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Jellyfish, as representatives of marine fauna, contain toxic chemicals in their bodies and, if they come into contact with humans, can pose a threat to their health and safety. The article describes a clinical observation of a patient who received a chemical injury as a result of contact of the right upper limb with a venomous jellyfish (Medusa kornerot) and was hospitalized for 35 days with acute poisoning with animal toxin, chemical burns, toxic-allergic dermatitis, epidermolysis, soft tissue necrosis and compression-ischemic neuropathy. Laboratory results confirmed the presence of an inflammatory process, but without allergic and autoimmune components (leukocytosis 16,7 x 109/l, acceleration of ESR to 21 mm/h), revealed an increase in the level of transaminases upon admission: alanine aminotransferase 138.3 u/l (norm 0-31 u/l), aspartate aminotransferase 94,8 u/l (norm 0-31 u/l), gamma-glutamyltransferase 97 u/l (norm 0-32 units/l). Previous drug therapy, including the introduction of tetanus serum (once), antihistamines (chloropyramine), hormonal (prednisone), anticoagulants (heparin sodium), antispasmodics (Metamizole sodium, pitofenone hydrochloride, fenpiverinium bromide), antiplatelet agents (pentoxifylline, nicotinic acid), calcium gluconate, multivitamins in therapeutic doses, the application of bandages «gelonet», «fibrotul Argentum», was not effective enough. Complex therapy with cellular metabolism regulators, antihypoxants, cholinesterase inhibitors using hyperbaric oxygenation and membrane plasmapheresis allowed to achieve a lasting effect: to stop the pain syndrome, normalize the disturbed functions of internal organs and the affected limb, avoid surgery, and fully restore working capacity. This complex of therapeutic measures should be used in the treatment of patients with this pathology

Breast cancer is the second most common cancer worldwide, accounting for 25% of all female cancers. Although the survival rate has increased significantly in the past few decades, patients who develop secondary site metastasis as well as those diagnosed with triple negative breast cancer still represent a real unmet medical challenge. Previous studies have shown that chloropyramine (C4) inhibits FAK-VEGFR3 signalling. More recently, C4 is reported to have SASH1 inducing properties. However, C4 exerts its antitumour and antiangiogenic effects at high micromolar concentrations (>100 μm) that would not be compatible with further drug development against invasive breast cancer driven by FAK signalling. In this study, molecular modelling guided structural modifications have been introduced to the chloropyramine C4 scaffold to improve its activity in breast cancer cell lines. Seventeen compounds were designed and synthesized, and their antiproliferative activity was evaluated against three human breast cancer lines (MDA-MB-231, BT474 and T47D). Compound 5c was identified to display an average activity of IC50 = 23.5–31.3 μm, which represents a significant improvement of C4 activity in the same assay model. Molecular modelling and pharmacokinetic studies provided more promising insights into the mechanistic features of this new series.

Introduction: Current international guidelines recommend H1 and H2- antihistamines as a second or third- line drugs for the management of anaphylaxis. Aim: To present positive cardiovascular and dermatological effects of Chloropyramine and Ranitidine as the combination of H1 and H2- antihistamines in additive therapy of anaphylaxis. Patients and methods: In a retrospective study two groups of 146 patients who met the NIAID/FAAN criteria for the diagnosis of anaphylaxis were compared. Experimental group consisted of 62 patients who received combination of Chloropyramine H1- antihistamines and Ranitidine H2- antihistamines. Control group consisted of 84 patients who received only Chloropyramine H1- antihistamines. Results: A statistically significant differences of diastolic pressure and central pulse (p< 0.001), a higher values of diastolic pressure, and a lower values of central pulse in the experimental group of patients were recorded at the end of the prehospital treatment of anaphylaxis. The increase in the mean arterial blood pressure at the end of the treatment is higher in the experimental group compared to the initial values, with an average difference of 15 mmHg (%95 CI= 7,95-21,95). Total prehospital time and time recovery of the skin urticaria and itch was shorter in the experimental group for 18 minutes (95% CI= 11,95-25,95). Conclusion: Positive cardiovascular effects and a faster resolving of the skin symptoms justify the use of combination Chloropyramine and Ranitidine as an additive therapy of anaphylaxis that is not life- threatening, and of a rapid progression.

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines. Subsequent in silico connectivity screening demonstrated that the clinically approved antihistamine drug, chloropyramine, increased SASH1 mRNA levels. Chloropyramine has previously been shown to have anti-tumour activity in breast cancer in part through modulation of FAK signalling, a pathway also regulated by SASH1. This study demonstrated that chloropyramine increased SASH1 protein levels in breast cancer cells. Consistent with this the agent reduced cell confluency in 7/8 cell lines treated irrespective of their ER status but not apoptosis incompetent MCF7 cells. In contrast SASH1 siRNA-transfected breast cancer cells exhibited reduced chloropyramine sensitivity. The prognostic significance of SASH1 expression was also investigated in two breast cancer cohorts. Expression was associated with favourable outcome in ER-positive cases, but only those of low histological grade/proliferative status. Conversely, we found a very strong inverse association in HER2+ disease irrespective of ER status, and in triple-negative, basal-like cases. Overall, the data suggest that SASH1 is prognostic in breast cancer and could have subtype-dependent effects on breast cancer progression. Pharmacologic induction of SASH1 by chloropyramine treatment of breast cancer warrants further preclinical and clinical investigation.

The aim of the study was to identify the effect of high dietary zinc oxide (ZnO) levels on the histamine-induced secretory-type response and histamine metabolism in the porcine proximal colon. After weaning at d 26, 3 diets with low (LZn), normal (NZn), and high (HZn) concentrations of zinc (57, 164, or 2,425 mg/kg) were fed to a total of 120 piglets. Digesta and tissue samples were taken from the ascending colon after 7 ± 1, 14 ± 1, 21 ± 1, and 28 ± 1 d. Partially stripped tissue was mounted in Ussing chambers, and histamine was applied either to the serosal or mucosal compartments. Tissue was pretreated with or without aminoguanidine and amodiaquine to block the histamine-degrading enzymes diamine oxidase (DAO) and histamine -methyltransferase (HMT), respectively. Gene expression and catalytic activity of DAO and HMT in the tissue were analyzed. The numbers of mast cells were determined in tissue samples, and histamine concentration was measured in the colon digesta. Colon tissue from another 12 piglets was used for functional studies on histamine H and H receptors by using the neuronal conduction blocker tetrodotoxin (TTX) and the H and H receptor blocker chloropyramine and famotidine, respectively. After serosal histamine application to colonic tissue in Ussing chambers, the change of short-circuit current (Δ) was not affected by pretreatment and was not different between Zn feeding groups. The Δ after mucosal histamine application was numerically lower ( = 0.168) in HZn compared to LZn and NZn pigs. Mast cell numbers increased from 32 to 46 d of life ( < 0.05). Further studies elucidated that the serosal histamine response was partly inhibited by chloropyramine or famotidine ( < 0.01). The response to mucosal histamine tended to be decreased when chloropyramine but not famotidine was applied from either the serosal or the mucosal side ( = 0.055). Tetrodotoxin alone or in combination with chloropyramine resulted in a similar reduction in the mucosal histamine response ( < 0.01). In conclusion, the present study could not identify marked changes in colonic histamine metabolism on dietary ZnO oversupplementation. For the first time, however, H receptors were functionally identified in the pig colon that are localized either on neurons or on cells that activate secretion via neurons. Luminal histamine can elicit a secretory-type response via these receptors.

The early phase of the ConA-induced inflammatory ascites was studied, with special reference to histamine. Concanavalin A (ConA), a cell-surface binding lectin was injected i.p. (25 mg/kg bw) to mice. After 1 h the animals were killed, the ascitic fluid collected and measured. Other agents were injected s.c., 10 min before the ConA-challenge. Exogenous histamine markedly inhibited the ConA-induced ascites. Release of endogenous vasoactive agents from the mast cells by Compound 48/80 had a similar, but slight effect. Cromolyn, a mast cell stabilizing agent, and chloropyramine, a histamine H1 receptor antagonist was ineffective. Although histamine increases endothelial permeability, it did not enhance the formation of ascitic fluid, on the contrary, it inhibited the ConA-induced ascites, presumably due to its known hypotonic effect. It is concluded that ConA-induced ascites is not mediated by mast cell histamine.

Introduction: SASH1 (SAM and SH3 domain-containing protein 1) is a putative tumor suppressor functioning in the control of apoptosis and cellular proliferation. Previously SASH1 has been shown to be down-regulated in approximately 90% of lung cancers, however little is known about the role of SASH1 in the pathogenesis of the disease. Our previously published data has shown that Chloropyramine a known competitive reversible H1-receptor antagonist, increases SASH1 protein level in breast cancer cells.

This article presents data about the importance of chloropyramine in the treatment of allergic diseases and acute respiratory viral infections.

Background/Aims: Bronchial asthma continues to be a big challenge to therapy. Mast cells play an important role in allergic asthma. Histamine and leukotrienes are established mast cell mediators, but antihistamines currently play no role in asthma therapy. Methods: Human bronchial strips were exposed to the mast cell activator compound 48/80 (200 μg/ml) in isolated organ experiments. Results: The contractile response was not inhibited by the H1 receptor antagonist antihistamine chloropyramine (0.3 μmol/l), the leukotriene cys-LT1 receptor antagonist MK 571 (3 μmol/l), the 5-lipoxygenase inhibitor MK 886 (5 μmol/l), the cyclo-oxygenase inhibitor indomethacin (5 μmol/l), tetrodotoxin, or atropine. Chloropyramine, combined with either MK 571 or MK 886 significantly reduced the response. Conclusion: A supra-additive effect is proposed for the antihistamine and the anti-leukotrienes, which might have relevance to human asthma therapy as well; such a combination deserves a large-scale clinical study. These data also indicate that substances like compound 48/80 should be denoted as mast cell activators rather than ‘histamine liberators'.

FAK is a tyrosine kinase that functions as a key orchestrator of signals leading to invasion and metastasis. Since FAK interacts directly with a number of critical proteins involved in survival signaling in tumor cells, we hypothesized that targeting a key protein-protein interface with druglike small molecules was a feasible strategy for inhibiting tumor growth. In this study, we targeted the protein-protein interface between FAK and VEGFR-3 and identified compound C4 (chloropyramine hydrochloride) as a drug capable of (1) inhibiting the biochemical function of VEGFR-3 and FAK, (2) inhibiting proliferation of a diverse set of cancer cell types in vitro, and (3) reducing tumor growth in vivo. Chloropyramine hydrochloride reduced tumor growth as a single agent, while concomitant administration with doxorubicin had a pronounced synergistic effect. Our data demonstrate that the FAK-VEGFR-3 interaction can be targeted by small druglike molecules and this interaction can provide the basis for highly specific novel cancer therapeutics.

The objective of this study was to evaluate the effect of pentadecapeptide BPC 157 in anaphylactoid reaction in rats and mice after intravenous dextran and white egg administration. Anesthetized mice and rats received intravenously 6%, 10%, 20%, 40%, 60%, 80%, 90% dextran and/or white egg (1ml/rat or 0.15ml/mouse) into their tails. Medication (/kg b.w., 5 ml/kg) was given intraperitoneally (BPC 157 10 µg, 1 µg, 10 ng, 10 pg/kg, chloropyramine 20 mg/kg, cimetidine 10 mg/kg intraperitoneally, alone or in combination while controls received an equivolume of saline), immediately after challenge or, alternatively, at 5 min after or 24 or 48 h before challenge. The effect was assessed at 5, 10, 20 and 30 min after dextran and/or white egg challenge. We commonly noted prominent edema involving the face, upper and lower lip, snout, paws and scrotum (presented with extreme cyanosis), poor respiration and the number of fatalities after dextran and/or white egg application. Contrary, BPC 157 regimens (10 µg, 1 µg, 10 ng, 10 pg/kg) effectively, may both prevent anaphylactoid reactions that may arise from dextran and/or white egg application and furthermore, rescue already advanced reactions when given after the challenge. Chloropyramine and cimetidine given alone were only moderately effective. When given together with BPC 157, the observed effect correlates with the strong effect of BPC 157 given alone. In conclusion, we advocate BPC 157 use in anaphylaxis therapy.

Neuropeptides, including substance P (SP) may play a role in neurogenic inflammation. Although SP-immunoreactive (SP-IR) axons are known to be present within the oral mucosa (OM) and salivary glands, the functional significance of SP in oral mucosa and sublingual salivary gland (SLG) is not fully understood. The present experiments were carried out to study the effects of SP infused into the left common carotid artery on vascular permeability in the OM and in the SLG of male rats. Vascular permeability was assessed on the basis of Evans Blue extravasation. Separate groups of animals received histamine (H 1 ) receptor antagonist (chloropyramine, 10 mg kg -1 i.v.) or prostaglandin synthesis inhibitor (indomethacin, 4 mg kg-' i.v.) prior to SP infusions. Infusion of SP in doses of 30 and 74 pmol min -1 increased the vascular permeability of OM by 162.3±16.3% (n=8, p

The oedema disk technique was used to study the effects of intraperitoneally administered H1-receptor antagonists (chloropyramine, cyproheptadine and dimethindene maleate) on the inflammation induced with dithranol in the mouse ear. In rats of the Wistar strain, oedema was induced in the hind paw by the subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface of the ear. Preliminary antihistamine treatment inhibited the development of oedema in the mouse ear, and of both types of oedema in rats, to statistically significant extents and in a dose-dependent manner.

Oedema was induced in one ear of male mice of the CFLP strain with capsaicin solution (10 microliters/40 micrograms/ear). The development in time and the extent of the oedema were determined by the oedema-disk gravimetric technique. The maximum oedema was attained in less than 1 h, and there was, subsequently, a gradual decrease. The extent of the mouse ear oedema induced in this way and measured after 60 min was inhibited to a statistically significant degree and in a dose-dependent manner by the antihistamine chloropyramine, the antihistamine-antiserotonin cyproheptadine, the non-steroidal anti-inflammatory agent piroxicam, the prostaglandin antagonist di-4-phloretin phosphate, and the lipoxygenase inhibitor nordihydroguairetic acid. The method proved suitable for the detection of oedema and for the biologically quantitative determination of the state of desensitization induced with capsaicin.

Using human platelet-rich plasma (PRP) we found that histamine concentration-dependently potentiated platelet aggregation induced by platelet-activating factor (PAF). When added separately, neither histamine nor chloropyramine, a competitive antagonist of H1 receptors, influenced platelet aggregation, however BN 52021, a specific PAF receptor antagonist, concentration-dependently inhibited the response. Chloropyramine reduced the potentiating effect of histamine on PAF-induced platelet aggregation, and when it was coadministered with BN 52021, inducing 63% inhibition of PAF-induced aggregation, the histamine-potentiated PAF response was completely abolished. This observation draws attention to the importance of cooperation between histamine and PAF in mediation of platelet aggregation in human PRP, and points to the powerful antiaggregatory effect of BN 52021 combined with an antagonist of H1 receptors.

A 33-yer-old woman with no history of atopy, diagnosed of psoriatic arthritis, received 200 mg I.V. infliximab, with previous oral administration of loratadine and betamethasone, that was well tolerated. Two minutes after a second infusion two weeks later, with the same pretreatment, the patients suffer dyspnea, laryngeal spasm, generalized tremor, vomiting, hypotension, sinusal tachycardia, anxiety and hyposemia. She recovered in 45 minutes, after the administration of I.V. hydrocortisone, chloropyramine, adrenaline and oxygen. Several reports of infliximab-induced anaphylactic reactions have been published, especially in patients with Crohn's disease, that have been attributed to a type I (acute or delayed) hypersensitivity reaction mechanism.

Purpose: Previous reports demonstrate that chloropyramine has anti-tumor efficacy as a single agent, and in combination with cytotoxic agents like doxorubicin through modulation of the FAK-VEGFR-3 pathway. Since limited information is available about the pharmacokinetics of chloropyramine, we investigated the pharmacokinetics and tissue distribution of the drug following a single intraperitoneal (IP) injection. Methods: Female CD-1 mice received a single 50mg/kg dose of chloropyramine; plasma and tissue samples were collected at serial timepoints of 0.5, 1.0, 2.0, 4.0, and 6.0 hours. The tissues included brain, heart, spleen, liver, lung, muscle, and sternum. Each timepoint contained three mice. Chloropyramine concentrations were determined in both plasma and tissues, using a validated LC-MS/MS. Assay was validated with an LLOQ of 0.25ng/ml with the calibration curve ranging from 0.25-100ng/ml (3.42-12.4%CV). Noncompartmental PK analysis was performed using WinNonlin (Pharsight, Version 5.3). Pharmacokinetic parameters including: Maximal concentration (Cmax), terminal elimination half life (T1/2), area under the curve (AUC0-6hr), apparent clearance (Cl/F), apparent volume of distribution (Vd/F), and partition coefficients (Kp). Results: Following IP injection, chloropyramine followed either a mono- or bi-exponential decay in both plasma and tissues. Chloropyramine is cleared from plasma and all tissues within 12hr; thus chloropyramine does not exhibit a great potential for accumulation. Cmax was achieved within 1.0 hour for plasma and all tissues. Chloropyramine distributes well into various tissues such as the spleen, liver, lung, kidney, brain, and heart. The highest level of chloropyramine was achieved in lung tissue with a mean (sd) Cmax concentrations of 41.6 (11.6) μg/ml, respectively. In contrast, the mean Cmax in plasma was approximately 0.5 μg/ml; much less compared to tissues. The mean T1/2 was 0.83 (0.19) hr. The lungs exhibited the highest total tissue penetration of chloropyramine, representing a mean AUC of 51.3 μg-hr/g. The least total exposure was in muscle, with a mean AUC of 8.5 μg-hr/g. The apparent CL/F from plasma was 28.5 L/hr/kg while it was 0.9 L/hr/kg for lung tissue. Conclusions: These results illustrate the wide tissue distribution of chloropyramine, despite of the short plasma half-life. In addition, these results are of great importance because it provides supportive evidence of the tissue levels that will lead to anti-tumor efficacy through inhibition of FAK and VEGFR-3. Thus, evaluation of plasma and tissue concentrations of the drug elucidates the pharmacokinetics of this compound in an effort to identify target tissues into which it has a high degree of penetration to maximize antitumor efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4257. doi:10.1158/1538-7445.AM2011-4257

The crystal structure of N-(4-chlorobenzyl)-N',N'-dimethyl-N-(2-pyridinio)-1,2-ethanediammonium tetrachlorocopper(II), (C16H22ClN3)[CuCl4], contains the dication of chloropyramine, a potent anti-allergic agent effective on H1-type receptors. The CuCl42− anion exhibits a flattened-tetrahedral geometry. The ammonium H atom is weakly bonded to two Cl atoms of the anion and the pyridyl N atom is involved in a short hydrogen bond to a Cl atom of the anion.

In isolated rat hearts effects of chloropyramine (CP), histamine H1 antagonist, and famotidine (FA), H2 antagonist, upon two different myocardial injuries, ischaemia-reperfusion and hypoxia-reoxygenation were studied. In both types of injury the effects of drugs were seen mainly during reperfusion and reoxygenation, respectively. During reperfusion neither CP nor FA influenced amplitude of contractions, but CP lowered heart rate, +dp/dtmax. and coronary flow. During reoxygenation CP and FA lowered early posthypoxic contractions, whereas CP decreased and FA increased heart rate. CP and FA did not significantly influence the post-ischaemic and posthypoxic lactate dehydrogenase (LDH) release. Present results indicate the existence of H1 and H2 receptors in rat heart as well as their involvement in both types of studied injuries.

Volume flow (Jv), potential difference (delta psi), short-circuit current (io) and electrical resistance (R) were measured simultaneously across bovine tracheal epithelium in vitro. Under basal conditions, with no applied hydrostatic or osmotic pressure gradients (delta P = 0, delta phi = 0), no spontaneous Jv was observed. delta psi was 31 +/- 2 mV (lumen negative ), io 161 +/- 8 microA cm-2 and R 202 +/- 9 omega cm2, n = 50. When a delta pi was applied, by adding 20 - 80 mM sucrose into the medium bathing either the luminal or the serosal side of the tissue, a linear relationship was found between delta pi and Jv toward the lumen or toward the serosa. The apparent hydraulic conductivity (apparent Lp) was 4.6 - 4.9 10(-6) cms-1 atm-1. Histamine 10(-4) M did not induce any spontaneous Jv under basal conditions and had no effect on io nor on R. However, histamine caused a 100% increase in Jv elicited by sucrose gradients. It was concluded that histamine exerts a selective action on the hydraulic conductivity of bovine tracheal epithelium. Experiments using H1-receptors antagonists (diphenhydramine, dimetindene, chloropyramine) and H2-antagonists (cimetidine, metiamide) or a H2-agonist (impromidine) showed that the increase of Lp induced by histamine was mediated via H2-receptors.

Histamine administered intraventricularly or into the anterior hypothalamic preoptic region induced dose-dependent hypothermia in rats with chronic i.c.v. cannula. This hypothermia was almost totally abolished by both the histamine H1- and H2-receptor antagonists, mepyramine or chloropyramine and metiamide or cimetidine, respectively, give i.c.v. prior to histamine. In behavioural thermoregulation studies histamine considerably diminished the mean duration of dwelling of the rat under the heat lamp. This effect was abolished by histamine H1- but not by H2-receptor antagonists. It is concluded that histamine induces hypothermia by lowering the set point of the hypothalamic thermostat by means of H1-receptors. Histamine H2-receptor blockers antagonized the increase in tail skin temperature after histamine administration, suggesting that h2-receptors are involved in a heat loss mechanism.

Histamine (10-50 microgram) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30-60 min after administration. Histamine H1-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H2-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H1-receptor antagonist, mepyramine, but not by the H2-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H1- than H2-receptors.

The blockade of histamine receptors by repeated i.p. administration of 10-20 mg/kg of chloropyramine and tripelennamine, the potent H1-receptor antagonists, or by the i.c.v. administration of 2 mg/kg of metiamide and cimetidine, the highly selective H2-receptor antagonists, led to significant enhancement in the hypothalamic HD2(L-histidine carboxylase; EC 4.1.1.22.) activity and the histamine content; whereas the activation of the histamine H1-receptor by 4 mg/kg i.e.v. doses of 2-pyridylethylamine, the specific histamine H1 agonist, resulted in significant diminution in both the synthesis and level of this amine. These compounds either do not influence the hypothalamic HD in vitro or cause opposite effects in relatively high concentrations. After repeated administration of either agonists or antagonists, no significant alteration have been observed in the hypothalamic HNMT (histamine-N-methyl-transferase; EC 2.1.1.8.) activity. There were, however, two exceptions: 2 mg/kg i.c.v. doses of 2-methylhistamine and 4-methylhistamine produced remarkable inhibitions in the hypothalamic HNMT activity. These effects do not seem to correspond to the agonistic character of the compounds, but mask the indirect actions and create difficulties in the discovery of regulatory events. The regulatory influence which suppresses or stimulates the basal activity of HD under the activation or the inhibition of the functional state of histamine receptor, is assumed to be mediated through the cyclic AMP system.

Mild stress of restraint for 10 min at an ambient temperature of 18 degrees C increased serum corticosterone levels in rats considerably. Histamine given intravenously prior to restraint alone significantly further intensified the stress-induced elevation of serum corticosterone. Dimaprit and cimetidine failed to modify corticosterone responses to the mild stress. Severe stress of restraint and cold of 3 h duration increased serum corticosterone and free fatty acid levels considerably. Histamine given prior to stress exposure left the corticosterone and hyperlipaemic responses to severe stress unchanged. Dimaprit inhibited and cimetidine intensified the stress-induced hyperlipaemia. The most striking finding in the present experiment was a powerful inhibition of gastric stress ulcer generation by intraventricularly administered histamine. Dimaprit was similarly effective. This strong anti-ulcer effect of histamine was abolished by intraventricular pretreatment of rats with either H1- or H2-receptor antagonists, chloropyramine or cimetidine. The results may suggest that in the rat a mild stress does not fully activate central histaminergic pathways involved in corticosterone responses. During severe stress histamine considerably prevents gastric ulcer generation and both H1- and H2-receptors mediate this action of histamine.

2784 cases of birth defects taken from the Finnish register of congenital malformations for 1964-72 and the same number of matched controls were reviewed to discover which mothers had used tricyclic antidepressants during pregnancy. Use of an imipramine/chloropyramine combination in the first trimester was associated with two craniofacial malformations and one centralnervous-system anomaly. In one case of malformation, amitriptyline had been taken in early pregnancy and in another case it had been taken during the third trimester. There was one amitriptyline user among the controls.