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The purpose of this study was to compare the cumulative fraction absorbed-time profile method of paracetamol with the shorter proportional area under the curve method of paracetamol by pretreating normal volunteers with cisapride, codeine and metoclopramide with and without neostigmine. Both methods are sensitive and comparable in defining early phase liquid gastric emptying, with the proportional area under the curve method having the advantage of providing the relevant information with a two-hour study period.

The biphasic cutaneous hypersensitivity response elicited by intradermal administration of S. haematobium antigen to patients with schistosomiasis may be used as a model for drug effects on cell dynamics. As the effects of H1- and H2-blockade, and the possible involvement of H3-receptors, have not been elucidated, we have examined the effects of combinations of cetirizine, cimetidine and betahistine on the response of patients with confirmed schistosomiasis. The skin blister technique was used. After intradermal administration of antigen, blister fluid containing inflammatory cells was collected on microscope slides at 6 and 24 h, and a differential cell count was done; and the area of induration was measured at 0.25, 1, 6 and 24 h. These baseline tests were repeated after 3 days of pretreatment with cetirizine 20 mg/d, after the addition of cimetidine 1200 mg/d for 3 further days, and finally after adding on betahistine 32 mg/d for 3 days. Simultaneous H1- and H2-blockade with cetirizine plus cimetidine caused a significantly greater reduction in induration than cetirizine (H1-blockade) alone; the reductions from the baseline value were 70%, 78%, 89%, 97%, and 33%, 53%, 43%, 30%, at times 0.25, 1, 6 and 24 h, respectively. The triple combination with the addition of betahistine (H1- and H2-agonist and H3-antagonist) resulted in reductions of 37%, 63%, 95% and 97% at the same times. The most striking changes in cellular dynamics were a significant increase in eosinophil (6 h) and neutrophil (6 h) vacuolation, and enhancement of monocyte (24 h) and basophil (6 h) accumulation, when the betahistine was added.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of the anticholinergic agent, propantheline, the opiate, codeine, and the prokinetic agent, metoclopramide, on oral-caecal transit time and on the absorption of theophylline from a sustained-release formulation were examined in six healthy male volunteers. 2. A cross-over randomised sequence design was followed, allowing at least 2 weeks interval between studies. On each occasion 500 mg theophylline in a sustained-release formulation was taken simultaneously with 2 g sulphasalazine at zero time. On three of the four occasions one of the following treatments was given concurrently at -0.5 h, +3.5 h, and +7.5 h: 30 mg codeine phosphate, 30 mg propantheline bromide, or 10 mg metoclopramide monohydrochloride. 3. The appearance of sulphapyridine in the plasma was used to assess oral-caecal transit time and the mean fraction absorbed-time profile of theophylline was calculated from serial serum theophylline concentration measurements using the Wagner-Nelson method. 4. Codeine increased the mean (s.d.) oral-caecal time (h) significantly (5.14 +/- 0.94) compared with the control value (3.78 +/- 0.34). Propantheline inhibited peristaltic contractions to such an extent that the oral-caecal transit time in five of the volunteers was between 9 and 25 h, while sulphapyridine appeared in the 9 h serum sample of the sixth. Metoclopramide did not significantly alter the oral-caecal transit time. 5. Despite the observed changes in oral-caecal transit time the rate and extent of theophylline absorption was similar with all regimens.

Levamisole is known to have anti-anergic properties in immune compromised, but no or only marginal effects in immunologically competent subjects. In this study the possibility that levamisole would act as an 'immunoadjuvant' with roxatidine, a histamine H2 receptor blocker, is explored in healthy animals. Sixteen female, inbred Sprague-Dawley rats acted as lymphocyte donors and were treated for 8 days with either a roxatidine-levamisole combination, or levamisole alone, or roxatidine alone or placebo. Five randomly bred guinea pigs and eight inbred BD IX rats acted as lymphocyte acceptors. The in vivo effects of the four treatment modalities on transferred lymphocytes were expressed as the sizes of the allogeneic and xenogeneic graft-versus-host reactions as well as the radioactivity in each AGVHR. The combination of levamisole and roxatidine significantly augmented the cell mediated immune response in vivo and resulted in the most reactive lymphocytes as indicated by the AGVHR's and XGVHR's. These cells mediated reactions with significantly larger wheals as well as more lymphocyte proliferation in each reaction site than those caused by either levamisole or placebo treatment.

Dosing intervals for sustained-release theophylline preparations depend on the rate of formulation absorption, the rate of elimination by the patient, and clinically acceptable fluctuations in serum concentration. A comparative study of intersubject variation in fraction absorbed-time profiles, a process-independent method of comparing rates of absorption, was performed with 6 sustained-release preparations in 6 healthy male volunteers. The sulphasalazine/sulphapyridine method of assessing orocaecal transit time was implemented so that upper gastrointestinal and colonic absorption could be estimated. Time until 90% absorption varied from 4.43 hours to 7.46 hours and the mean percentages of theophylline remaining to be absorbed from the colon were limited to between 7.5% and 29.7% with the various formulations. There was a great intersubject variability in the rate of theophylline absorption and also considerable differences among the volunteers in their formulation-to-formulation absorption profiles. Promotional literature depicting mean or group data masks this variability in absorption profiles. Because host factors related to gastro-intestinal physiology impose highly variable theophylline absorption profiles on sustained-release formulations, it is technically impossible to formulate a suitable once-a-day product for the majority of patients.

Allergic cutaneous challenge causes mast cell and basophil mediator release which recruit inflammatory cells to the site of antigen administration. This secondary cell infiltration and mediator release is responsible for the changes seen during the late phase of allergic diseases. In this randomised, double-blind, cross-over, placebo controlled study, it was demonstrated that, at steady-state drug concentrations, chlorpheniramine reduced the wheal-and-flare reaction by about 50% compared to the 75% reduction, on average, by cetirizine and ketotifen. Cetirizine significantly reduced eosinophil vacuolisation at all observation periods, i.e. 2,6,10 and 24 h, and also inhibited basophil accumulation significantly at 10 h (75% reduction), while chlorpheniramine had a negligible effect on these variables. These changes would indicate that the late phase reaction was modified, especially as eosinophil vacuolisation is known to correlate with late phase intensity, T-lymphocyte infiltration and subsequent tissue damage. It further supports previous speculation that cetirizine inhibit late histamine release by acting on basophils. The extent of induration in the late phase reaction did not differ significantly among the three treatments. Cetirizine and ketotifen, noticeably although not significantly, reduced eosinophil and lymphocyte recruitment. As these two antihistamines differ structurally and in regard to receptor specificity, it is possible that they exert their actions on other, unspecified, receptors.

1. To test the hypothesis that the in vivo inhibition of angiotensin converting enzyme in a patient who presents atopy, results in a significant increase in cutaneous bradykinin and prostaglandin production, the effect of enalapril on the cutaneous hypersensitivity reaction was examined in 10 atopic volunteers. 2. A crossover study design was used and volunteers were randomly allocated to treatment with either enalapril (10 mg) alone, or in combination with indomethacin (75 mg), with and without ketotifen (1 mg). Drugs were administered twice daily for 2 days. 3. Allergen (Southern Grass Mix) was administered intradermally 2 h after last drug dosage and the surface areas of the immediate wheal-and-flare-reactions were measured 15 min later. The late phase of the cutaneous response was evaluated 6 h later by determining skinfold thickness and surface area. 4. Enalapril alone had no effect on any of the parameters measured. 5. The cutaneous hypersensitivity reaction was significantly reduced with regard to both immediate and late cutaneous responses when the indomethacin and ketotifen combination was added to enalapril therapy. 6. When only indomethacin was added to enalapril pretreatment the flare reaction was significantly reduced, but whealing was unaffected. 7. This study presents further evidence that mast cell mediators other than prostaglandins are involved in the cutaneous hypersensitivity reaction. Furthermore, that endogenous bradykinin production after enalapril pretreatment either never reaches the supraphysiological concentrations used in previous experiments, or that bradykinin is rapidly and effectively broken down to inactive peptides by other carboxypeptidase enzymes.

Histamine-2 receptor blocker therapy (cimetidine) was combined with nonspecific Bacillus Calmette-Guerin (BCG) immunomoderation in order to obtain a more directed immunostimulatory response. To establish this the local xenogeneic graft-versus-host reaction (XGVHR) was used as objective in vivo parameter. In this placebo-controlled experiment the lymphocytes of inbred Sprague-Dawley rats were transferred intradermally to partially immunosuppressed guinea pigs after treatment with either or both of the test substances. The surface areas of the local XGVHRs were evaluated 48 and 72 h later. The local XGVHRs caused by lymphocytes obtained from rats treated with either cimetidine or BCG alone did not differ significantly from those caused by lymphocytes obtained from placebo-treated rats. Combination therapy, however, resulted in significant augmentation of the local XGVHR, clearly indicating a synergistic effect between cimetidine and BCG. The XGVHR appears to be a satisfactory model for evaluating drug effect on cell-mediated immune reaction in vivo.

The in vivo pharmacological effects of cimetidine on delayed hypersensitivity reactions in healthy volunteers were studied using the tuberculin skin test as parameter. Cimetidine clearly enhanced this reaction when it was administered well before antigenic stimulation.

A case of congenital lateral pharyngeal cyst is reported and a classification of pharyngeal cysts is given.

Microbiological analyses and antibiotic sensitivity tests were done on 26 patients with acute maxillary sinusitis during the first 9 months of 1986. Positive cultures were obtained in 23 of the patients, with anaerobes cultured in 13 (50%). Haemophilus influenzae was cultured in all non-producers of beta-lactamase. Therapy with erythromycin and chloromycetin appeared to be equally effective in aerobic cases and metronidazole was effective in all anaerobic cases.