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PubMed1982

Role of histamine H1- and H2-receptors in postprandial intestinal hyperemia.

Studies were conducted in anesthetized dogs to assess whether histamine H1- and/or H2-receptors play a role in post-prandial intestinal hyperemia. The vascular and metabolic responses of jejunal segments to intra-arterial infusion of histamine and luminal placement of food before and after administration of tripelennamine, an H1-receptor antagonist, metiamide, an H2-receptor antagonist, and the combination of both antagonists were compared. Administration of the antagonists had no effect of jejunal blood flow and intestinal oxygen uptake (VO2). Tripelennamine or metiamide alone attenuated while the combination of both blocked the histamine-induced increases in blood flow and VO2. Metamide alone had no effect on the food-induced increases in flow and VO2. Tripelennamine significantly attenuated the food-induced increase in flow and blocked the increase in VO2. A 30% increase in flow was reduced to 15% after tripelennamine. The effects of tripelennamine plus metiamide were statistically the same as those of tripelennamine alone. It is concluded that endogenous histamines may play a role in postprandial intestinal hyperemia, and the effect is primarily mediated by the H1-receptors.

Animals↗

PubMed1997

Interactions between H1-antagonists and opioids: a drug discrimination study.

We previously demonstrated that combination of opioids, pentazocine and dihydrocodeine, with the histamine H1-receptor antagonists tripelennamine and chlorpheniramine could enhance their rewarding effects in rats. In the present study, the effects of combined treatment with opioids and H1-antagonists on discriminative stimulus effects were examined in rats trained to discriminate between cocaine (10 mg/kg) or morphine (3.0 mg/kg) and saline, since it is believed that discriminative stimulus effects of abused drugs are related to their rewarding effects. Tripelennamine and chlorpheniramine, but not pentazocine or dihydrocodeine, generalized to the discriminative stimulus effects of cocaine. Pentazocine (3.0 mg/kg) and dihydrocodeine (5.6 mg/kg) significantly potentiated the cocaine-like discriminative stimulus effects of low doses of tripelennamine and chlorpheniramine, respectively. On the other hand, pentazocine and dihydrocodeine, but not tripelennamine or chlorpheniramine, generalized to the discriminative stimulus effects of morphine. Neither 1.0 or 3.0 mg/kg tripelennamine nor chlorpheniramine affected the morphine-like discriminative stimulus effects of pentazocine and dihydrocodeine, respectively. These results suggest that the potentiation of the cocaine-like discriminative stimulus effects of H1-antagonists by opioids may be involved in the enhanced rewarding effects of combinations of opioids and H1-antagonists.

Analgesics, Opioid↗

PubMed1985

Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole.

Antihistamines are being increasingly administered in combination with various other agents, with adverse drug reactions the frequent result. The present study consisted of two experiments. Experiment 1 examined the toxicological response of rats to nicotine tartrate (0.0, 2.0, 4.0, and 8.0 mg/kg) in combination with either of two H1-histamine receptor antagonists, the ethylene diamine tripelennamine HCl (0.0, 16.0, 32.0, and 64.0 mg/kg) or the aminoethyl ether diphenhydramine HCl (0.0, 32.0, 64.0, and 96.0 mg/kg). Adult female rats received intraperitoneal injections when housed 12 per cage and toxicological response (number dead per group) was assessed 24 hours post-treatment. The results showed that over the dose ranges employed, and when given alone, nicotine was completely non-lethal, tripelennamine was virtually non-lethal and diphenhydramine was toxic only at the highest dose (5 of 12, at 96.0 mg/kg). However, when nicotine and the antihistamines were delivered in combinations, the toxicological response was markedly altered. Tripelennamine in combination with nicotine yielded supra-additive interaction, with the degree of potentiation being a simple linear function of nicotine within each dose of tripelennamine. The interaction between nicotine and diphenhydramine was more complicated, with certain dose combinations yielding supra-additivity, yet with others yielding antagonism. It was suggested that seizure-precipitated cardiopulmonary collapse was the immediate cause of death, plausibly mediated by central mechanisms. As such, Experiment 2 examined the influence of adding the proconvulsant pentylenetetrazole (PTZ) (0.0, 10.0, and 20.0 mg/kg) to nicotine (0.0, 2.0, 4.0, and 8.0 mg/kg)-tripelennamine (0.0 and 32.0 mg/kg) combination treatments. Effects were assessed both at 1.0 and 24.0 hours post-injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Studies on tertiary amine UDP-glucuronosyltransferases from human and rabbit hepatic microsomes.

The conversion of tertiary amines to quaternary ammonium glucuronides was investigated in human liver microsomes, and characteristics of the UDP-glucuronosyltransferase (UGT) catalyzing quaternary ammonium glucuronidation were evaluated. In addition, a rabbit liver microsomal UGT mediating this reaction was studied. The kinetics of quaternary ammonium glucuronidation of cyproheptadine, tripelennamine, amitriptyline, and doxepin in intact human liver microsomes was determined. Tripelennamine was found to have the lowest apparent KM and was used as a representative substrate for further studies. A polyclonal antibody preparation raised in sheep against rabbit liver p-nitrophenol UGT was found to inhibit tripelennamine glucuronidation in solubilized human liver microsomes, but had no effect on p-nitrophenol, 4-methylumbelliferone, 4-aminobiphenyl, estriol, morphine, or naloxone glucuronidation. This antibody also inhibited tripelennamine glucuronidation in solubilized rabbit liver microsomes, but had little or no effect on estrone, testosterone, estradiol, androsterone, and morphine glucuronidation. Chlorpromazine competitively inhibited tripelennamine glucuronidation. This inhibition was markedly enhanced by UV light irradiation. [3H] Chlorpromazine binding to solubilized human liver microsomes was also increased by UV light. The binding was antagonized by substrates for tertiary amine UGT but not by substrates for morphine UGT. These studies suggest that the tertiary amine UGT is photo-affinity-labeled by chlorpromazine. Furthermore, it would appear from immunoinhibition and [3H]chlorpromazine labeling experiments that tertiary ammonium glucuronidation is catalyzed by a unique and distinct UGT in rabbit and human liver microsomes.

Amines↗

PubMedDate not supplied

Opiate mixed agonist-antagonist interactions with histamine antagonists vs. morphine.

Anecdotal reports of polydrug abuse in humans using tripelennamine and pentazocine prompted our investigation of drug interactions between tripelennamine, morphine and various synthetic mixed agonist-antagonists in mice. Pentazocine, nalbuphene and butorphanol, at doses of 4.0-8.0 mg/kg, all showed frank or borderline intrinsic antinociceptive activity and potentiated the tripelennamine response, whereas cyclazocine, an experimental compound with very strong mixed agonist-antagonist qualities at 5.0 mg/kg, showed intrinsic antinociceptive activity but was not potentiated by tripelennamine and actually blocked the tripelennamine response. In a comparative study, pentazocine, butorphanol and nalbuphene had no effect on morphine antinociception whereas cyclazocine completely abolished the antinociceptive effects of morphine. Cimetidine blocked the response of cyclazocine, but not nalbuphene, pentazocine or butorphanol. Our findings demonstrate that the mechanism of action of cyclazocine is significantly different from that of the other mixed agonist-antagonists studied. They also suggest possible histaminergic involvement in antinociception, as well as a locus for antinociception separate from the opiate receptor.

Analgesics↗

PubMed1975

Influence of histamine H1- and H2-receptor blockers on sympathetic vasodilator and vasoconstrictor responses in canine paw.

1 Vasodilator responses to histamine, bradykinin and sympathetic nerve stimulation were elicited in the perfused paw of dogs treated with bretylium (15-20 mg/kg) and atropine. The H2-receptor blocking agent, burimamide, when administered in the dose of 5 mg/kg intravenously and 4 mg intra-arterially did not depress significantly these vasodilator responses. The subsequent administration of tripelennamine in the dose of 2.5-5 mg/kg intravenously and 4 mg intra-arterially produced a significant blockade of the response to histamine and reduced the sustained vasodilator response to nerve stimulation. 2 In guanethidine-treated dogs, tripelennamine administered in the same dose following burimamide produced a blockade of the response to histamine comparable to that in the bretylium experiments, but decreased only the sustained vasodilator response to stimulation at 1 Hz. When the order of administration of the antihistamines was reversed in another group of guanethidine-treated dogs, tripelennamine had only a slight blocking effect on the response to histamine and did not affect the responses to nerve stimulation. Burimamide exerted a significant blocking effect on the response to histamine, but not to nerve stimulation. Another H2-receptor blocking agent, metiamide, when given after tripelennamine, also had a marked blocking effect on the response to histamine and almost abolished the vasodilator response to 4-methylhistamine, an H2-agonist. Nevertheless, even in the presence of this profound histamine blockade, the sustained vasodilator response to nerve stimulation remained unchanged. 3 In another group of experiments vasoconstrictor responses to exogenous noradrenaline and sympathetic stimulation were initially depressed by burimamide and later returned to control values. Tripelennamine increased these responses by its uptake blocking action. 4 It is concluded that the sustained vasodilator response is not antagonized by a specific antihistaminic action. The decrease in the sustained vasodilator response produced by antihistamines is produced attributable to potentiation of a residual adrenergic vasoconstricotr effect not completely blocked by bretylium.

Animals↗

PubMed1981

Mesenteric vascular reactivity to histamine receptor agonists and antagonists.

Response patterns of intestinal blood flow, oxygen extraction and consumption, blood flow distribution, and motility were assessed during intraarterial infusions of histamine, histamine after H1 or H2 blockade, dimaprit or dimaprit after H2 blockade. Histamine produced an initial peak response of blood flow with a slow decrease thereafter. Oxygen extraction was evenly depressed throughout the infusion, and oxygen consumption increased at the beginning. All initial responses were blocked by tripelennamine. Ranitidine, a new H2 antagonist, accelerated the decay of all responses. Dimaprit produced effects identical to those of histamine after tripelennamine. Distribution of blood flow was unchanged at the beginning of histamine infusion, but subsequently showed a shift to muscularis which was blocked by tripelennamine. Histamine usually stimulated intestinal contractions and this effect was abolished by tripelennamine. Thus, H1 stimulation, besides producing an initial vasodilation, increases oxygen uptake and redistributes flow to the muscularis.

Adrenergic Agonists↗

PubMed1986

Mechanisms of irritative activity of compound 48/80 on rat gastric mucosa.

A single intraperitoneal injection of compound 48/80 (48/80) (0.5-3 mg/kg) into anesthetized rats caused a dose-dependent reduction of the transmucosal potential difference (PD) and intraluminal pH (pH), and induced gastric lesions within 2 h. These same changes were seen with an intraperitoneal injection of histamine, but not with serotonin. There was a significant correlation between the lesion index and the PD reduction, although the integrity of the resting gastric mucosal barrier remained unaltered. The PD reduction caused by 48/80 was dose-dependently inhibited by tripelennamine (H1-antagonist) and FPL-52694 (mast cell stabilizer) and partially suppressed by methysergide (serotonin antagonist), but the changes in pH were prevented by FPL-52694 and cimetidine (H2-antagonist). The reduction of PD and pH induced by histamine was inhibited by tripelennamine or cimetidine, respectively, but these responses were not inhibited by FPL-52694 or methysergide. Gastric lesions induced by 48/80 were potently inhibited by tripelennamine and FPL-52694, and partially by cimetidine, whereas those induced by histamine were significantly prevented by tripelennamine and cimetidine, but not by FPL-52694. Methysergide had no effect on the development of gastric lesions in response to 48/80 or histamine. These results suggest that a single injection of 48/80 reduced the PD and stimulated acid secretion, thereby producing gastric lesions. These effects of 48/80 may be due to activation of H1- and H2-receptors by acutely released endogenous histamine.

Animals↗

PubMed1986

Some behavioral effects of histamine H1 antagonists in squirrel monkeys.

Graded dose of the histamine H1 antagonists tripelennamine (0.1-3.0 mg/kg), promethazine (0.1-3.0 mg/kg), diphenhydramine (0.3-10.0 mg/kg) and chlorpheniramine (0.3-1.7 mg/kg) increased rates of nonsuppressed responding under a second-order schedule of food presentation to a maximum beyond which responding was increased less or decreased. In contrast, the H2 antagonist, cimetidine, had no effect or decreased responding at the highest doses studied (56.0-100.0 mg/kg). Intermediate doses of tripelennamine, diphenhydramine and promethazine also increased rates of food-maintained responding that were suppressed by electric shock. Maximal increases in rates of suppressed responding were comparable to those produced by effective doses of chlordiazepoxide (3.0-10.0 mg/kg). Under identical conditions, clozapine (0.1-1.0 mg/kg) increased responding to a lesser extent, and d-amphetamine (0.01-0.3 mg/kg) and cimetidine (3.0-100.0 mg/kg) either did not increase or, at the highest doses, only decreased rates of suppressed responding. Doses of tripelennamine and diphenhydramine that increased rates of nonsuppressed and suppressed responding also maintained self-administration in cocaine-trained squirrel monkeys under a second-order schedule of i.v. injection. Rates and patterns of responding maintained by tripelennamine and diphenhydramine were comparable to those maintained by cocaine and d-amphetamine under identical conditions. The results show that histamine H1 antagonists can have pronounced rate-increasing effects on nonsuppressed and suppressed behavior, and that they can serve as reinforcers in monkeys. These effects occur at doses that probably are greater than those required to saturate H1 sites of action in central nervous system and may not be mediated solely through histaminic mechanisms.

Animals↗

PubMed1996

Effects of H(1)-antagonists on discriminative stimulus effects of cocaine and methamphetamine in rats.

The effects of H(1)-antagonists, such as tripelennamine, chlorpheniramine and pyrilamine, on the discriminative stimulus effects of cocaine and methamphetamine in rats were examined. Rats were trained to discriminate between cocaine (10mg/kg, i.p.) or methamphetamine (1.0mg/kg, i.p.) and saline, with responses maintained under a fixed-ratio 10 (FR10) schedule of food delivery. In generalization tests, tripelennamine generalized to the discriminative stimulus effects of cocaine and methamphetamine, while chlorpheniramine only generalized to cocaine. These generalizations of tripelennamine and chlorpheniramine were attenuated by the dopamine receptor antagonist haloperidol. Furthermore, tripelennamine and chlorpheniramine, but not pyrilamine, potentiated the discriminative stimulus effects of cocaine and methamphetamine. These results suggest that some H(1)-antagonists possess cocaine- and/or methamphetamine-like discriminative stimulus effects which may be mediated by the dopaminergic system, and as a result the discriminative stimulus effects of cocaine and methamphetamine were potentiated by these H(1)-antagonists.

Journal Article↗

PubMed1978

Inhibition of canine gastric acid secretion by an H-1 receptor antagonist to histamine.

Histamine H-2 receptors are thought to mediate gastric acid secretory responses, whereas H-1 receptors supposedly regulate mucosal vascular responses to histamine. In an in vivo chambered canine stomach flap preparation, the H-1 receptor antagonist, tripelennamine, injected intraarterially (22.1 mumol/kg) into the stomach flap reduced histamine-stimulated (1.25 micron/kg/min intravenously) acid secretion by approximately two thirds with a secondary reduction in gastric mucosal blood flow. This antisecretory action does not appear to be due to nonspecific mucosal damage. The H-2 receptor antagonist, metiamide, injected intraarterially (2.5 mumol/kg) also inhibited gastric acid secretion by about two thirds as did intravenously injected metiamide (4.5 mumol/kg), whereas intravenously administered tripelennamine (40.8 mumol/kg) was ineffective as an acid secretory inhibitor. Intraarterial tripelennamine reduced the secretory actions of the H-2 agonist, 4-methylhistamine (2.2 micron/kg/min intravenously), while intravenous metiamide depressed the gastric mucosal dilator responses to the H-1 agonist, 2-methylhistamine (5 micron/kg/min intravenously). Both histamine-receptor antagonists also reversed the systemic circulatory depressor effects of histamine and its analogs. These results suggest the need for reevaluation of inferences based upon the assumed specificity of H-2 and H-1 agonists and antagonists.

Animals↗

PubMed1986

Effects of histamine-receptor antagonists on histamine-stimulated renin secretion.

The effects of histamine H1- and H2-receptor antagonists on histamine-stimulated renin secretion were examined in anesthetized dogs. Tripelennamine (H1 blocker) further enhanced renin secretion in the presence of exogenous histamine. Moreover, tripelennamine alone increased renin secretion. These effects are probably due to non-specific properties of the drug and not to interaction of tripelennamine with H1 receptors. Conversely, cimetidine (H2 blocker) significantly inhibited histamine-induced increases in renin secretion, renal blood flow, and sodium excretion without any changes in mean arterial blood pressure or glomerular filtration rate. Cimetidine alone had no effect. We conclude that H2 receptors mediate the effect of histamine on renin secretion in dogs with innervated, intact kidneys.

Animals↗

PubMed1985

The role of histamine H1 and H2 receptors in the canine kidney.

The functional role of H1 and H2 receptors in mediating the effects of histamine on renal hemodynamics and tubular function was investigated in anesthetized dogs. Histamine, infused directly into the renal artery, caused decreases in renal vascular resistance and increases in total renal blood flow without significant changes in mean arterial blood pressure or glomerular filtration rate. These hemodynamic effects of histamine were inhibited by the H2-receptor antagonist, cimetidine, but not by the H1-receptor antagonist, tripelennamine. Histamine also caused increases in fractional urine flow and the fractional excretion of sodium and calcium with a concomitant decrease in urine/plasma osmolality. These tubular effects of histamine were antagonized by both tripelennamine and cimetidine. Histamine-induced increases in the fractional excretion of potassium were blocked only by tripelennamine. These results suggest that (1) both H1 and H2 receptors mediate the effects of histamine on urinary dilution and tubular reabsorption; (2) H2 receptors mediate the effects of histamine on renal hemodynamics, indicating that H2 receptors are present in the renal vasculature, and (3) H1 receptors may exist in the renal tubules.

Animals↗

PubMed1989

Effects of thiazinamium chloride on human isolated bronchial muscle preparations.

In human bronchial muscle preparations contracted with histamine, the rank order potency for the relaxant effect of various antagonists was: thiazinamium chloride less than tripelennamine less than atropine (pD2 values: 7.78, 6.16 and greater than 4 for each antagonist, respectively). These antagonists also relaxed human isolated bronchial muscle preparations contracted with acetylcholine. The rank order potency was: atropine less than thiazinamium chloride less than tripelennamine (pD2 values: 7.76, 6.94 and 4.05, respectively). Tripelennamine and thiazinamium chloride displaced histamine concentration-effect curves and atropine and thiazinamium chloride antagonized acetylcholine curves in human isolated bronchial muscle preparations. These results suggest that thiazinamium chloride may have important therapeutic value in airways disease since this drug not only relaxed human isolated airway muscle preparations but also antagonized contractile responses in these tissues to both histamine and acetylcholine.

Atropine↗

PubMed1985

Antihistamine selection in patients with allergic rhinitis.

Seven hundred eighty-two patients diagnosed as having either seasonal allergic rhinitis or perennial allergic rhinitis in a solo allergy practice were given five different antihistamine products representing each of the five classes of antihistamines. The following products were evaluated for 2 weeks each: tripelennamine, diphenhydramine, chlorpheniramine, hydroxyzine, and trimeprazine. Symptoms and side effects were graded 0 to 4. The more troublesome side effects, graded 3 or 4, were tabulated. The antihistamine products in order of increasing frequency of significant side effects were: trimeprazine, chlorpheniramine, hydroxyzine, diphenhydramine, and tripelennamine. The order of antihistamine preference by the patients was chlorpheniramine (27%), diphenhydramine (22%), tripelennamine (20%), hydroxyzine (16%), and trimeprazine (14%). Only seven of 758 patients (less than 1%) were unable to find an acceptable antihistamine class. Patients remained on their antihistamine class of first choice 78% of the time after 1 year, 71% after 3 years and 51% after 5 years. The antihistamine pack provides a rational approach to antihistamine selection in patients with allergic rhinitis.

Chlorpheniramine↗

PubMedDate not supplied

Antihistaminic-opioid combination: effect on locomotor activity in mice.

Various laboratory studies have been recently prompted by reports indicating abuse by heroin addicts of the narcotic agonist-antagonist pentazocine combined with the antihistaminic tripelennamine. For what concerns the effects on locomotor activity, it was demonstrated that three histamine H1 receptor antagonists, chlorpheniramine, diphenhydramine and tripelennamine enhance morphine-, but not amphetamine and scopolamine-induced hyperactivity in mice. These results suggested that antihistaminics may specifically interfere with locomotor effects of opioids. Such hypothesis was strengthened by further findings indicating enhancement by tripelennamine of the locomotor stimulation induced by buprenorphine, a drug possessing morphine-like properties.

Amphetamine↗

PubMed1994

Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain.

To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids.

Animals↗

PubMed1990

Effects of antihistaminics on naloxone-induced withdrawal in morphine-dependent mice.

Some histamine H1 (tripelennamine, diphenhydramine and cyclizine) and H2 (ranitidine and cimetidine) antagonists (1 and 10 mg/kg) were administered to morphine-dependent mice to evaluate the changes on naloxone-induced abstinence syndrome. When antihistaminics were administered 30 min before naloxone (1 mg/kg) on day 4 of morphine addiction, the two doses of three H1 antagonists and the higher dose of ranitidine inhibited shaking behavior. Furthermore, the two doses of tripelennamine and the higher dose of diphenhydramine, cyclizine and cimetidine enhanced jumping behavior. When antihistaminics were administered chronically (during the 4 days of morphine addiction), tripelennamine, cyclizine and ranitidine (all at 10 mg/kg) inhibited shaking behavior. The three H1 antihistaminics used enhanced the number of jumps per mouse whereas ranitidine decreased this response. No significant changes were found in the rest of the withdrawal symptoms after the antihistaminics were administered. The participation of serotonergic and catecholaminergic mechanisms is discussed.

Animals↗