. In pituitary adenomas which concurrently produced and secreted Prl, cyproheptadine likewise suppressed Prl release in a dose-related manner. This effect of cyproheptadine was not blocked by coincubation with serotonin. Similarly, coincubation with a dopaminergic antagonist, haloperidol, failed to reverse the inhibitory action produced by cyproheptadine. When coincubated with dopamine, cyproheptadine further inhibited GH and Prl secretion. These results suggest that cyproheptadine possesses a direct action on human somatotroph adenoma cells to inhibit GH and Prl secretion by an unknown mechanism that is different from serotonergic and dopaminergic systems.

Acromegaly↗
PubMed1990

A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia.

Anorexia, cachexia, and resultant weight loss are major clinical problems in a substantial proportion of patients with advanced cancer. Effective means of alleviating these problematic symptoms are lacking. Extensive clinical data demonstrate a weight enhancing effect for the serotonin antagonist, cyproheptadine, in several clinical situations. In addition, sound basic research suggests that cyproheptadine may be helpful in patients with cancer anorexia/cachexia. Because of this, the authors performed a randomized, placebo-controlled, double-blinded clinical trial using cyproheptadine, 8 mg orally three times a day in 295 patients with advanced malignant disease. Patients assigned to cyproheptadine had less nausea (P = 0.02), less emesis (P = 0.11), more sedation (P = 0.07), and more dizziness (P = 0.01) than placebo patients. Patients' appetites, measured by serial patient-completed questionnaires, appeared to be mildly enhanced by cyproheptadine. Unfortunately, cyproheptadine did not significantly abate progressive weight loss in these patients with advanced malignant disease; patients assigned to cyproheptadine lost an average of 4.5 pounds per month compared to 4.9 pounds per month for patients assigned to a placebo (P = 0.72).

Adult↗
PubMedDate not supplied

Effect of cyproheptadine on serum leptin levels.

Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship.

Adolescent↗
PubMed1979

Paradoxical short-term effects of cyproheptadine on insulin and glucagon release in the rat.

The administration of cyproheptadine (25 mg/kg; i.p.) resulted in an increase of plasma insulin and glucagon (measured using 30 K antibody) 30, 60 and 120 min after injection to fasted rats. This dose of cyproheptadine also induced a hyperglycemia whereas a lower dose (5 mg/kg; i.p.), which did not alter plasma hormone levels, was associated with a hypoglycemia. Fed rats showed a reduction of plasma insulin with a similar elevation of blood glucose after cyproheptadine. Administration of an exogenous load of arginine resulted in increases of plasma insulin and glucagon of a greater magnitude than induced by cyproheptadine, however, cyproheptadine pretreatment (25 mg/kg) completely suppressed the pancreatic response to the amino acid, resulting in blood hormone levels similar to values seen after cyproheptadine administered alone. Cyproheptadine pretreatment also prevented the hyperinsulinemia and hypoglucagonemia resulting from glucose loading. alpha-Adrenergic receptor blockade (with phentolamine), beta adrenergic receptor blockade (with propranolol) and adrenodemedullation did not alter pancreatic responsiveness to the drug.

Adrenal Medulla↗
PubMed2004

A comparison of the pharmacokinetics of oral and sublingual cyproheptadine.

BACKGROUND: Cyproheptadine is reported to be effective in treating serotonin syndrome. It is only available as an oral preparation and administration after SSRI overdose treated with activated charcoal is problematic. Sublingual administration may circumvent this problem. The pharmacokinetics of sublingual cyproheptadine are not characterized. This study compares the pharmacokinetics of cyproheptadine following oral and sublingual administration. METHODS: Cross-over, non-blinded, volunteer study using five healthy males. Eight milligrams of oral and sublingual cyproheptadine were administered on separate occasions with a one-week washout period. Sublingual arm subjects were pretreated with 50 g of oral activated charcoal 30 min prior to cyproheptadine, to prevent any gut absorption. Serum cyproheptadine concentration was measured at baseline, 30 min, and 1, 2, 3, 4, 6, 8, and 10 h by liquid chromatography and mass spectroscopy. RESULTS: Mean C(max) for oral and sublingual were 30.0 microg/L and 4.0 microg/L respectively: mean T(max) were 4 h and 9.6 h; mean AUC were 209 and 25 microg x hr/L. Mean +/- SEM within-subject difference between oral and sublingual C(max) was 25.9 +/- 4.1 (p = 0.003) and AUC was 184 +/- 31 (p = 0.004). CONCLUSIONS: Serum concentrations after sublingual cyproheptadine are significantly less than after oral administration. At these concentrations, the sublingual route is unlikely to be effective in treating serotonin syndrome.

Administration, Oral↗
PubMed2004

A chart review of cyproheptadine for stimulant-induced weight loss.

Youths with attention deficit hyperactivity disorder often experience weight loss on stimulants, which may limit optimal dosing and compliance. Cyproheptadine has been shown in medical samples to stimulate weight gain. We conducted a retrospective chart review of 28 consecutive pediatric psychiatry outpatients prescribed cyproheptadine for weight loss or insomnia while on stimulants. Of these, 4 patients never took cyproheptadine consistently, and 3 discontinued it within the first 7 days due to intolerable side effects. Data were analyzed for 21 other patients (age range 4-15 years) who continued with 4-8 mg of cyproheptadine nightly (mean final dose = 4.9 mg/day) for at least 14 days (mean duration = 104.7 days). Most had lost weight on stimulant alone (mean weight loss was 2.1 kg, mean weight velocity was -19.3 g/day). All 21 gained weight taking concomitant cyproheptadine, with a mean gain of 2.2 kg (paired t = 6.87, p < 0.0001) and a mean weight velocity of 32.3 g/day. Eleven of 17 patients who had reported initial insomnia on stimulant alone noted significant improvements in sleep with cyproheptadine added. We conclude that concomitant cyproheptadine may be useful in youths with attention deficit hyperactivity disorder for stimulant-induced weight loss, pending future randomized controlled trials.

Adolescent↗
PubMed1992

Further analysis of the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the responses of the rat aorta to 5-hydroxytryptamine.

1. The aim of the present study was to analyse the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the rat aorta contractile responses to 5-HT. Initially phenoxybenzamine treatment was used to determine whether spare receptors exist at the maximum responses to 5-HT. Then the reversibility of the inhibitory effects of phentolamine, dihydroergotamine, cyproheptadine and ketanserin against the fast and slow response of the rat aorta to 5-HT were determined. 2. Phenoxybenzamine caused non-parallel rightward shifts of the 5-HT concentration-response curves with reduced maximal responses. The KA values for 5-HT to produce fast and slow responses were 2-5 x 10(-5) M. These KA values are much higher than those previously reported for 5-HT at 5-HT2-receptors and suggest that the 5-HT2-receptor of the rat aorta is 'atypical'. The rat aorta has spare 5-HT-receptors for the maximal fast and slow responses to 5-HT. 3. Phentolamine, dihydroergotamine, cyproheptadine and ketanserin inhibited the fast and slow responses to 5-HT. Phentolamine and ketanserin and the higher concentrations of dihydroergotamine and cyproheptadine tested had greater inhibitory effects on the fast than slow 5-HT responses possibly because the fast 5-HT response did not always reach equilibrium in the presence of antagonists. 4. The inhibitory effects on 5-HT responses of phentolamine at 10(-6)-10(-5) M were readily reversible, those of cyproheptadine at 10(-9)-10(-8) M and ketanserin at 10(-8) M were slowly reversible and those of dihydroergotamine at 10(-9)-10(-8) M were irreversible by washing in drug-free Krebs. 5. The inhibitory effects of phentolamine and ketanserin were not altered by increasing the treatment time whereas some of the effects of cyproheptadine and the effects of dihydroergotamine on responses to 5-HT were increased by prolonging the contact time with the antagonist from 75 to 150 min. 6. The present study shows that at the rat aorta 5-HT2-receptor, phentolamine is a competitive readily reversible, cyproheptadine and ketanserin are competitive slowly reversible and dihydroergotamine is a competitive irreversible antagonist.

Animals↗
PubMed1983

Effects of cyproheptadine on electrophysiological properties of isolated cardiac muscle of dogs and rabbits.

The effects of cyproheptadine were studied on cardiac Purkinje and ventricular muscle fibres of the dog and on cells of the sinoatrial (SA) node region of rabbit hearts, by means of electrophysiological techniques. Cyproheptadine (2-8 microM) decreased, in a dose-dependent manner, the plateau amplitude and the action potential duration to 50% repolarization of Purkinje and ventricular muscle cells. Higher concentrations also depressed the action potential amplitude, the overshoot and the maximum rate of rise of the upstroke. These effects were only partially reversed on washing. A four fold increase in Ca concentration of the standard Tyrode solution antagonized the effects of cyproheptadine on the action potential characteristics. The 'slow response' obtained in K-depolarized isoprenaline-treated fibres was blocked by cyproheptadine (4 microM). Cyproheptadine (10 microM) depolarized and suppressed the automaticity of spontaneously beating Purkinje fibres. The frequency of discharge of the SA node cells was slowed or abolished by cyproheptadine (2-4 microM). Atropine (2.6 microM) did not affect the negative chronotropic effect, whereas adrenaline (5 microM) reversed it. It is suggested that cyproheptadine depresses the slow inward current in all types of myocardial fibres studied. Higher concentrations might also affect the fast inward sodium current system.

Action Potentials↗
PubMed1976

Suppression by cyproheptadine of human growth hormone and cortisol secretion during sleep.

The effect of cyproheptadine on plasma growth hormone and cortisol levels was studied in seven male volunteers with polygraphic sleep monitoring. Sleep-related growth hormone release was completely inhibited in three of the seven normal subjects by the intravenous infusion of cyproheptadine (5 mg) which was started at the onset of sleep. In the other four, growth hormone release during sleep was significantly decreased or delayed by cyproheptadine when the drug infusion was started at 7:00 p.m., 1-2 h before the onset of sleep. The usual increase in plasma cortisol in the early morning was completely suppressed in all five subjects given cyproheptadine infusions from 4:00 to 7:00 a.m. The intravenous infusion of cyproheptadine increased slow wave sleep, although the time from sleep onset to the first occurrence of slow wave sleep was not affected. In contrast, rapid eye movement sleep was significantly decreased by cyproheptadine. These results suggest that cyproheptadine inhibits growth hormone and ACTH secretion during sleep in man, possibly by antagonizing serotoninergic mechanisms although other actions of the drug are not ruled out.

Adrenocorticotropic Hormone↗
PubMed1997

Acute effects of bromocriptine, cyproheptadine, and valproic acid on plasma adrenocorticotropin secretion in Nelson's syndrome.

Previous studies have found that bromocriptine, cyproheptadine, and valproic acid can reduce ACTH secretion in Nelson's syndrome, but none of these agents has achieved widespread use due to their failure to normalize ACTH in most patients. The current study was undertaken to determine whether these three agents, which act through different mechanisms, decrease plasma ACTH synergistically when administered together. Six adult female patients (mean age, 41 yr) with Nelson's syndrome were studied. ACTH was measured every 20 min for 8 h, 2 h before and 6 h after each of the following six treatments: placebo, bromocriptine (2.5 mg), cyproheptadine (8 mg), valproic acid (1 g), cyproheptadine plus valproic acid, and the combination of all three drugs. The sequence of treatments was determined randomly, and there was an interval of at least 2 days between each treatment. The hourly ACTH values were averaged, and the percent maximal suppression of plasma ACTH, relative to the baseline values before drug administration, was compared among the six treatments. Basal plasma ACTH levels in the six patients ranged from 40-3324 pmol/L (normal range, 1-8). The percent maximal suppression of ACTH after administration of placebo (6 +/- 11%), cyproheptadine (17 +/- 15%), valproic acid (37 +/- 10%) or the combination of cyproheptadine and valproic acid (19 +/- 14%) did not achieve statistical significance. Bromocriptine, on the other hand, caused a significant decrease in plasma ACTH (52 +/- 8%; P < 0.05), as did the combination of bromocriptine, cyproheptadine, and valproic acid (58 +/- 12%; P < 0.05). However, the combined effect of the three drugs did not significantly exceed the effect of bromocriptine alone. We conclude that at the doses studied, bromocriptine had the greatest acute effect in suppressing ACTH secretion in Nelson's syndrome, and that combined administration with valproic acid and cyproheptadine did not further increase this acute ACTH-suppressive effect.

Adrenocorticotropic Hormone↗
PubMed1984

Calcium entry blocker activity of cyproheptadine in isolated cardiovascular preparations.

Cyproheptadine was compared with nifedipine, verapamil and diltiazem for calcium entry blocker activity in isolated cardiovascular preparations. Using rat aortic strips, all compounds (10(-7) M) inhibited both the contraction caused by the readdition of calcium (1.0 mM) into regular buffer or buffer containing potassium (130 mM) or norepinephrine (10(-5) M) and the potassium-stimulated uptake of 45Ca. The rank order of potency for these experiments was in general nifedipine greater than cyproheptadine greater than or equal to verapamil greater than diltiazem. The same order of potency also was found for the four compounds in relaxing potassium (40 mM)-contracted aortic strips (IC50 values: nifedipine, 2.6 X 10(-9) M; cyproheptadine, 6.3 X 10(-8) M; verapamil, 7.6 X 10(-8) M; and diltiazem, 2.1 X 10(-7) M), but cyproheptadine was the least potent agent in antagonizing the spontaneous contractions of the rat portal vein (IC50 values: nifedipine, 6.6 X 10(-9) M; verapamil 7.7 X 10(-8) M; diltiazem 9.6 X 10(-8) M; and cyproheptadine 3.9 X 10(-7)M). None of the compounds (10(-7) M) inhibited the contraction to norepinephrine (10(-5) M) in rabbit aortic strips bathed in calcium-free buffer (1 mM ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid). Nifedipine, verapamil and diltiazem were more potent in inhibiting the restoration of contractility by isoproterenol in potassium-depolarized rabbit papillary muscles than decreasing force in normally polarized muscles; cyproheptadine was equipotent when tested in these two preparations. Cyproheptadine was the least potent of the four compounds in lowering perfusion pressure in the perfused canine hindlimb.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

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

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.

Administration, Oral↗
PubMed2001

Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

BACKGROUND: DMXAA (5,6-dimethylxanthenone-4-acetic acid) is a new drug synthesized in this laboratory and currently in phase I clinical trial. In mice it acts as an antivascular drug, selectively inhibiting tumour blood flow and inducing tumour haemorrhagic necrosis with resultant tumour regression. It also induces the synthesis of tumour necrosis factor (TNF), nitric oxide and serotonin. Cyproheptadine, a type 2 serotonin receptor antagonist, is known to reduce the degree of tumour necrosis-induced TNF in mice. We investigated the pharmacological interaction between a suboptimal dose of DMXAA (20 mg/kg) and cyproheptadine (20 mg/ kg) using mice with Colon 38 tumours that are sensitive to DMXAA. METHODS: Mice with or without tumours were treated with DMXAA and/or cyproheptadine. Concentrations of plasma and tissue DMXAA and the serotonin metabolite 5-hydroxyindoleacetic acid were measured by high performance liquid chromatography. TNF concentrations were measured by ELISA. RESULTS: While DMXAA alone (20 mg/kg) showed little or no antitumour activity, coadministration with cyproheptadine was curative in four of five mice. DMXAA half-lives in plasma and tumour tissue were increased 5.1- and 5.6-fold, respectively, and the appearance of DMXAA glucuronides in bile was almost completely inhibited for up to 4 h. Serum TNF was low and unchanged by cyproheptadine, and plasma concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were also not substantially changed. CONCLUSION: The augmentation by cyproheptadine of the induction of tumour response to DMXAA reflects a pharmacological interaction, leading to increased plasma and tumour half-lives, and to reduced excretion. However, serum TNF concentrations were not increased, suggesting that the increased anti-tumour effects are mediated by an increased local tumour response, arising from the extended tumour DMXAA concentrations.

Animals↗