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PubMed1985

Sedation and the stimulus properties of antihistamines.

A group of six rats was trained to discriminate the effects of diphenhydramine (10 mg/kg; 30 min pretreatment time) and saline in a two-lever choice task using a fixed ratio schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. Diphenhydramine established stimulus control in each of the subjects. The mean number of sessions prior to the onset of criterion performance was 26 (standard error = 7). A second group of six rats was similarly trained with chlorpheniramine (10 mg/kg; 30 min pretreatment time) and saline. Four of the group reached criterion performance in a mean of 56 sessions (SE = 7). The diphenhydramine stimulus generalized completely to promethazine, azatidine, and chlorpheniramine. In rats trained with chlorpheniramine, only promethazine and azatidine substituted completely while diphenhydramine yielded intermediate results, i.e., significantly different from both training conditions. It is concluded that the relative propensity of antihistamines to induce sedation in humans is not correlated with distinctive stimulus properties in the rat.

Animals↗

PubMed1986

The effect of antihistaminic drugs on pentazocine antinociception in the rat.

The antinociception produced by pentazocine, diphenhydramine, promethazine, chlorpheniramine, cyclizine and chlorcyclizine in the rat has been measured with a low-temperature (51.5 degrees C) hot-plate from 15 to 75 min following drug administration. The mean reaction times measured at 15 min and the area under the antinociception curves following administration of pentazocine (5 to 30 mg/kg) were linear. Diphenhydramine, chlorpheniramine, promethazine, cyclizine, and chlorcyclizine showed mild antinociceptive potency. The antinociception produced by SC pentazocine (5 and 10 mg/kg) was potentiated, rather than in a simple additive manner, by simultaneous IP administration of 20 mg/kg of diphenhydramine, promethazine, cyclizine, or chlorpheniramine, but not by chlorcyclizine. After concurrent administration of pentazocine and diphenhydramine, diphenhydramine did not alter pentazocine concentrations in the brain and plasma 15 to 75 min following drug administration, nor did pentazocine change diphenhydramine concentrations. Results of this study demonstrate that pentazocine antinociception can be potentiated by several antihistamines and that the potentiation was not due to a mutual effect on metabolism but rather through an as yet undefined mechanism.

Animals↗

PubMed1993

Effect of cetirizine, a new H1 antihistamine, on the early and late allergic reactions in a bronchial provocation test with allergen.

BACKGROUND: Cetirizine is a highly sensitive H1 antihistamine with particular antiallergic properties, which has been shown to be effective in the treatment of allergic rhinitis, urticaria, and hay-fever-associated asthma. METHODS: To assess the effect of cetirizine on the late allergic reaction to a specific bronchial provocation test (BPT) with allergen, we selected 25 patients with allergic asthma as determined by history, skin tests, and specific IgE levels. They were challenged with increasing doses of a cat or mite extract until a 20% drop in forced expiratory volume in 1 second (FEV1) was recorded. Sixteen patients (11 men and 5 women with a mean age of 22 years; range, 18 to 48 years) exhibited a dual response (early and late allergic reactions). These 16 patients underwent a second BPT 2 weeks later, and each again showed a dual response. They were then randomized to receive either a placebo (8 patients) or cetirizine, 15 mg twice daily (8 patients) in a double-blind fashion. After 7 days of treatment, they underwent a third BPT with the same allergen dose as given in the second BPT. RESULTS: The intensity and duration of early allergic reaction were not affected by cetirizine, whereas all parameters of late allergic reaction were statistically significantly improved in the cetirizine group when compared with those of the placebo group (maximum FEV1 decrease, p = 0.046; FEV1 [area above the curve], p = 0.027; maximum airway resistance increase, p = 0.021; airway resistance [area under the curve], p = 0.036). CONCLUSIONS: Cetirizine produced a significant protective effect against an allergen-induced late allergic reaction in a BPT. Cetirizine might therefore be effective in the treatment of asthma.

Adolescent↗

PubMed1994

A laboratory study of patients with chronic allergic rhinitis: antihistamine effects on skilled performance.

Twenty-four patients with chronic allergic rhinitis participated in a study of antihistamine effects on skilled performance. They were tested while experiencing symptoms and when they were free of symptoms. Within each symptom condition, they attended two sessions; each patient received a placebo capsule at one session and a 50 mg diphenhydramine capsule at the other. Subjects performed a battery of skilled performance tests, which included the Divided-Attention, Visual Backward Masking, Stimulus Response Conflict, and Vigilance tests. They rated the treatments and their performance. Affective states were assessed with the Profile of Mood States. Symptoms did not affect performance. Diphenhydramine impaired vigilance performance and measures of Divided Attention and Stimulus Response Conflict. Visual Backward Masking performance was not affected. The largest performance changes occurred when diphenhydramine was administered to subjects when they were free of symptoms.

Adult↗

PubMed1987

Genotoxicity, toxicity, and carcinogenicity of the antihistamine methapyrilene.

The antihistamine methapyrilene hydrochloride (MP) has been shown to be a potent hepatocarcinogen in rats, but not in hamsters or guinea pigs. This finding is in contrast to the relative nongenotoxicity of this compound. MP has been evaluated for genotoxicity in a wide variety of short-term tests and has generally demonstrated little genotoxic activity. One exception to this is the mouse lymphoma L5178Y mutagenesis assay, in which MP produced a very significant increase in small colony mutants with concomitant chromosomal damage in these cells. MP also induced positive responses in several cell transformation assays. One potentially very significant effect of MP is that it induces a large increase in hepatic cell proliferation coupled with mitochondrial proliferation in the livers of treated animals. This effect is discussed as a possible mechanism of liver tumor induction in rats.

Aminopyridines↗

PubMed1984

A study of the potential genotoxicity of methapyrilene and related antihistamines using the hepatocyte/DNA repair assay.

Methapyrilene and four related antihistamines were evaluated for their ability to cause DNA repair measured autoradiographically as unscheduled DNA synthesis (UDS) in primary cultures of Fischer-344 rat hepatocytes. Methapyrilene failed to induce UDS at all doses tested while pyrilamine and tripelennamine induced a concentration-dependent increase in DNA repair. Doxylamine and thenyldiamine, previously untested in this system, induced a weak response at the highest non-toxic doses tested. Methapyrilene was clearly cytotoxic at doses of 100 microM and higher, as judged by morphology, and precursor incorporation into RNA and protein. Precursor incorporation into RNA was irreversibly inhibited 90% and 55% at 1000 microM and 100 microM methapyrilene, respectively, while precursor incorporation into protein was inhibited 80% and 60%. These data verify the genotoxicity of pyrilamine and tripelennamine and the failure of methapyrilene to elicit DNA repair, and suggest that doxylamine and thenyldiamine may be weak DNA-damaging agents.

Aminopyridines↗

PubMed1991

Eosinophil infiltration: effects of H1 antihistamines.

This article reviews the contribution of cell-mediated inflammatory responses to the immediate immunoglobulin E-dependent allergic reaction. Apparently eosinophils play an important part in the pathogenesis of allergic reactions. Some new H1 antihistamines may also have non-H1-mediated antiinflammatory properties. In two double-blind, placebo-controlled, crossover studies of allergic and normal subjects, we showed that oral cetirizine, at dosages of 10 and 20 mg/day, significantly inhibited wheal-and-erythema reactions induced by grass pollen, 48/80, histamine, platelet-activating factor acether, and N-formyl-methionyl-leucyl-phenylalanine. In the first study, cutaneous eosinophil migration was significantly inhibited by cetirizine at pollen and 48/80 skin test sites (61%, p less than 0.01, and 53%, p less than 0.01, respectively), although no change was observed at histamine skin test sites. Inhibition of neutrophil accumulation was also observed at pollen and 48/80 sites (41%, p less than 0.1, and 31%, p less than 0.1, respectively). Monocyte accumulation was not affected by cetirizine. In the second study, cetirizine suppressed the eosinophil influx induced by pollen, platelet-activating factor, 400 ng, and platelet-activating factor, 40 ng (63%, p less than 0.001; 58.5%, p less than 0.001; and 57.8%, p less than 0.01, respectively). This inhibition was effective 2 hours after challenge and persisted through hours 4, 8, and 24. N-Formyl-methionyl-leucyl-phenylalanine induced a weak eosinophil accumulation that was inhibited by cetirizine.

Cell Movement↗

PubMed1983

C5a and antigen-induced tracheal contraction: effect of a combination of an antihistamine and cyclo-oxygenase inhibitors.

Our previous studies with C5a, a cleavage product of the fifth component of complement, have shown that the antihistamine diphenhydramine and the cyclo-oxygenase inhibitor aspirin do not inhibit the C5a-induced contraction of isolated guinea pig trachea (Regal, Eastman & Pickering, 1980; Regal & Pickering, 1981). We investigated the effect of cyclo-oxygenase inhibitors in the presence of diphenhydramine to determine if cyclo-oxygenase products were contributing to the contraction beyond any effect they might have on histamine release. A combination of a cyclo-oxygenase inhibitor and diphenhydramine caused a delay in onset and decrease in magnitude and duration of the C5a-induced contraction. Indomethacin itself also caused a slight inhibition. In contrast, a combination of aspirin and diphenhydramine did not inhibit the initial portion of antigen-induced tracheal contraction any more than diphenhydramine alone and enhanced the later portion just as aspirin alone. Cross tachyphylaxis experiments demonstrated that antigen pretreatment significantly inhibited a subsequent C5a-induced tracheal contraction, though C5a pretreatment did not affect a subsequent antigen-induced contraction. Thus, cyclo-oxygenase products do contribute to C5a-induced tracheal contraction, and histamine participation in the presence of cyclo-oxygenase inhibitors is suggested. Our studies demonstrate the dissimilarities of C5a and antigen-induced contraction as regards inhibition by aspirin plus diphenhydramine, yet suggest common pathways leading to the contractile response as evidenced by cross tachyphylaxis experiments.

Animals↗

PubMed1988

Effect of disodium cromoglycate (DSCG) and antihistamines on postirradiation cerebral blood flow and plasma levels of histamine and neurotensin.

In an attempt to elucidate mechanisms underlying the irradiation-induced decrease in regional cerebral blood flow (rCBF) in primates, hippocampal and visual cortical blood flows of rhesus monkeys were measured by hydrogen clearance, before and after exposure to 100 Gy, whole-body, gamma irradiation. Systemic blood pressures were monitored simultaneously. Systemic arterial plasma histamine and neurotensin levels were determined preirradiation and postirradiation. Compared to control animals, the irradiated monkeys exhibited an abrupt decline in systemic blood pressure to 23% of the preirradiation level within 10 min postirradiation, falling to 12% by 60 min. A decrease in hippocampal blood flow to 32% of the preirradiation level was noted at 10 min postirradiation, followed by a slight recovery to 43% at 30 min and a decline to 23% by 60 min. The cortical blood flow for the same animals showed a steady decrease to 29% of the preirradiation levels by 60 min postirradiation. Animals given the mast cell stabilizer disodium cromoglycate and the antihistamines mepyramine and cimetidine before irradiation did not exhibit an abrupt decline in blood pressure but displayed a gradual decrease to a level 33% below preirradiation levels by 60 min postirradiation. Also, the treated, irradiated monkeys displayed rCBF values that were not significantly different from the nonirradiated controls. The plasma neurotensin levels in the irradiated animals, treated and untreated, indicated a nonsignificant postirradiation increase above control levels. However, the postirradiation plasma histamine levels in both irradiated groups showed an increase of approximately 1600% above the preirradiation levels and the postirradiation control levels. These findings implicate histamine in the postirradiation hypotension, but not necessarily in the direct responsibility for the decrease in regional cerebral blood flow seen immediately postirradiation in the primate.

Animals↗

PubMed1988

Clinical improvement in advanced cancer disease after treatment combining histamine and H2-antihistaminics (ranitidine or cimetidine).

In a randomized study 31 patients with advanced cancer disease in whom classical anticancer therapy had been abandoned received a daily combination of subcutaneous histamine and oral H2-antihistaminics. In 27 patients, treatment induced a marked clinical improvement as shown by a large rise in performance status (Karnofsky scale). Ten patients were still alive 3-14 months after initiation of treatment. Average survival in the 31 treated patients (172 +/- 113 days) was significantly longer than in 34 non-treated patients with similar advanced cancer (26 +/- 16 days, P less than 0.00001). In six treated patients, the size of liver and lung metastases decreased. Histamine was perfectly tolerated up to 4 mg/day.

Adult↗

PubMed1986

Mutagenicity studies of selected antihistamines, their metabolites and products of nitrosation.

Methapyrilene, four structurally related antihistamines, three metabolites of methapyrilene and two products of the reaction of methapyrilene with nitrite were all tested for mutagenicity to Salmonella typhimurium. The two products of the methapyrilene-nitrite reaction have also been identified as metabolites of methapyrilene. None was mutagenic alone, either with or without rat liver S-9 activation. After reaction with sodium nitrite in acetic acid solution (nitrosation), the products of five of the ten compounds were mutagenic. These compounds were methaphenilene, 2-thiophenemethanol, 2-thiophenecarboxylic acid, N-(2-pyridyl)-N'N'-dimethylethylenediamine and N-(2-thenylmethyl)-2-aminopyridine.

Aminopyridines↗

PubMed1980

The induction of unscheduled DNA synthesis by antihistamines in primary hepatocyte cultures.

The autoradiographic identification of chemically-induced, unscheduled DNA synthesis in primary cultures of adult rat hepatocytes is currently being validated as a predictive test for mutagens/carcinogens. Of 8 antihistaminic drugs tested, 2, pyrilamine maleate and tripelennamine HCl, were positive for unscheduled DNA synthesis. Further investigation of the mutagenic/carcinogenic potential of these compounds in alternate test systems is suggested.

Animals↗

PubMed1989

Effect of the antihistamine, methapyrilene, as an initiator of hepatocarcinogenesis in female rats.

The antihistamine methapyrilene was examined for its ability to initiate hepatocarcinogenesis in rats. Rats were first subjected to partial hepatectomy and then were intubated with one of four doses (30, 100, 200 or 300 mg/kg) of methapyrilene hydrochloride (or an equivalent amount of water for controls, or 10 mg diethylnitrosamine/kg for positive controls). Rats were then fed 0.05% phenobarbital in the diet for 3, 6 or 9 months. The number and volume of altered hepatic foci were quantified with the histochemical markers gamma-glutamyl transpeptidase, glucose-6-phosphatase, and ATPase. The number of foci induced was increased 2- to 4-fold by the highest dose of methapyrilene at all 3 time points, but the only statistically significant increase was produced by the 200 mg/kg dose after 3 months of promotion. This study shows that methapyrilene may act as a weak initiator.

Adenosine Triphosphatases↗

PubMed1993

Antinociceptive effects of H1- and H2-antihistaminics in mice.

1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistaminics in mice: the p-benzoquinone(PBQ)-writhing test and caudal compression test. 2. Mepyramine, lupitidine (SKF 93479), and famotidine produced significant antinociceptive effects dose-dependently, during both the PBQ-writhing and caudal compression tests. 3. However, ranitidine did not reveal any antinociceptive effect. 4. Icotidine (SKF 93319) produced significant antinociception and also augmented the analgesic effect of morphine, on the caudal compression test. 5. However, mepyramine, famotidine, and lupitidine did not affect morphine-induced analgesia on the caudal compression test and displayed a nonsignificant potentiation on morphine-induced analgesia in the PBQ-writhing test.

Analgesics↗

PubMed1994

Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current.

Antihistamines, more formally termed H1 receptor antagonists, are well known to exert sedative effects in humans, yet their locus and mechanism of action in the human brain remains unknown. To better understand this phenomenon, the effects of histamine upon human cortical neurons were studied using intracellular recordings in brain slices maintained in vitro. Bath application of 50 microM histamine induced a depolarization which could be attributed to reduction of a background voltage-independent "leakage" potassium current: the depolarization was associated with an increase in apparent input resistance, under voltage clamp its reversal potential approximated the potassium reversal potential, and the histamine-induced current exhibited little voltage dependence. The pharmacology of the histamine-induced depolarization of human cortical neurons was studied by use of both agonists and antagonists. Depolarizing responses were blocked by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine nor the H3 antagonist thioperamide. The H3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H1 receptor. These effects of neuronal histamine upon cortical neurons are likely to affect synaptic transmission in several ways. The depolarization per se should increase the likelihood that excitatory synaptic potentials will evoke an action potential. The increase in whole-cell input resistance evoked by H1 receptor activation should make the cell more electrotonically compact, thereby altering its integrative properties. We hypothesize that these mechanisms would allow histamine, acting at cortical H1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H1 receptors by systemically administered H1 receptor antagonists would be sedating.

Cerebral Cortex↗

PubMed1986

The influence of antihistamine compounds on the oral intake of different addictive drugs.

The influence of two antihistamines on the oral intake of various drugs with addictive potency was investigated in rats. Under the chosen conditions neither tripelennamine nor diphenhydramine have reinforcing properties. The reinforcing potency of addictive drugs is not augmented by the both substances. On the contrary, in some cases they led to a decrease in oral intake of the drug solutions offered.

Amphetamine↗

PubMed1992

The intravenous self-administration of antihistamines by rhesus monkeys.

Rhesus monkeys were trained to lever press for infusions of cocaine during daily, 1-h experimental sessions. Following stabilization of the cocaine-maintained baselines, various antihistamines were substituted for cocaine to determine whether they would be self-administered. The results indicated that all monkeys tested self-administered tripelennamine and chlorpheniramine. One monkey out of the four self-administered pyrilamine, but only at a single (300 microgram/kg) high dose. Phenyltoloxamine, cimetidine and hydroxyzine were not self-administered. These results further illuminate differences amongst H1 antagonists in their potential for self-administration and, when examined in context with other reports, suggest that stimulant-like properties may help mediate their reinforcing effects when present.

Animals↗

PubMed1993

Determination of mizolastine, a new antihistaminic drug, in human plasma by liquid-liquid extraction, solid-phase extraction and column-switching techniques in combination with high-performance liquid chromatography.

For the determination of mizolastine (2-[[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4- piperidinyl]methylamino]-4(3H)-pyrimidinone, SL 85.0324), a new antihistaminic drug, in human plasma, three methods were developed based on liquid-liquid extraction, solid-phase extraction and column-switching in combination with high-performance liquid chromatography with ultraviolet detection. The liquid-liquid extraction method included a back-extraction step that preconcentrates the drug into a small aqueous volume, resulting in very high sensitivity (0.5 ng/ml of plasma); it can be used in conventional bioanalytical laboratories that do not have sophisticated automatic devices. The solid-phase extraction method is performed by using a robotic system (Benchmate). It is completely automated from the initial sampling to the final injection into the chromatograph. It has a good sensitivity (1 ng/ml of plasma), but requires an expensive apparatus and skilled analysts. The column-switching method is based on a solid-phase extraction performed on-line with chromatographic analysis; it is not completely automatic, because some operations are performed manually. The device required for valve switching is not expensive and can be managed by a simple integrator or a personal computer; it is very easy to use and affords a sensitivity (2.5 ng/ml of plasma) that generally satisfies the needs of pharmacokinetic investigations of mizolastine. The conditions were similar for all the three methods: a C8 type column, an eluent of phosphate buffer and acetonitrile, and a spectrophotometric ultraviolet detector operated at 285 nm.

Autoanalysis↗