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Two patients with the carcinoid syndrome whose symptoms were difficult to control with drugs and who had early signs of right heart valvular changes are reported on. Left hemihepatectomy was believed to be justified; resection of the left half of the liver, a tumor of the small bowel, and lymph node secondaries in one patient and resection of a tumor of the small bowel and the quadrate hepatic lobe in another patient resulted in symptom-free periods of twelve and four months, respectively. These cases support the adoption of more aggressive surgical treatment of this manifestation of carcinoid tumors.

Cyproheptadine and LSD, two known antagonists of the peripheral effects of 5-HT, were administered i.v. to conscious rabbits at different times before the intracerebroventricular (i.c.v.) administration of 5-HT, NAD or dopamine. Cyproheptadine (which had a slight hypothermic effect) antagonized the rise in temperature induced by 5-HT; this antagonism was dose-related and appeared to be specific in that the hyperthermia induced by noradrenaline or dopamine was hardly modified. Interactions between LSD (which is hyperthermic alone) and 5-HT were more complex — both potentiation and depression being observed.

The present study was designed to acquire further understanding of the differences in the immune response of mice orally (OS) or subcutaneously (SS) sensitized to Nematospiroides dubius . Two immunosuppressive agents and skin tests were utilized in this regard. Rabbit antimouse thymus serum (RAMTS) and cyproheptadine (antihistamine-antiserotonin) were similarly effective in suppressing the immune response of subcutaneously sensitized mice. When compared to normal rabbit serum and SS control (sensitized, untreated) animals, observations of the intestinal tunica muscularis in the immunosuppressed SS groups revealed granulomatous lesions in which fewer eosinophils enveloped the sequestered parasite. Cyproheptadine was more successful than the other treatments in interrupting the immune expulsion of N. dubius from orally sensitized mice, but this was only at a borderline significance level. The size and intensity of the active cutaneous anaphylactic skin tests in OS mice injected with an adult or larval antigen, was greater than the response elicited in SS mice or uninfected control mice injected with the same preparations. Similarly, the reaction in subcutaneously sensitized mice exceeded that observed in the noninfected controls.

Since neurotransmission and selected enzymes of the serotonin/adrenalin pathway are altered during endotoxicosis, a variety of neurophilic drugs, some active on defined loci in the tryptophan-serotonin pathway, were evaluated for their ability to modify endotoxin lethality. Among the various putative neurotransmitters, only leucine had some sensitizing effect on endotoxin toxicity. If given prior, and not subsequent, to challenge, p-chlorophenyl-alanine (but not the other analogues) consistently lowered the LD50 of endotoxin in mice and impaired cortisone proctection against endotoxic death. This effect could not be related to the possible increase in endogenous concentrations of tryptophan, as a result of inhibition of tryptophan hydroxylase by p-chlorophenylalanine (PCPA). Additionally, the endotoxin toxicity in normal mice could not be modified by the serotonin antagonists cyproheptadine and LSD-25. The inorganic mercurial HgCl2 (but not its organic analoge p-chloromercuribenzoate), behaved like PCPA in its ability to modify the endotoxin lethality. These results are discussed in relation to hepatic enzyme induction and a common receptor-effector system possibly coordinating a variety of inter- and intra-cellular responses.

An adenylate cyclase (EC 4.6.1.1) that is activated specifically by low concentrations of serotonin has been identified in homogenates of the thoracic ganglia of an insect nervous system. The activation of this enzyme by serotonin was selectively inhibited by extremely low concentrations of D-lysergic acid diethylamide (LSD), 2-bromo-LSD, and cyproheptadine, agents which are known to block certain serotonin receptors in vivo . The inhibition was competitive with respect to serotonin, and the calculated inhibitory constant of LSD for this serotonin-sensitive adenylate cyclase was 5 nM. The data are consistent with a model in which the serotonin receptor of neural tissue is intimately associated with a serotonin-sensitive adenylate cyclase which mediates serotonergic neurotransmission. The results are also compatible with the possibility that some of the physiological effects of LSD may be mediated through interaction with serotonin-sensitive adenylate cyclase.

The venom ‘Bothrops jararaca’ anda high molecular weight fraction obtained from it induced vasculotoxic effects when applied on the exposed surface of the lung of the dog and increased the vascular permeability when injected into the rat skin. These effects were compared to those evoked by other venoms and potential mediators. The increase in vessel permeability due to ‘B. jararaca’ venom was feebly affected by antiserotonin and antihistamine agents and was presumably due to kinin release. The effect on the lung surface was related to the coagulant and necrogenic properties of the venom and was suppressed by EDTA, promethazine and specific antiserum. A kinin releasing enzyme extracted from the venom increased the vascular permeability but had no effect on the lung. Venoms from ‘Crotalus adamanteus’ and from ‘Crotalus durissus terrificus’ also increased the vascular permeability, but were inhibited by antihistamine/antiserotonin agents; this blockade uncovered a marked skin hemorrhagic effect due to ‘Crotalus adamanteus’. Despite this activity, no vasculotoxic effect was found when ‘Crotalus adamanteus’ venom was applied to the lung. Effects of the tested venoms and enzymes are highly specific for either vascular bed, depending upon the availability on the challenged sites of different tissue components and on the specific properties of the venoms.

A case of the carcinoid syndrome associated with a proximal myopathy is reported. Histology showed advanced atrophy of type II muscle fibres but no inflammation. Perinuclear acid phosphatase was increased. Electron microscopy revealed persistence of the Z-line until the muscle fibre had been severely disrupted. Similar lesions have been observed in the hereditary muscular dystrophy in mice, and also in these animals and in rats when injected with 5-hydroxytryptamine (5-HT). Treatment with cyproheptadine caused a documented response in the patient's debilitating diarrhoea and also produced symptomatic improvement in her muscular power. We suggest that the myopathy is due to circulating 5-HT or is a non-metastatic complication of the carcinoid tumour.

1 In nialamide-treated mice, L-5-hydroxytryptophan produced a dose-dependent hypoglycaemic response which was independent of whether the animals had been fed or fasted. 2 This response was accompanied by a head-twitching response which was also dose-dependent. 3 The hypoglycaemic response was not accompanied by an elevation in plasma immunoreactive insulin levels and was fully manifest in alloxan diabetic animals. 4 5-Hydroxytryptophan did not increase the in vitro glucose uptake of adipose tissue or skeletal muscle, either on incubation of the tissues in contact with the drug or on incubation of tissues removed from mice injected with the drug. 5 Both the hypoglycaemic and head-twitching responses were prevented by pretreatment with methysergide or cyproheptadine and augmented by mepyramine treatment.

The effects of electrolytic lesions of the midbrain raphe nuclei were used as indicators for the role of 5-hydroxy-tryptamine in the mediation of stereotyped and circling behaviour observed after peripherally administered dopaminergic agonists, apomorphine, D- and L-amphetamine, methylphenidate and piribedil, and intrastriatal dopamine in the rat. Lesions of the medial and/or dorsal raphe nuclei reduced the stereotypic effects of all agents, especially apomorphine. Following asymmetric lesions of the medial raphe nucleus (but not the dorsal nucleus or reticular formation) all agents, excepting piribedil, enhanced or induced a contralateral circling behaviour in a dose-dependent manner. Apomorphine and D-amphetamine induced an ipsilateral circling in animals with substantia nigra lesions. The circling effects observed after nigral and raphe lesions were shown to add or subtract dependent upon location of lesions on the same or opposite sides. Haloperidol and methiothepin inhibited the circling induced by apomorphine and D-amphetamine in both substantia nigra- and raphe-lesioned rats in similar doses to those inhibiting stereotyped behaviour. Atropine, aceperone and cyproheptadine were without significant effect. Lesions of the raphe nuclei reduced the stereotypic effectiveness of bilateral intrastriatal dopamine but did not significantly modify the asymmetries induced by unilateral intrastriatal dopamine, although the normal effectiveness of haloperidol in enhancing these dopamine asymmetries was abolished by the raphe lesions. The medial and dorsal raphe nuclei play an important role in the development of stereotyped behaviour and the medial nucleus is also important for the control of circling behaviour. The demonstrated relationship between dopamine and 5-hydroxytryptamine (possibly within the striatum) in the mediation of behavioural states indicative of antiparkinson activity may be relevant to the disease state.

The narcotic agonist methadone increases the amplitude of intestinal phasic contractions and can retard intestinal propulsive activity. Like morphine, methadone may produce its intestinal effects by release of local 5-hydroxytryptamine (5-HT). The ability of the 5-HT receptor blocking agent cyproheptadine to antagonize the intestinal effects of methadone was evaluated in vitro and in vivo. In vascularly perfused segments of dog isolated intestine, cyproheptadine-decreased the stimulatory effect of methadone and 5-HT, but not the effect produced by bethanechol, a cholinergic agonist. Atropine decreased responses to methadone, 5-HT, and bethanechol because one component of 5-HT action is mediated by intramural cholinergic nerves. Cyproheptadine also antagonized the methadone-induced reduction in transit of test meals in mice. The LD 50 of methadone was not altered by cyproheptadine. The ability of a 5-HT blocking agent to antagonize the intestinal effects of methadone suggests a potentially useful means of overcoming one of the troublesome side effects of the narcotic drugs.

Azatadine (6–11-dihydro-11-[1-methyl-4-piperclylidene]-5H{5,6}cyclohepta{1,2-b}pyridine maleate {1∶2}), a nitrogen analog of cyproheptadine has been studied for its antiallergy properties. It was compared in vivo and in vitro to cyproheptadine and seven (7) standard antihistamines: chlorpheniramine, promethazine, diphenhydramine, phenindamine, chloropyriline, tripelennamine and chlorcylizine; an antiserotonin, methysergide; and an anticholinergic, atropine. Azatadine possesses potent antihistaminic, anticholinergic, antiserotinin and antianaphylactic properties. In vitro, azatadine's antihistamine potency is equal to chlorpheniramine, cyproheptadine, phenindamine, chloropyrilene and greater than the rest of the antihistamines studied. Its anticholinergic potency is 1/3 that of atropine, equal to promethazine and cyproheptadine and greater than the rest of the antihistamines studied. Its antiserotonin potency is 1/4 that of methysergide, equal to promethazine and greater than the rest of antihistamines studied. In vivo, azatadine's ability to protect guinea-pigs from histamine lethality (i.v.) and histamine-induced dyspnea is greater than all of the antihistamines studied. Its ability to protect guinea-pigs from acetylcholine-induced dyspnea is equal to atropine and greater than all of the antihistamines studied. Its ability to protect guinea-pigs from serotonin-induced dyspnea is 1/6 that of cyproheptadine, 1/8 that of methysergide and greater than all of the antihistamines studied. Azatadine is a more potent antianaphylactic agent and has greater therapeutic indices than cyproheptadine in both mice and guinea-pigs.

Participation of α-adreniceptors in the effects of 5-HT and tryptamine on the isolated rat stomach fundus preparation was investigated. The effects of recognized anti-5-HT agents were also investigated to determine whether or not the same type of receptors was involved in the response of the rat fundus to 5-HT and tryptamine. Methylsergide was shown to be a very active, slowly reversible inhibitor of the 5-HT-induced contrations. The degree of inhibition was dependent on the time of pre-incubation and reached its maximum after approximately 2 hr. The α-adrenolytic agent piperoxan appeared to be a competitive antagonist of 5-HT. Piperoxan was able to prevent or reduce the anti-5-HT activity of mianserin, cyproheptadine and methysergide, indicating a common site of all action. All antagonists affected the 5-HT contractions more than those induced by tryptamine. It is concluded, that the effect of 5-HT on the isolated rat stomach fundus is the result of an interaction of 5-HT with one type of receptor. This receptor probably is the classical D-tryptamine receptor. The response to tryptamine is the result of an interaction by tryptamine with two different types of receptors. One type of receptors is identical to the receptor mediating the response to 5-HT, whilst the other type of receptor is more resistant to inhibition by emthylsergide, piperoxan, cyproheptadine or mianserin, and might be identical with the PRT-receptor, described earlier as being resistant to inhibition by phenoxybenzamine.

In rats treated with gradually increasing amounts of morphine hydrochloride until they tolerated fatal doses, levallorphan precipitated acute body weight loss and elicited a variety of other typical withdrawal symptoms. Cyproheptadine markedly reduced this b.w. loss and abolished the drug-induced withdrawal syndrome. Fenfluramine also suppressed the major signs of the levallorphan-induced morphine withdrawal; however the combination of the three drugs proved to be very toxic. Since both agents interfere with different hypothalamic feeding mechanisms these results are accordant with the hypothesis of Kerr and Pozuelo (1971) that morphine dependence and tolerance are due to a functional disorganization of the hypothalamic centers concerned wit the regulation of food intake.

In the previous report (1), the authors showed that the brain noradrenaline level in rat was induced to elevation, in the state of electric shock, compared with that in non-treated animals. On the other hand, pretreatment with some tranquil lizing agents, chlorpromazine, azacyclonol inhibited the increase of noradrenaline level in shocked state, while, chlordiazepoxide had no effect on noradrenaline level. In addition to the previous paper, other tranquillizing agents, tetrabenazine, thioridazine and cyproheptazine were employed in this experiment in order to examine their effect on both noradrenaline and dopamine levels of rat brain in abnormal environment, i.e., electrically shocked state.

A case of Urticaria pigmentosa xanthelasmoidea bullosa with generalized vascular symptoms (flushes) is reported. Blisters already appeared at the second day of life. The daily medication of 2 times 2 mg cyproheptadine soon stopped the formation of bullae, calmed the pruritus, and the flushes disappeared. Possible interrelationships between histamine and 5-hydroxytryptamine in the symptomatology of bullous urticaria pigmentosa are pointed out in the light of the action of cyproheptadine as a combined serotonin-histamine antagonist and of methysergide as a selective antiserotonin agent, respectively.

It has been confirmed that tyramine has positive inotropic and chronotropic actions on the dog isolated atrium. These responses were incompletely and reversibly inhibited by cocaine, but completely and irreversibly blocked by phenoxybenzamine. Blockade of the atrial β-receptors by dichloroisoprenaline could be overcome by noradrenaline and by larger doses of tyramine. With the aortic strip of the reserpinized rabbit for assay, tyramine was shown to release a vasoactive material from the dog atrium whose receptors were blocked by dichloroisoprenaline. The use of an antihistamine and an anti-5-hydroxytryptamine agent (cyproheptadine) appeared to exclude the possibility that the effect was due to the release of histamine or 5-hydroxytryptamine from the atrium by tyramine. Further observations of the action of the vasoactive material on the guinea-pig ileum and on the rat fundal strip strongly suggested that the material was a catechol amine. It was concluded that under these conditions tyramine acts by liberating catechol amines from storage sites so that the amines are free to act at receptor sites. The behaviour of the atrium to tyramine in the presence of cocaine or of phenoxybenzamine suggests that the liberation of catechol amines by tyramine differs from the release due to adrenergic nerve stimulation. It is suggested that, after an infusion of tyramine, there is a much slower release of catechol amines than after stimulation of adrenergic nerves.

In mice and rats, the influence of controlled variations in the central levels of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT) on the convulsive threshold in electro- and pentetrazole seizures was studied. The threshold for maximal electroconvulsions was lowered by treatments depressing the central levels of 5-HT and noradrenaline, by the 5-HT antagonist cyproheptadine, and the α-adrenolytic phentolamine. Treatment with l-DOPA or 5-hydroxytryptophan (5-HTP) raised the threshold. The results point to a significance of 5-HT and noradrenaline for the sensitivity to electroconvulsion. The threshold for the clonic component of the pentetrazole convulsion was depressed by treatments lowering the central level of noradrenaline, and by the β-adrenolytic propranolol; it was elevated by l-DOPA (only in mice). Depletion of 5-HT by p-chlorophenylalanine lowered the threshold only in rats, but it was increased by 5-HTP in both species. Thus, noradrenaline plays a role in the mediation of the clonic pentetrazole convulsion, and 5-HT does so in the rat, whereas its importance remains dubious in the mouse. The threshold for the tonic extensor component of the pentetrazole convulsion (only determined in mice) was lowered by p-chlorophenylalanine and cyproheptadine, and slightly elevated by 5-HTP. There was no indication for a crucial role of noradrenaline or dopamine in this component of the pentetrazole convulsion. The effect of treatments with (+)-amphetamine and (+)-p-chloroamphetamine on the convulsive thresholds point to a predominantly noradrenergic stimulation by the former, and a mixed influence of the latter on the metabolism of central 5-HT and noradrenaline.

The central antimuscarinic actions of several drugs, atropine, phenoxybenzamine, cyproheptadine, imipramine and chlorpromazine, were determined by their ability to antagonize oxotremorine-induced facilitation of the electrically evoked flexor reflex and production of the steping reflex in the chronic spinal dog. The drug actions and interactions were determined by sequentially infusing the antagonist, methylatropine and oxotremorine and observing changes in flexor reflex amplitude. The facilitation of the flexor reflex and evocation of the steping reflex produced by oxotremorine in the methylatropine pretreated animal are thought to be due to a direct action on the spinal cord. Atropine, cyproheptadine, imipramine and chlorpromazine depressed the amplitude of the flexor reflex and phenoxybenzamine produced a slight enhancement. The interaction studies demonstrated that atropine almost completely prevented the spinal cord effects of oxotremorine while phenoxybenzamine showed no antagonism. Imipramine, chlorpromazine and cyproheptadine demonstrated the same relative degree of partial antagonism and antimuscarinic activity in the spinal cord. These findings suggest that facilitatory muscarinic cholinergic neurons may be present either as a parallel pathway in the segmental reflex or longitudinally oriented pathways in the spinal cord.

Electron microscopical analysis of endothelial linings of the aortic lumen and of the vasa vasorum was made in man, rhesus monkey, dog, rabbit, rat, chicken and pigeon with reference to permeability of the arterial wall, because cholesterol and other substances accumulating in atheromatous lesions have been known to be transported mainly by infiltration into the lesions from the blood stream across the endothelial lining. Porous capillaries were found in vasa vasorum of man, rabbit and pigeon and a well developed vacuole system in the endothelial cells of man and chicken. For the present experiment of atherosclerosis the rabbit has been chosen. In the succeeding experiments we found substances capable of inhibiting the edematous arterial reaction such as pyridinolcarbamate and its derivatives as well as estrogens and glucocorticoids. We have tested these substances for the prevention of atherosclerosis of cholesterol-fed rabbits and also for the treatment of established atherosclerosis of the animals. The first important finding was the correlation between their inhibiting potency against the edematous arterial reaction and their property of preventing atherosclerosis. The second Important finding was appearance of atrophy, necrosis and calcification of arterial wall along with the atheroma-preventive effect of estrogen and prednisolone and the absence of such effects in pyridinolcarbamate, while the latter substance enhances the regeneration of smooth muscles in the lesions. Dosages of 10 to 30 mg per kg of pyridinolcarbamate given by mouth daily have shown the atheromatous mass with foam cells, necrosis and degenerative foci being replaced by regenerated smooth-muscle, collagen and elastic fibers, and the cholesterol content of arterial wall was definitely reduced in the course of 6 to 30 weeks of the treatment, without any untoward effect. Histoenzymatic analysis revealed the increased enzymatic activity of glycolytic enzymes Including glucose-6-phosphate dehydrogenase in the arterial wall of animals treated with pyridinolcarbamate and the decreased enzymatic activity of glycolytic enzymes in that of animals treated by estrogen. The results reported in this paper show that the author's edematous arterial reaction has opened a way toward finding antiatherosclerotic agents which may prove to be useful in the prevention and treatment of human atherosclerosis. ACTA PATH. JAP. 19: 15˜43, 1969.

Pancreatic islet β-cells undergo structural changes in rats which are given daily 45 mg./kg. oral doses of cyproheptadine. The ultrastructural features of this lesion were studied after 1, 2, 4, 7, and 14 days of treatment. There was progressive degranulation of β-cells which was largely complete at two days, although a few granules were still evident at fourteen days. The rough endoplasmic reticulum underwent sequential changes of cisternal dilation, vesiculation, vesicle fusion, and vacuole formation. No normal appearing rough endoplasmic reticulum remained in β-cells of seven- and fourteen-day-treated rats. Ribosomes were lost from much of the surface of the vacuoles and vesicles which appeared to be derived from rough endoplasmic reticulum in these cells. Other cytoplasmic organelles of β-cells retained generally normal structure. Autophagy and necrosis were absent. Alteration in the glucose tolerance test was observed after two daily doses of cyproheptadine. Alpha and delta cells of islets and acinar cells appeared to be unaffected.

A series of antihistamines representing many structural types and pharmacological spectra antagonized isolation-induced fighting in mice. Antagonism of fighting by these compounds was correlated with anti-cholinergic potency as measured by prevention of physostigmine-induced lethality but did not correlate with antihistaminic or anti-tetrabenazine potency. Antagomism of fighting was not related to effects of these drugs on spontaneous motor activity.

Selected agents were evaluated orally in the male rat for their capacity to prevent carrageenin-induced pedal edema and to alter liver sulfhydryl levels. Indomethacin was the most potent anti-inflammatory agent, followed by tetrabenazine and chlorpromazine. Cryogenine and phenylbutazone were equieffective, with cyproheptadine, aspirin, and sparteine being least potent. Carrageenin-induced pedal edema alone did not lower liver sulfhydryl content. Aspirin elevated the sulfhydryl concentration both in the presence and absence of carrageenin-induced edema, while chlorpromazine, indomethacin, phenylbutazone, cryogenine, tetrabenazine, and sparteine were without significant effect at anti-inflammatory dosages. Cyproheptadine lowered liver sulfhydryl levels, but this was considered to be a nonspecific or toxic effect resulting from the high dosages employed.

Eleven experimental models of acute connective-tissue reactions were designed for comparative investigations in the rat: anaphylactoid edema, ischemic necrosis, formalin-induced pedal inflammation, various forms of calciphylaxis and calcergy, thrombohemorrhagic phenomena (THP), acute conditioned necrosis (ACN), and delayed tissue-clearance of dyes. Several of these reactions can only be produced by the conjoint application of two drugs (a “conditioner” and a “challenger”), both of which are inactive in themselves. Furthermore, the same lesion (calcification, necrosis, thrombosis) can be produced by several pairs of agents, as long as their members belong to appropriate categories. Even temporary ischemia, produced by the short-term application of a clip to a skin fold, though well tolerated in itself, can act as a challenger and elicit qualitatively different topical lesions (dye accumulation, thrombosis with hemorrhage, calcification, or necrosis) whose nature depends upon the conjoint application of conditioning factors. All these findings suggest that, despite chemical and pharmacologic differences, the members of any one group of conditioners and challengers have some latent pathogenic potencies in common and that they can be conveniently classified on this basis. The following drugs were found to block the manifestations of some of the above mentioned acute connective-tissue reactions: chlorpromazine, compound 48/80, cyproheptadine, dibenzylchloroethylamine, heparin, histamine, 5-hydroxytryptamine (5-HT), phenoxybenzamine, phentolamine, and polymyxin. The ischemic necrosis produced by long-term application of the skin clip is prevented by various systemic stressors (spinal-cord transection, restraint, starvation, forced muscular exercise); apparently, systemic stress can induce “cross-resistance” against the damaging effect of topical stress. 5-HT and mast-cell dischargers possess a pro-inflammatory effect upon the poditis elicited by the intrapedal injection of various irritants. These same compounds delay the tissue clearance of intracutaneously administered dyes; they also act as conditioners for the production of ACN by the subcutaneous administration of normally rapidly absorbed and well-tolerated irritants. Hence, the influence of mast-cell products upon inflammation, dye absorption, and necrosis is presumably due to a single mechanism: the retardation of tissue clearance. The implications of these findings for the pharmacologic analysis of acute connective-tissue reactions are briefly discussed.

The effectiveness of five different serotonin antagonists in the prevention of migraine was compared in 290 patients followed for periods of up to three years. Methysergide 3-6 mg. daily was most effective, with 20% of treated patients becoming headache-free and a further 44% remaining more than "half improved." The corresponding figures for BC105 were 10% and 40%, respectively.The results with BC105 were significantly better than those with placebo (P0.02). The total improvement rates with methdilazine (45%) and cyproheptadine (43%) were better than those with placebo (32%) but did not achieve statistical significance. A new preparation, methylergol carbamide maleate, which is chemically related to methysergide, did not give better results than placebo.

The antiserotonin action of several compounds was investigated in the vasculature of the isolated perfused human placenta. Average onset, duration of action, and per cent decrease at maximal antagonism were used to discern the antiserotonin capability of the smallest effective dose of each compound necessary to antagonize the pressor action of serotonin. Their ability to antagonize the vasoconstrictor effect of serotonin, in decreasing order of effectiveness, was: cyproheptadine, LSD, diphenhydrarnine, chlorpromatine, prornethazine, promatine, and dibenamine. Cyproheptadine, which had a relatively short duration of action, caused the greatest decrease to the pressor action of serotonin, while chlorpromazine and diphenhydramine exhibited the longest duration of action. The mechanisms by which these agents antagonized the vasopressor effect of serotonin are attributed to a blockade of α-adrenergic receptors, competition for specific receptor sites, and/or direct negative musculotropic action. It is suggested that the human placenta, rather than tissues of other species, may serve as the organ of choice to evaluate the potential effectiveness of serotonin antagonists useful in therapeutics.

The majority of the drugs tested as angiotensin antagonists in this investigation were from two pharmacologic classes: negative musculotropic agents (papaverine, sodium cobaltinitrite, isosorbide dinitrate, nitroglycerin, sodium nitrite, and dipyridamole) and agents which selectively block α-adrenergic receptors (dibenamine, phentolamine, tolazoline, and hydralazine). Of the direct smooth muscle depressants, sodium nitrite and dipyridamole were the most effective; dibenamine and phentolamine were the most potent adrenergic blocking agents employed. Atropine, cocaine, and cyproheptadine were also tested as antagonists of the pressor effect of angiotensin and exhibited only moderate effectiveness. Lidoflazine, a specific angiotensin antagonist, was the most potent compound tested in this study; the degree of antagonism exhibited by it, however, was only slightly greater than either dibenamine or phentolamine. The results indicate that the pressor effect of angiotensin in the perfused human placenta is primarily the result of a direct stimulation of vascular smooth muscle and secondarily to a stimulation of α-adrenergic receptors.

1. Whole blood histamine content was measured in 80 patients with myeloproliferative disease. Increased levels were found in 60 per cent of patients with uncontrolled polycythemia vera, in 7 per cent of patients with polycythemia vera being controlled by myelosuppressive therapy, and in 71 per cent of a group with "spent" polycythemia, myeloid metaplasia and myelofibrosis. 2. The excretion of histamine in the urine was measured in 60 patients, 30 with elevated blood histamine and 30 with normal blood histamine. The urine findings paralleled the blood findings in 90 per cent of the cases. 3. Measurements of cell-poor and cell-rich fractions of blood showed that the histamine is contained in the white cell fraction. Elevated basophil counts were present in 50 per cent of the patients and occurred with the greatest frequency in the groups with elevated blood and urine histamine. A rough correlation between the basophil count and the histamine content of blood and white cell fractions was observed in normal subjects and most cases with myeloproliferative disease. Data obtained in some cases of myeloproliferative disease suggest that the histamine content of the basophil may be abnormal and that other granulocytes may contribute to the total leukocyte histamine. 4. Myelosuppressive agents produced a reduction in histamine (expressed per 109 myeloid cells) and a decrease in urine histamine as control of the myeloproliferative process was achieved. Treatment with phlebotomy alone produced no change in histamine levels. 5. The incidence of pruritus, upper gastrointestinal distress and urticarial manifestations was increased 7-fold, 4-fold and 12-fold, respectively, in patients with elevated histamine levels as compared with those who had normal histamine levels. 6. Cyproheptadine, a potent antihistaminic, successfully controlled pruritus, relieved pyrosis and suppressed urticarial eruptions in patients with elevated histamine levels. Suppression of the reaction to subcutaneously administered codeine (a histamine-releaser) afforded objective evidence that cyproheptadine blocked the effects of histamine release in vivo. 7. The metabolism of histamine and the role of elevated histamine levels in the clinical manifestations and pathophysiology of myeloproliferative disease are discussed.

Antihistamines, representing the major chemical classes, administered intraperitoneally to mice in non-toxic doses potentiated the lethal effects of an LD10 dose (3·5 mg/kg) of oxotremorine in a dose related manner. Atropine and methylatropine were highly effective in blocking oxotremorine lethality alone and when it was potentiated by antihistamines. The antagonism by methylatropine suggests a peripheral site of toxicity. Antihistamines might enhance lethality by interfering with the inactivation of oxotremorine by liver microsomal drugs enzymes in a manner similar to SKF 525A.

(1963). Effect of Breathing High Pressure Oxygen Upon Tissue Oxygen Tension in Rat and Mouse Tumours. Acta Radiologica: Therapy, Physics, Biology: Vol. 1, No. 4, pp. 233-252.

A single large po or sc dose of indomethacin, 80 times the antiinflammatory dose, produced a high incidence of intestinal perforations 72 hr after administration to fed rats; the perforations were confined to the mid-portion of the small intestine. When food was withheld from indomethacin-treated rats, the lesion incidence after a dose of 16 mg/kg po was reduced from 100% to zero. In a 72-hr study, it was found that food deprivation only on the day of drug administration prevented the intestinal perforations, while feeding the rats on the day of drug administration produced 100% ulcer incidence. Lesions produced by sc drug administration could also be prevented by starvation. The incidence of intestinal perforation was altered by the duration of food deprivation and the amount of food consumed. Intestinal ulcers could also be prevented, after either po or sc administration, by ligation of the bile duct. It appeared possible that there was a relationship between food intake, bile flow, and intestinal ulcers. Bile duct ligation reduced the incidence of intestinal perforation after indomethacin from 100% to zero. A time response curve indicated that bile duct ligation up to 8 hours after drug administration reduced the incidence of perforation; however, a 60% incidence of intestinal lesions was found when the bile duct was ligated 3 hours after indomethacin was given. When segments of the small intestine were isolated as Thiry loops, ulceration was prevented in the loops but occurred in the anastomosed intestine.

1. The possible role of brain histamine in behavioural performance was studied in rats using thirst-induced water consumption, continuous (Sidman) avoidance, and reinforcement withdrawal test systems. 2. Parenteral administration of a variety of antihistamines to rats decreased thirst-induced water consumption; this effect could be antagonized by administration of histamine directly into the brain by a ventricular cannula. 3. When intraventricular doses of histamine were administered to rats at weekly intervals, an adaptation was seen in the effects of the amine on continuous avoidance behaviour. With succeeding doses, the initial period of depression of avoidance responding was shortened and the subsequent rebound stimulation disappeared. 4. The results support the hypothesis that histamine in the brain is involved in several behavioural phenomena.

Included in this report is a brief summary of the carcinoid syndrome based on a case history of a patient followed from diagnosis to death and post-mortem examination. The current status of treatment of this condition is discussed.

The vasoconstrictor action of 5-hydroxytryptamine (5-HT) in the human placental preparation is about 10 times stronger than that of adrenaline and is antagonized by anti-adrenaline compounds like phentolamine. Both 5-HT and adrenaline are antagonized by yohimbine and chlorpromazine. Specific and strong anti-5-HT action is demonstrated for lysergic acid diethylamide (LSD) and tryptamine. Both LSD and tryptamine in larger doses have a vasoconstrictor action. Mescaline has no certain modifying effect on the action of 5-HT, but itself causes vasoconstriction in large doses. The antihistamine drug phenbenzamine in histamine blocking doses abolishes the action of 5-HT in half the preparations tested. The ganglionic blocking agent trimetaphan in large doses antagonizes the action of 5-HT added subsequently, and also, to a lesser degree, the effect of adrenaline. Hexamethonium and tetraethylammonium bromides are ineffective in this preparation. No certain modifying action of reserpine on subsequently added 5-HT could be demonstrated, and the same was true for heparin even in very high concentrations.

Endotoxin or PGF2α-induced abortion could be prevented in both normal and ovariectomized mice by pretreatment with progesterone: in neither case was intrauterine death of fetuses prevented. Relatively large doses of norepinephrine, histamine, 1 -DOPA, bradykinin, angiotensin or oxytocin had little or no effect on abortion, diarrhea or fetal death in 16 day pregnant mice. Serotonin (5-HT) proved effective in the induction of maternal diarrhea and fetal death. This observation, together with the observed reduction in endotoxin or PGF2α-induced fetal death by a large dose of the 5-HT antagonist, cyproheptadine, initially implicated 5-HT as the agent of intrauterine fetal death. However, small doses of the 5-HT inhibitors, cyproheptadine or methysergide, which effectively blocked 5-HT-induced fetal death, failed to reduce fetal death caused by endotoxin or exogenous PGF2α. Furthermore, combination treatments of pregnant mice with small doses of endotoxin, 5-HT and the monoamine oxidase inhibitor, iproniazid, failed to augment the toxic manifestations of either endotoxin or 5-HT. The present results argue against the role of 5-HT in intrauterine fetal death caused by either endotoxin or exogenous PGF2α. Rather, it is suggested that endogenous prostaglandins are responsible for fetal death as well as abortion and diarrhea in this experimental model.

SUMMARY Subcutaneous injection of the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine hydrochloride (Periactin) produced a significant decrease in uptake of [14C]5-HT (serotonin) in the myometrium and to a lesser degree in the ovaries, foetuses and heart of pregnant rats. This effect of cyproheptadine was considerably increased in rats pretreated with the monoamine oxidase inhibitor pargyline hydrochloride. These results suggest that the anti-abortive effect of cyproheptadine is based on specific inhibition of the contractile effect of 5-HT on the myometrium. The hypothesis is advanced that cyproheptadine competes with serotonin for its receptors and thus blocks the effect of serotonin.

Severe hypoglycemia and increased deaths were observed among two strains of endotoxin-poisoned mice within 3 to 6 hr after tryptophan injection. Sensitivity to tryptophan could be demonstrated in Rockland Farms mice by 4 hr after endotoxin and in Carworth Farms (CF-1) mice by 10 hr after endotoxin. If allopurinol was given to CF-1 mice concurrently with endotoxin, severe hypoglycemia and increased deaths were observed when tryptophan was given only 4 hr after the bacterial poison. Cyproheptadine, an antiserotonin drug, decreased the number of deaths as well as the depletion of blood glucose in both strains of endotoxin-poisoned mice given a delayed injection of tryptophan. In most instances, liver glycogen was depleted by 8 to 10 hr after endotoxin. Correlation of liver glycogen levels with sensitivity to tryptophan was not as consistent as the correlation between blood glucose levels and hyperreactivity to the amino acid. The data show that severe hypoglycemia is a significant factor which must be considered in resolving the basis for increased deaths among endotoxin-poisoned mice given tryptophan.