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Oxatomide was evaluated in a double-blind study of 35 patients with chronic urticaria. For 5 weeks patients received at random either 30 mg oxatomide b.i.d. or a placebo. Oxatomide significantly reduced not only the duration of the attacks but also the severity of erythema, lesions and itching. This lower level of suffering was clearly reflected by a diminished need for additional antiallergic medication. The overall response to treatment was rated excellent or good in 72% of the oxatomide-treated patients against only 23% of the controls which is a significant difference. Sleepiness was reported in 1 patient of each group.

Infection with Trichinella spiralis in mice was accompanied by allergic sensitization as evidenced by anaphylactic death after intravenous injection of the antigen. Pre-treatment of the animals with oxatomide, a new orally active anti-allergic drug, resulted in significant protection of the animals; the lowest effective dose of the compound was 1.25 mg/kg orally. In contrast to cyproheptadine, oxatomide offered little protection against serotonin toxicity in mice. The present data suggest that, in this model of systemic hypersensitivity, the anti-anaphylactic effect of oxatomide can be attributed mainly to inhibition of release of allergic mediators.

Plasma levels, biotransformation and excretion of oxatomide were studied after single oral doses of 14C-oxatomide in male rats, dogs and humans. Oxatomide was very well absorbed, and almost completely metabolized in the three species. Excretion of the metabolites was very rapid and complete within a few days; the 14C label was excreted more in the faeces (54-62%) than in the urine (27-40%). Major metabolic pathways of oxatomide were oxidative N-dealkylations at the piperazine nitrogens and at the benzimidazolone nitrogen in rats and man, and also aromatic hydroxylation at the benzimidazolone moiety in man. The main urinary metabolite in the three species was 2,3-dihydro-2-oxo-1H-benzimidazole-1-propanoic acid, resulting from the oxidative N-dealkylation at the 1-piperazine nitrogen.

Different types of anti-allergic agents have been compared for their ability to inhibit the antigen-induced contraction of isolated lung parenchymal strips and ilea of guinea pigs. Extremely low concentrations of the lipoxygenase inhibitor NDGA inhibit the contraction of the lung parenchymal strips and higher concentrations block the ileal phase II-contraction (both predominantly caused by the developing SRS-A), but do not inhibit ileal phase I-contraction (caused by released histamine). The H1-antihistamine clemastine predominantly antagonizes phase I of the ileum contraction, and the anti-allergic drug oxatomide reduces all three types of contraction. The degranulation inhibitor DSCG does not influence the contraction of the lung strip, but produces a slight inhibition of both ileal contractions. The PAF-antagonist BN 52021 influences these three contractions in the opposite way to DSCG. As these various types of anti-allergic agents influence these three contractions in a different manner, the models can be used for judging the mechanism of action of a new anti-allergic compound.

SUMMARY The antagonistic activity of oxatomide, and its effects on evoked histamine release and histamine-N-methyl transferase activity in skin, have been studied. Oxatomide antagonizes HI activity in a dose-dependent but non-competitive manner. It also shows seme atropine-like activity. Oxatomide did not cause detectable inhibition of antigen-stimulated histamine release from skin slices of sensitized guinea-pigs although the possibility that oxatomide may cause weak inhibition could not be excluded. In the presence of low concentrations of histamine, oxatomide suppressed human skin histamine-N-methyl transferase, but in the presence of higher substrate concentrations it enhanced activity of this enzyme. These observations; which were limited by the poor solubility of oxatomide in aqueous media, should encourage further in vivo studies of oxatomide's histamine-suppressing properties in the human subject.

Several Ca2+ antagonists with either Ca2+-entry blocking or calmodulin (CaM) antagonistic properties and antiallergic drugs were investigated for their effects on mediator release from mast cells induced by different secretagogues (compound 48/80, concanavalin A, antigen-IgE and Ca2+ ionophore A23187) and for their ability to inhibit the function of CaM or phospholipid/Ca2+-dependent protein kinase (C-kinase). The effects of the different agents--with the only exception of cromolyn sodium--on histamine release elicited by compound 48/80 correlated well with their actions on two CaM-dependent enzymes whereas the activity of C-kinase was far less altered, or not altered at all. CaM antagonism of cloxacepride, picumast, oxatomide, fendiline and bepridil correlated not only with the inhibition of exocytosis evoked by compound 48/80 but also with that induced by A23187, concanavalin A and antigen-IgE. This indicates an action of these substances distal to the generation of the Ca2+ signal since the various secretagogues elevate the intracellular Ca2+ concentration by different mechanisms. However, prenylamine and thioridazine inhibited concanavalin A- and antigen-IgE-induced mediator release more potently and more effectively than that elicited by compound 48/80 or A23187. Therefore inhibition of allergic histamine release by these drugs may in part be dependent on an impairment of the Ca2+ signal. Since for each of two agents inhibition of histamine release (evoked by different releasers) parallels that of serotonin release it may be concluded that these mediators are secreted via the same mechanism. The results obtained with agents exhibiting different pharmacological properties but which share one common property, namely antagonism of CaM, strengthen the view that CaM is involved in exocytosis of mediators from mast cells.

Ninety-one hay fever patients received either 0.5 mg/kg oxatomide b.i.d. or 0.4 mg/kg diphenhydramine b.i.d. in a two-month double-blind study. If necessary this dose could be doubled. The results showed that fewer oxatomide patients needed to double this starting dose and to use a nasal spray. Oxatomide proved to be more effective than diphenhydramine in limiting the severity of the hay fever attacks, as evidenced by the findings that oxatomide patients had fewer complaint-days, and that more of these patients were rated by the investigators to have excellent or good results. Apart from daytime fatigue, transient in several patients, no oxatomide-induced side-effects were found.

The antiallergic effectiveness of twelve compounds was studied in ascaris hypersensitive dogs by measuring allergen-induced skin reactions before and 1, 4, 20, and 72 hr after oral treatment. The specific serotonin S2-antagonist ritanserin at 2.5 mg/kg and the selective histamine H2-antagonist cimetidine at 10 mg/kg did not reduce the allergic wheals. Chlorpheniramine and clemastine were inactive at 2.5 mg/kg. The remaining eight compounds studied over a wide dose range produced peak activity at markedly different doses and time intervals (hr). The lowest oral ED50-values in mg/kg were: levocabastine: 0.0035 (4); R 57 959: 0.048 (20); astemizole: 0.13 (20); ketotifen: 0.20 (4); cyproheptadine: 0.21 (4); azatadine: 0.32 (4); oxatomide: 1.26 (20); terfenadine: 1.26 (1). The lowest oral ED50-values in dogs and in rats (compound 48/80 lethality test) were similar, the largest difference being a fourfold potency gain of oxatomide in dogs. The short-acting compounds in rats (azatadine, cyproheptadine, ketotifen, and terfenadine) had also a duration of action of less than 12 hr in dogs. Levocabastine, R 57 959, astemizole, and oxatomide acted more than 16 hr. Maximal inhibition of the allergic wheal volumes was highest with levocabastine (90%); it reached 80% with R 57 959 and ranged from 67 to 78% with the remaining compounds. On the basis of their activity characteristics in dogs, levocabastine and R 57 959 are potentially very effective antiallergic drugs.

This double-blind study suggests that oxatomide may be considered a first-line alternative in the treatment of allergic follicular conjunctivitis. For 4 weeks 18 patients were treated with oxatomide at a dosage of 30 mg b.i.d. A randomized control group of 17 patients received a placebo. Already after 2 weeks, and more marked after 4 weeks, oxatomide produced a significantly higher reduction of itching and follicles than the placebo, involving a lower use of supplementary antihistamine medication. Globally, an excellent or good result was obtained in 78% of the oxatomide-treated patients but only in 29% of the placebo-treated patients. In the drug group 1 patient had gastrointestinal complaints and 1 felt slightly sleepy.

A new type of antiallergic drug, oxatomide (60 mg daily), was compared with the antihistaminic, mequitazine (10 mg daily), in a 5-week double-blind randomized study involving 26 patients with chronic urticaria. In the 13 oxatomide-treated patients, papules, erythema and pruritus were significantly suppressed after 2 weeks, which was markedly more rapid than with mequitazine. Slight somnolence was reported by 3 patients on oxatomide and 1 on mequitazine; in the latter case, severe urine retention was also reported. Another patient on mequitazine had to discontinue treatment because of severe drowsiness.

The effects of the H1-antihistamines astemizole, oxatomide and pyrilamine, of the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), on the ionophore A23187 (5 mumol/l)-induced release of cysteinyl-leukotrienes (LT) and thromboxane (TX) B2 from mixed human leukocytes were investigated in comparison to those of the cyclooxygenase inhibitor indomethacin and the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA). In contrast to pyrilamine both astemizole and oxatomide inhibited the release of cysteinyl-LT and TXB2 with IC50 values between 4 and 23 mumol/l. Both astemizole and oxatomide were about twice as effective in inhibiting cysteinyl-LT release as compared to TXB2 release. Similar to astemizole and oxatomide the calmodulin antagonists trifluoperazine and W-7 inhibited the eicosanoid release. W-7 was, however, clearly less effective and in contrast to trifluoperazine no difference was observed in its potency to inhibit cysteinyl-LT or TXB2 release. The H1-antihistamines, astemizole and oxatomide as well as the calmodulin antagonists did not cause intracellular retention of the eicosanoids tested. The reference compounds indomethacin and NDGA proved to be the most potent inhibitors. The results demonstrate that the therapeutic antihistamines astemizole and oxatomide as well as the classical calmodulin antagonists trifluoperazine and W-7 are able to inhibit eicosanoid formation.

Fifty-six patients with chronic allergic rhinitis were selected for a randomized double-blind study comparing oxatomide with a placebo. At the end of the 1-month treatment period symptoms had disappeared or were markedly improved in 81% of the oxatomide-treated patients compared with only 17% of the placebo group. Therapeutic control was achieved in most patients with a dose of 30 mg bid. Improvements were characterized by a reduction in the number, duration and severity of episodes of rhinitis. Oxatomide also significantly reduced the requirements of patients for additional antiallergic medication. No significant side effects were reported.

Since the pharmacological treatment of allergic diseases is used in patients with alteration of the immune response due to atopy and possible concomitant infections, we have investigated the possible effects of such drugs as cromolyn, theophylline, ketotifen, oxatomide, astemizole, fenoterol, pirenzepine, and rosaprostol on the in vitro immune response, in order to obtain experimental data and, as a consequence, clinical conclusions. In a series of investigations by our group and other authors the following immunological parameters have been considered: T cell activation induced by different pathways (i.e. autologous stimulation, PHA, anti-CD3, -CD2 and -CD28 monoclonal antibodies), and lymphokine production (i.e. IL-1, IL-2 and gamma-IFN). For a more detailed experimental model the experiments have been performed both in bulk culture and by using T cell clones derived from the peripheral blood. The results show cromolyn to have an enhancing effect, theophylline and ketotifen a suppressing effect, whereas the remainder show no effect on the immune response. These data are considered and discussed from the aspect of their possible clinical relevance and also in light of the in vivo data previously reported.

Background Plasma membrane fluidity of polymorphonuclear leukocytes (PMN) was investigated in 10 allergic asthmatic children before and after oxato-mide treatment. Methods Membrane fluidity was studied by measuring the steady state fluorescence anisotropy of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) incorporated into polymorphonuclear leukocyte (PMN) plasma membranes. Results There was an increase in membrane fluidity at the surface of PMN from asthmatic children. Oxatomide treatment significantly decreased PMN membrane fluidity. Conclusions These data suggest that oxatomide may induce changes in the physicochemical properties of the PMN plasma membrane in asthmatic subjects. These changes may modify the functional activities of PMN.

Oxatomide is a new potent inhibitor of anaphylactic and allergic reactions. After oral administration, the compound both inhibits the release of endogenous histamine and prevents the effects of exogensous histamine, at comparable doses. The combination of these effects appears to be the basis of the effectiveness of oxatomide in allergic reactions and may lead to clinical application different from classical antihistaminics and from cromoglycate.

A double-blind trial comparing a new antihistaminic agent (oxatomide) with clemastine was carried out in 30 patients with chronic urticaria. The study included over-all clinical assessment by patient and clinician as well as determination of excretion of 1,4-me-thylimidazoleacetic acid determined by a reversed-phase ion-pair high-performance liquid chromatographic method. It was found that the effect of oxatomide was equal to that of clemastine.

RHC 2851 has been investigated for its antiallergic activity in three in vitro and two in vivo models of anaphylaxis. We have also compared its activity profile in these models with that of disodium cromoglycate (DSCG), doxantrazole, ketotifen and oxatomide. RHC 2851, given i.p., was 6 times more potent than DSCG, and given orally it was 3 times more potent than doxantrazole. As an inhibitor of mediator release, the activity profile of RHC 2851 was identical to that of DSCG in the following respects: inhibition of IgE-mediated in vitro release of histamine from rat mast cells (RMC) but not human basophils (HuB), possession of tachyphylactic properties and demonstration of rapid loss of inhibitory activity as a function of time before antigen challenge as well as inability to inhibit IgG1-mediated release of histamine, both in vitro and in vivo, and lack of mediator antagonist activity. Ketotifen and oxatomide did not inhibit either IgE or IgG1-mediated release of histamine in vitro or in vivo, and were potent mediator antagonists in vivo. We conclude that RHC 2851 is an orally effective inhibitor of mediator release with a mechanism of action similar to that of DSCG and different from that of ketotifen and oxatomide.

The anti-histaminic drugs ketotifen and oxatomide have a dual effect on rat peritoneal mast cells. At high concentrations they induce histamine release, whereas at low concentrations they inhibit secretion evoked by IgE-directed ligands. The latter effect is observed in the presence and absence of exogenous calcium. The significance of this result for the general mode of action of anti-anaphylactic drugs is discussed. Neither compound liberates histamine from isolated mesenteric cells from the rat or guinea pig, further emphasizing the functional heterogeneity of mast cells from different sources.

A series of 4-(diarylhydroxymethyl)-1-[3-(aryloxy)propyl]piperidines was synthesized and evaluated for antiallergy activity. Several analogues had potent activity in the passive foot anaphylaxis (PFA) assay, an IgE-mediated model useful in the detection of compounds possessing antiallergic activity. In particular 1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone (1, AHR-5333) was more potent than oxatomide and terfenadine in this assay.

Oxatomide, a histamine H1-antagonist, was also found to inhibit histamine secretion stimulated by allergen and other ligands in a variety of in vitro models: 1. Isolated rat peritoneal mast cells, stimulated to secrete by specific antigen, dextran and concanavalin A; 2. Antigen-stimulated histamine secretion by basophil leucocytes from patients with allergic asthma; and 3. Anti-IgE-induced histamine release from chopped human lung passively sensitized with IgE from allergic asthmatics. Although oxatomide was active in inhibiting histamine secretion stimulated by these various means, it possessed a histamine-releasing effect on its own when used in high concentration, particularly in rat peritoneal mast cells. This effect was less pronounced in human basophils, and was not observed in human lung mast cells. Thus, the inhibition and stimulation of histamine release by oxatomide seemed to be independent actions.

A series of 12-(cyclic alkylamino)-6H-indolo[2,1-c][1,4]benzodiazepines were synthesized that possess antihistamine and antiserotonin activities as well as ability to inhibit mediator release. Compound 6a, 12-(4-methyl-1-piperazinyl)-6H-indolo[2,1-c][1,4]benzodiazepine was a more potent inhibitor of serotonin release than disodium cromoglycate (DSCG) and ketotifen and approximately equivalent to oxatomide. In the in vivo tests (PCA and ALA), compound 6a was equivalent or superior to DSCG and oxatomide. These agents have potential for the treatment of a variety of allergic conditions.

A series of 12-(cyclic alkylamino)-6H-indolo[2,1-c][1,4]benzodiazepines were synthesized that possess antihistamine and antiserotonin activities as well as ability to inhibit mediator release. Compound 6a, 12-(4-methyl-1-piperazinyl)-6H-indolo[2,1-c][1,4]benzodiazepine was a more potent inhibitor of serotonin release than disodium cromoglycate (DSCG) and ketotifen and approximately equivalent to oxatomide. In the in vivo tests (PCA and ALA), compound 6a was equivalent or superior to DSCG and oxatomide. These agents have potential for the treatment of a variety of allergic conditions.

The effects of oxatomide on the release of histamine and leukotriene C4 (LTC4) from human lung fragments and granulocytes were examined and the findings compared with the effects of the antiallergic drugs ketotifen, azelastine and tranilast. Oxatomide inhibited the release of both histamine and LTC4 from human lung fragments in cases of passive sensitization with human IgE myeloma serum upon anti-ε stimulation. IC50 values for the release of LTC4 from human lung fragments were as follows: oxatomide, 2.35 × 10––5M; azelastine, 27.2 × 10––5M; ketotifen, 52.1 × 10––5M; tranilast, 62.9 × 10––5M. Oxatomide also inhibited the release of both histamine and LTC4 from human mixed leukocytes stimulated by the calcium ionophore A23187. IC50 values for the release of LTC4 from human mixed leukocytes were as follows: oxatomide, 1.67 × 10––5M; azelastine, 3.65 × 10––5M; ketotifen, 12.2 × 10––5M; tranilast, 15.1 × 10––5M. The effects of oxatomide on the release of LTC4 from purified human neutrophils and eosinophils were also given attention. Oxatomide inhibited the release of LTC4 from eosinophils more effectively than from neutrophils and mixed leukocytes. As there is evidence that eosinophils play an important role in the development of late asthmatic responses and/or in the aggravation of asthma, oxatomide is expected to be an effective treatment for such conditions.

The effects of oxatomide, a new anti-allergic drug, in protecting guinea pigs from acute anaphylactic shock have been evaluated by studying the morphologic changes in the lung with special focus on the topographical relationship between bronchiolar smooth muscle and peribronchiolar mast cells, during the anaphylactic reaction. After ovalbumin challenge of passively sensitized guinea pigs, the mast cells in the peribronchiolar area present the following characterstic alterations: general shape changes with the formation of multiple cytoplasmic pseudopods, a variable decrease in the number of granules, mitochondrial swelling and, most peculiarly, a consistent appearance of intranuclear microtubules. Cations, being localized with an oxalate-pyroantimonate precipitation technique, are displaced from the nuclei and the cytoplasm of mast cells that are presumed to be causally involved in the anaphylactic phenomenon. Guinea pigs, which have been orally treated with 2.5 mg/kg oxatomide before ovalbumin challenge show, together with a suppression of the anaphylactic symptoms, an almost total lack of the characterstic nuclear and mitochondrial changes in the peribronchiolar mast cells. These observations strongly suggest that at least part of the drug’s protecting effect can be attributed to its inhibiting action on mediator release from mast cells. The possible connection that might exist between mediator release, intracellular cation distribution and the appearance of intranuclear microtubules is discussed.

Oxatomide potently (ED50 0.9 mg/kg orally, -2 h) attenuates the reduction of pulmonary tidal volume elicited by PAF (250 ng/kg i.v.) in anaesthetized, ventilated and propranolol-treated guinea-pigs. The increase of the pulmonary inflation pressure elicited by PAF (40 ng/kg i.v.) in such animals, ventilated at a fixed tidal volume, is also significantly reduced by the compound, but substantially higher doses (5 mg/kg i.v., -15 min) are required. The potency of oxatomide in the latter respect (50.4% reduction) is equivalent to that of ketotifen at 5 mg/kg i.v. (55% reduction). In spontaneously breathing, anaesthetized guinea-pigs, oxatomide (5 mg/kg i.p., -1 h) significantly reduces the increase in pulmonary resistance, but not the reduction in dynamic compliance, elicited by PAF (30, 60, 90 ng/kg i.v.), suggesting a pharmacological interference mainly with PAF-induced processes in the larger airways. Changes in arterial blood pressure, haemoconcentration, thrombocytopenia and leukopenia induced by PAF in vivo, contraction of guinea-pig lung parenchymal strips, production of superoxide anion by alveolar macrophages, aggregation and release of ATP by platelets challenged with PAF in vitro are not affected by the compound. These observations suggest that oxatomide attenuates the PAF-induced pulmonary reactions by inhibiting the release and/or the effect of allergic mediators elicited by the phospholipid rather than by a direct antagonism at the PAF receptors.

The preparation of several derivatives to oxatomide (A), with the benzimidazolinone moiety replaced by another heterocyclic residue is described. In some cases changes to the basic chain of (A) were also considered. All the new compounds were evaluated as antihistaminics (H1) and antianaphylactics. The derivatives where the heterocyclic moiety was an unsubstituted or phenylsubstituted 2-pyrrolidone or 2-piperidone residue showed antihistaminic and antianaphylactic activities similar to those of oxatomide while modification of the basic side chain with elimination of the benzhydryl group, gave a complete loss of activity. The pharmacological screening was completed by the evaluation of the barbiturate induced sleep prolongation and of acute toxicity.

The effect of some drugs on phospholipase A2 (PLA2)-induced histamine release from rat peritoneal mast cells was investigated. 1. PLA2 (Naja naja) caused the release of histamine from rat peritoneal mast cells in a dose related fashion. 2. The release of histamine by PLA2 was decreased by the removal of each of calcium and glucose from the reaction medium (Tyrode's solution). 3. p-Bromophenacyl bromide and mepacrine, PLA2 inhibitors, inhibited the release of histamine caused by PLA2. 4. Cinnarizine and nifedipine, calcium channel blockers, and oxatomide, KC-404, tranilast and disodium cromoglycate, anti-allergic agents, also inhibited the PLA2-induced histamine release. 5. When prednisolone (0.5 mg/kg) was administered i.p. 2, 3 and 4 h prior to the harvest of the mast cells, the amount of histamine released by PLA2 ex vivo was significantly decreased. Hydrocortisone, prednisolone and dexamethasone clearly inhibited the release of histamine from mast cells when they were administered 4 h prior to harvest of the cells.

Sixty-three patients completed a double-blind placebo-controlled study of oral oxatomide (30 mg t.d.s.) in the management of seasonal allergic rhinitis and/or conjunctivitis. Hay fever symptom scores were significantly lower for oxatomide-treated patients than for the placebo group on the majority of days during periods of high pollen counts. Moreover, on days when pollen counts were 10/m3 or more, a statistically significant positive correlation between symptom score and pollen count was demonstrated for the placebo group but not for the oxatomide group. Oxatomide also appeared to be superior to placebo in terms of patients' requirements for supplementary mepyramine (Anthisan) tablets, and the doctor's global assessment. Side-effects were reported by four patients in the oxatomide group and by three receiving placebo.

Oxatomide inhibits the release of histamine from rat peritoneal mast cells in vitro induced by C 48/80, antigen, anti-IgE and ionophore A 23 187, without effect on non-specific release by n-decylamine. Its effect is concentration- and pH-dependent and decreases with increasing extracellular Ca2+-concentrations. Prolonged incubation does not enhance the inhibition, which is lost after one single wash-out. Aminophylline and isoproterenol are not potentiated by oxatomide. The present study points to an effect of oxatomide on a Ca2+-dependent process at the level of cell membrane common to antigen, C 48/80 and ionophore A 23 187.

The new antiallergic drug oxatomide was evaluated in 40 schoolchildren suffering from severe allergic seasonal rhinoconjunctivitis. Antihistamine drugs had earlier given insufficient symptomatic relief. Double–blind technique was used. There was no significant difference in effect between oxatomide, the antibistamine cinnarizine in combination with phenylpropanolamine and placebo. The results do not support the hypothesis that oxatomide is superiot to antibistamine drugs in the treatment of severe seasonal rhinoconjunctivitis.

The effect of oxatomide, an orally active antiallergic drug, on immunoreactive LTC4 (iLTC4) production has been studied in rat peritoneal exudate cells (PEC) and guinea-pig lung fragments using the calcium ionophore A23187 and specific antigen in vitro. Oxatomide (10(-5) M) inhibited iLTC4 release by 70% with A23187 from rat PEC, and by 48% with antigen from guinea-pig lung. Oxatomide is supposed to affect the biosynthesis pathway of leukotrienes, because oxatomide inhibits 5-lipoxygenase from guinea-pig peritoneal leukocytes with an IC50 17 microM. Oxatomide also depressed the release of PGD2 from rat peritoneal mast cells stimulated by A23187 (IC50 4.2 microM). The effects of oxatomide on iLTC4 and PGD2 release were more potent than other antiallergic drugs (DSCG, ketotifen, tranilast).

We evaluated the ability of morphine to release histamine when injected intradermally in man. Mathematic analysis of the dose-response (wheal) relationship suggested that two different effects were involved. The effect of low doses of morphine (0.05 to 1 µg) was clearly antagonized by naloxone (0.4 or 1.2 mg im 30 minutes before), whereas the effect of higher doses (5 to 50 µg) was not modified. The median effective doses of morphine (ED50) for the low dose range effect were 0.07 ± 0.01 and 0.08 ± 0.01 µg before naloxone and 0.14 ± 0.02 and 0.15 ± 0.03 µg after 0.4 and 1.2 mg doses, respectively. Astemizole (45 mg po 30 minutes before) and oxatomide (60 mg po 120 minutes before) produced similar inhibition of histamine-induced wheals, but there were clear differences in their effects on wheals elicited by morphine. Morphine ED50 values for the low dose range effect rose from 0.09 ± 0.01 to 0.20 ± 0.01 µg after astemizole and from 0.08 ± 0.01 to 0.46 ± 0.04 µg after oxatomide. Opiate receptors may be involved in some of the effects produced by morphine injection in the human skin, but morphine-induced wheals seem to offer a suitable model for the evaluation of agents capable of inhibiting histamine release in man. Clinical Pharmacology and Therapeutics (1985) 38, 365–370; doi:10.1038/clpt.1985.189

2016