Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.

Trypanocidal resistance in Trypanosoma evansi in vitro: effects of verapamil, cyproheptidine, desipramine and chlorpromazine alone and in combination with trypanocides.

A study was conducted in vitro to assess the ability of calcium antagonists to reverse trypanocidal resistance in Trypanosoma evansi. Susceptibility patterns of sensitive and resistant parasites were evaluated against calcium antagonists of several chemical classes (verapamil, cyproheptidine, desipramine and chlopromazine), alone and in combination with suramin, diminazene aceturate or melarsen oxide cyteamine. The putative resistance modulators were intrinsically antitrypanosomal, but were unable to reverse resistance to any of the trypanocides tested. It was thus concluded that resistance to these trypanocides in T. evansi may differ from drug resistance mechanisms occurring in cancer cells, malaria or in South American trypanosomosis, where calcium antagonists have successfully reversed resistance.

Peptidergic mechanisms in feeding behaviour.

Hyperphagia was induced in mice by p.o. administration of different types of CNS depressant drugs, like chlordiazepoxide 25 mg/kg diazepam 2.5 mg/kg, cyproheptadine 2 mg/kg and phenobarbitone 25 mg/kg. Such hyperphagia was abolished by pretreatment with naloxone 0.1 mg/kg sc. Naloxone per se at this dose produced no significant effect on the food intake. This is suggestive of the role of peptidergic mechanisms in the feeding behaviour in mice.

A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome.

Sixteen patients with metastatic neuroendocrine tumors and the malignant carcinoid syndrome were treated with cyproheptadine (Periactin, Merck, Sharp & Dohme, West Point, PA) at maximum tolerable doses that ranged from 12 to 48 mg daily. Usual side effects were mild sedation and dry mouth, but three patients found it impossible to sustain treatment due to nausea and vomiting. Most patients had significant relief of diarrhea, frequently associated with weight gain. Relief of flushing was uncommon. The therapeutic benefit produced by cyproheptadine would appear to be a peripheral effect because 5-hydroxyindoleacetic acid (5-HIAA) excretion in these patients was not reduced. Although there have been case reports of objective tumor regression with cyproheptadine therapy, this was not observed in any of these 16 patients. Cyproheptadine would appear to be a useful therapeutic tool for the management of diarrhea associated with the malignant carcinoid syndrome. An appropriate initial total daily dose is 0.4 mg/kg divided in three fractions with prompt modification to produce minimal and tolerable side effects.

Effect of cyproheptadine on glucose tolerance, serum insulin and structure of pancreatic islets in rats.

The effect of cyproheptadine (CPH) on glucose tolerance, serum immunoreactive insulin (IRI) and structure of pancreatic islets in albino rats has been studied. Hyperglycemia with glucose intolerance was observed after 10 days of administration of CPH (40 mg/kg, ip). There was insignificant change of fasting IRI after the treatment. Histological studies indicated degranulation and vacuolation of beta cells with enlargement of capillaries. Improvement in blood glucose, glucose tolerance and structure of islets with proliferation of small pancreatic ducts and cell cords were observed 10 days after the withdrawal of CPH.

Cytoplasmic vacuolation of pancreatic beta cells of rats after oral administration of a derivative of isoquinoline.

beta cells in islets of Langerhans were studied in Sprague-Dawley rats dosed by gavage with 0 (control), 75, 150, 250 or 300 mg/kg body wt/day S-H 966 BS [1-(1-oxido-4-thiomorpholino)-3-(1-piperazinyl)], an isoquinoline derivative. All doses caused a significant and dose-dependent increase in serum glucose (diabetes mellitus). At 250 mg/kg, degranulation of beta cells was discovered after 1 day and vacuole formation after 2 days. Ultrastructural alterations compared well with that seen after treatment with cyproheptadine and other structurally related compounds. The vacuolation of beta cells was fully developed following 6 weeks of daily treatment, when a dose-dependent elevation of blood glucose was first observed. The effects were more severe in males than in females. Lesions were reversible within 6 weeks except at 300 mg/kg in males.

N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-benzo-[5,6]cyclohepta [1,2-b]pyridines. Antihistamines with no sedating liability.

Conversion of the basic tertiary amino function of the potent antihistamine, azatadine (Optimine), to neutral carbamate function results in compounds which retain significant antihistamine activity with little or no CNS effects. In guinea pigs the N-ethoxycarbonyl derivative 4 had the same antihistamine potency as terfenadine, a clinically used non-sedating antihistamine. In mice, 4 was a potent antihistamine while lacking CNS effects. The 8-chloro-N-ethoxycarbonyl 5 (loratadine, Sch 29851) was the most potent antihistamine in the series, had no CNS side effects, and was selected for clinical evaluation.

Effects of cyproheptadine on the rat yolk sac membrane and embryonic development in vitro.

Electron-microscopic examinations of rat embryonic yolk sacs treated in vitro with 1.5 X 10(-5) M cyproheptadine showed proliferation of the lysosomal structures; other organelles remained unaffected, and also overall yolk-sac growth and vascularization were comparable to non-treated samples. Radioactive measurements with 125I-labelled albumin showed that yolk sacs and embryos of the cyproheptadine-treated group incorporated less radioactivity than the controls. Embryos inside the yolk sacs, treated either for 24 or 48 h, were severely retarded in growth and differentiation (approximately 50% of the controls). It is suggested that the specific action of cyproheptadine on yolk-sac lysosomal structures, combined with reduced macromolecular transport, is the cause of inhibited embryonic development.

The effect of cyproheptadine chlorhydrate on rat embryonic development.

The teratogenic effect of cyproheptadine chlorhydrate was studied in Wistar rats. Rats were given the substance by gastric intubation on days 6-15 of pregnancy in two experimental series. In the first series rats were treated at doses of 25 and 50 mg/kg/d and in the second one they received 15, 25 and 35 mg/kg/d. Controls received only an equivalent volume of water by the same route. Doses of 25 or more mg/kg/d are highly embryotoxic. At 15 mg/kg/d the effects were relatively minor. The major anomalies caused by the drug were edema and abnormal ossification of the ribs. Some other malformations were also found: craniorrhachischisis, cleft lip, cleft palate, hypoplastic limbs, micrognathy, micromelia, and vascular damage.

The teratogenicity of cyproheptadine in two generations of Wistar rats.

Four groups of pregnant Wistar rats were injected intraperitoneally at day 7, 10, 13 or 15 of gestation. Every lot in each group received either 10, 20, 30 or 50 mg/kg cyproheptadine. A fifth group received 2 mg/kg/day of this drug during the entire course of pregnancy. The maximum effect of this drug was found on the 13th and 15th day of gestation. The abnormalities observed in the 21 day old foetuses of the first generation (F1) were found mainly in the brain, kidney, liver as well as in the skull and sternum. Cyproheptadine produced post-natal mortality during the first month from 28.8 to 67.8%. The higher degree of mortality was produced in the rats receiving 2 mg/kg/day. The survivors of this F1 generation were treated in the same way as the parent generation (P). Their descendants (F2) showed similar results. Thus cyproheptadine, in all doses administered, produced signs of toxicity and/or teratogenic effects in rats.

Role of the pituitary in cyproheptadine-induced pancreatic beta-cell toxicity.

Hypophysectomized rats given cyproheptadine (40 mg/kg) for 10 days exhibited a loss of pancreatic immunoreactive insulin and ultrastructural changes in the cytoplasm of beta-cells. Sham-operated animals given cyproheptadine showed identical changes in pancreatic beta-cells except that cytoplasmic involvement progressed to the formation of large vacuoles. The pituitary is not directly involved with the cyproheptadine-induced depletion of pancreatic insulin but plays a role in the formation of large cytoplasmic vacuoles.

The use of antiserotonin-cyproheptadine HCL in pregnancy: an experimental and clinical study.

PIP: Habitual abortion of psychogenic origin may be associated with increased serotonin production. Serotonin is metabolized by monoamin oxidase (MAO) to hydroxyindole acetic acid (5-HIAA) which is excreted in the urine. When this metabolic system is inadequate excess serotonin may cause contractions of the estrogen-sensitized myometrium and, thus, abortion. In normal pregnancy and in nonpregnant women urinary 5-HIAA is 5.6 mg/day. Women suffering from habitual abortion os psychogenic origin showed 5-HIAA excretion of 10.6 mg/day during pregnancy with high amounts of nonmetabolized serotonin. In rats injection of pargyline HC1, a MAO inhibitor, produced abortion in 84%; a serotonin antagonist, cyproheptadine HC1, injected sc 4-8 hours prior to MAO inhibitor treatment preserved 42% of fetuses. No toxicity was shown in 92.8% of rat fetuses in a teratogenic study. Later 29 women with a total of 31 pregnancies were given 4 to 16 mg/day cyproheptadine HC1 for several months starting early in pregnancy. Previous study had revealed no other causes to explain their spontaneous abortions and treatments with progesterone, antibiotics, and vitamins in earlier pregnancies had been unsuccessful. After cyproheptadine HC1 treatment there were 3 spontaneous abortions, 23 normal infants delivered at term, and 5 premature deliveries of which 1 was a stillbirth. No teratogenic effects were observed. Reports by others in similar cases and results in a control group of 19 women in this study all give much higher rates of spontaneous abortion. Side effects were few and yielded to reduced dosage. It is recommended that patients suffering habitual abortion be examined for serotonin and 5-HIAA excretion. When indicated, treatment with antiserotonin drugs should be given. Observations indicate serotonin production or metabolism may be the decisive factor relating emotional stress to abortion.^ieng