Effect of patch type on the cumulative irritation potential of 4 test materials.

BACKGROUND: Many different patch systems are available for predicting contact dermatitis. It is important to determine the ideal patch to meet the objective of the testing method. OBJECTIVE: The 21-day cumulative irritation test is well accepted for predicting irritation after repeated exposures. The patch type must allow separation of materials to predict irritation potential in the marketplace. Three patch systems were compared to determine which best provides this separation and prediction. METHODS: Four test materials were evaluated using 3 patch systems in a 21-day cumulative irritation test. Tested were water, 0.06% sodium lauryl sulfate (SLS), and 2 underarm products (UAP), one having lower and one having higher irritation potential. The patch types were; Webril pad and 8-mm and 12-mm Finn Chambers. RESULTS: Both the 12-mm Finn Chamber and Webril pad showed the ability to differentiate the higher irritating UAP and the 0.06% SLS from the lower irritation UAP product and water. The 8-mm Finn chamber was less discriminating, showing the 0.06% SLS to be the same as water and the lower-irritating UAP. CONCLUSION: The Webril pad and the 12-mm Finn Chamber are better at discriminating irritation potential than is the 8-mm Finn Chamber. The 12-mm Finn Chamber might also allow discrimination with a lower degree of irritation.

Gallium arsenide-induced increase in serum corticosterone is not responsible for suppression of the IgM antibody response.

Previous investigations demonstrated gallium arsenide (GaAs) to be an immunosuppressive agent that alters the function of all cell types involved in the generation of a primary antibody response. In those studies, GaAs was administered as a particulate compound that remained in the lung at least 14 days after exposure. The extended presence of the particulate in the lung may induce a stress response that leads to the release of endogenous corticosteroids. In addition, some of the observed immunomodulatory effects of GaAs were similar to immunological alterations reported to be induced by corticosteroids. The present studies were designed to determine whether suppression of the immunoglobulin (Ig) M antibody-forming calls (AFC) response by GaAs was a result of a GaAs-induced increase in serum corticosterone. GaAs (50-200 mg/kg) significantly decreased the weights of both the thymus and spleen and the cellularity of the spleen. In addition, there was a GaAs-induced decrease in the CD4+/CD8+ thymocyte subpopulations and a concomitant increase in CD4+ and CD8+ cells. Within the spleen, there were no alterations in the percentages of CD4, CD8 or Ig-positive cells. However, when expressed as an absolute cell number, there was a 50% decrease in the numbers of CD4+ and CD8+ cells in the spleen. GaAs also dose-dependently suppressed (50-75%) the IgM AFC response. The GaAs-induced changes in cell populations and immune organ weights were correlated with an increase (6- to 10-fold) in serum corticosterone levels. The treatment of mice with the glucocorticoid antagonist mifepristone (also called RU 486) blocked the observed alterations in splenic and thymic cell populations induced by GaAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotransmitter feedback is not important in modulating the noradrenergic component of responses of rat vas deferens to twin pulse electrical field stimulation.

1. Drug effects on the full time-course of tension responses of the rat vas deferens to challenges of twin pulse field stimulation (TPFS) were examined. A microprocessor-controlled system was used to regulate stimulus delivery, on-line data collection and subsequent data analysis. 2. The second, noradrenergic phase of the response to the second stimulus of TPFS was missing when the interpulse interval was set at 3 s but was progressively restored as the interpulse interval was extended to 120 s. 3. With a 3 s interpulse interval, the missing second phase of the response to the second stimulus was not restored by the selective alpha 2-adrenoceptor antagonists yohimbine, imiloxan or idazoxan, indicative that alpha 2-adrenoceptor-mediated feedback inhibition of noradrenaline release is not the predominant mechanism modulating this response component. 4. Incubation with the P1-purinoceptor antagonist 8-phenyl-theophylline also failed to restore the missing noradrenergic component in the response to the second stimulus of TPFS. 5. Nevertheless, both responses to TPFS were impaired by the selective alpha 2-adrenoceptor agonist clonidine and by the P1-purinoceptor agonist 2-chloroadenosine, indicating the presence of functional presynaptic receptors of both types. These agonist-induced inhibitory effects were readily reversed by those antagonists which had failed to restore the missing noradrenergic component in the second response to TPFS.

Separation of putative alpha 1A- and alpha 1B-adrenoceptor mediated components in the tension response of the rat vas deferens to electrical field stimulation.

1. The effects of the putative alpha 1B-adrenoceptor antagonist, chloroethylchlonidine (CEC), on tension responses of the rat isolated whole vas deferens to single and multiple pulses of electrical field stimulation have been evaluated by use of a microcomputer system which enables the averaging of like-responses throughout their time course. 2. CEC (10(-7) to 3 x 10(-6) M) selectively and in a concentration-dependent manner blocked the noradrenergic component of the response to a single field stimulus in the absence or presence of nifedipine (10(-5) M, which blocked the purinergic but not the noradrenergic component of the response). The concentration-response curve of the vas to exogenously-applied noradrenaline (NA) was unaffected by CEC (10(-6) M) but was flattened by nifedipine (10(-5) M). 3. The tension response to 10 Hz trains of pulses was biphasic, with an early (less than 2 s) and a plateau (greater than 4 s) phase. We deduce from our pharmacological analysis that the early phase contains a putative alpha 1B-adrenoceptor component (susceptible to CEC or prazosin but not to nifedipine) and a P2-purinoceptor component (susceptible to suramin or nifedipine) whereas the plateau phase contains an alpha 1A-adrenoceptor component (susceptible to prazosin or nifedipine but not to CEC) and a P2-purinoceptor component (susceptible to suramin or nifedipine). 4. We suggest that the putative alpha 1B-adrenoceptors may be functionally confined to the synaptic region whereas the putative alpha 1A-adrenoceptors are excluded from this region. Trains of pulses would allow NA to accumulate and spill out beyond the synaptic region to reach and activate the putative alphalA-adrenoceptors.

A comparison of the effects of 6-hydroxydopamine and reserpine on noradrenergic and peptidergic nerves in rat brown adipose tissue.

While co-existence of noradrenaline and neuropeptide-Y is, by inference, indicated in sympathetic nervous projections to rat interscapular brown adipose tissue by the fact of their coincident disappearance from the tissue following 6-hydroxydopamine treatment of the animals, reserpine treatment produced a divergent effect suggestive of possible differences either in the localisation and/or release mechanisms for noradrenaline and the peptide within the same neurons. Thus reserpine produced a depletion of noradrenaline but not of the immunohistochemically demonstrable neuropeptide-Y in the nerve plexuses of the tissue.

Evidence for a postsynaptic action of neostigmine on muscarinic receptors in the anococcygeus muscle of the rat.

In the rat anococcygeus muscle neostigmine induces atropine-sensitive, significant leftward displacements of the log concentration-response curves to both noradrenaline and 5-hydroxytryptamine. Responses to high K+ were also potentiated by neostigmine. However, high K+ elicited only small and irregular overflows of tritium from [3H]noradrenaline pre-incubated tissues, in contrast to the large overflow elicited by field stimulation. In addition guanethidine blocked responses to field stimulation but not those to high K+. This is consistent with the dose-related responses to high K+ being elicited postsynaptically. These results indicate that postsynaptic muscarinic receptors are involved in the potentiation by neostigmine of rat anococcygeus muscle responses to field stimulation or exogenous agonists, possibly by an action on receptor operated ion channels. Additional support for a postsynaptic site of action comes from the failure of neostigmine to potentiate tension responses to nerve or field stimulation in the chick expansor secundariorum, a muscle which is devoid of postsynaptic muscarinic receptors.

The effects of neostigmine on the response of the rat anococcygeus muscle to field stimulation are not a consequence of cholinesterase inhibition.

Neostigmine (5 X 10(-7) to 5 X 10(-6) M) and physostigmine (10(-5) M) each augment the responses of the rat anococcygeus muscle to field stimulation whereas iso-OMPA (5 X 10(-6) to 5 X 10(-4) M) or BW 62c47 (5 X 10(-7) to 5 X 10(-5) M) do not. At a concentration of 10(-5) M, neostigmine. BW 62c47 and iso-OMPA respectively produced a 48, 50 and 68% inhibition of cholinesterase activity in homogenates of anococcygeus muscle. The ED50 for cholinesterase inhibition by neostigmine (1.4 X 10(-5) M) is approximately 15 fold greater than the ED50 for the augmentation of the response to field stimulation (9.5 X 10(-7) M). It is concluded that the action of neostigmine in augmenting the response of the rat anococcygeus muscle to field stimulation is not a consequence of cholinesterase inhibition even though stimulation of muscarinic receptors is implicated.

Neostigmine augments responses of the rat anococcygeus muscle to field stimulation.

1 The effects of neostigmine on noradrenergic transmission have been studied in the field stimulated, isolated anococcygeus muscle of the rat. 2 In those muscles where the excitatory response to field stimulation was not completely inhibited by guanethidine (5 X 10(-6) to 10(-5) M) or phentolamine (10(-6) M), atropine (5 X 10(-8) M) gave no further inhibition of the response. 3 The shape of the response to field stimulation was altered in a dose-dependent manner by neostigmine (5 X 10(-7) to 5 X 10(-6) M), such that a 'shoulder' appeared during the relaxation phase. The 'shoulder', present at all stimulation frequencies tested between 3 and 40 Hz, was abolished by atropine (5 X 10(-8) M) and unaffected by tubocurarine (10(-6) M). 4 Neostigmine (2.5 X 10(-6) M), whether alone or in the presence of atropine (5 X 10(-8) M), had no effect on the uptake or stimulation-induced release of [3H]-noradrenaline. 5 Using electron microscopy, small Schwann/axon bundles close to smooth muscle cells rarely showed cholinesterase staining, whereas larger bundles at the outer serosal aspects of the muscle exhibited dense staining. 6 It is concluded that the observed effects of neostigmine are not due to a presynaptic effect on noradrenergic transmission.

Observations on the muscle abnormality of the human sigmoid colon in diverticular disease.

1 Pharmacological experiments were performed on circular and longitudinal muscle strips of sigmoid colon from diverticular disease specimens, and their responses compared with those of similar muscle strips from sigmoid colon resected from carcinoma (control). 2 The longitudinal muscle strips from diverticular disease specimens were significantly less responsive to acetylcholine, histamine or noradrenaline than control longitudinal muscle strips. 3 The responses of the diverticular circular muscle strips showed a small decrease to acetylcholine, a small increase to noradrenaline and no change to histamine when compared to control strips.

Drugs and human memory: effects of low doses of nitrazepam and hyoscine on retention.

1 The effects of diazepam (5 mg) and hyoscine hydrobromide (0.3 mg) were assessed in two memory tasks: short-term retention of digit strings and the free recall of items from categorizable lists. 2 One hundred and two healthy subjects were tested in an independent-groups design. Subjects were assigned randomly to either placebo, diazepam or hyoscine groups. Treatments were administered orally under double-blind conditions. 3 The short-term retention of digits was impaired to an equivalent degree and locus for both drugs (P less than 0.05). This effect was ascribed to the action on primary memory. 4 The drugs produced no significant effects on the recall of categorizable lists either in terms of the number of words recalled or the cohesiveness of categorical recall. 5 These results demonstrate that drugs of different pharmacological actions produce isomorphic psychological deficits in memory and that 'anti-memory' effects on one task should not be extrapolated to all aspects of memory.

The effects of low doses of diazepam on human performance in group administered tasks.

1. The effects of diazepam in 5 mg dosage were assessed on a range of psychological tasks. Seventy-eight healthy subjects were tested in an independent groups design; subjects were randomly assigned to either control, placebo or drug group. Treatments were administered orally under double blind conditions. 2. Auditory vigilance performance was unimpaired, in terms of (a) correct detections, (b) false alarms or (c) the subjects' estimates of the duration of the task. 3. The short term retention of digit strings was impaired by diazepam (P less than 0.05), especially for those digits presented in the middle of the sequence. 4. Searching for a few letters among many was significantly impaired by diazepam (P less than 0.01). 5. Diaepam had no effect on performance at a mental arithmetic task; neither was there a placebo effect. 6. Results were discussed in the light of the characteristics of drug sensitive tasks. It was concluded that characteristics such as feedback of results, monotony, and memory load are more likely to be drug sensitive when in combination than in isolation.

Observations on the production of frozen-dried thin sections for electron microscopy using unfixed fresh liver, fast-frozen without cryoprotectants.

Thin sections of unfixed liver, fast-frozen without cryoprotectants, have been cut using conditions under which momentary thawing of the sections is unlikely to occur. A transfer stage which facilitates this procedure is described. Sections show hole damage probably due to ice-crystal formation during the freezing process and have well defined edges, but despite hole damage, some morphological features of the cell are discernible. Presumptive mitochondria appear smaller in frozen sections than in conventional Araldite sections. Sections devoid of hole damage have indistinct edges and are presumed to have undergone transient thawing. Carbon coating of freeze-dried sections to exclude atmospheric moisture during transference of sections to the electron microscope (EM) appear unnecessary as regards preservation of morphological structure. The results are discussed in relation to the limitations of the method and the potential value of the technique.

An inhibitory effect of atropine on responses of the vas deferens of the mouse to field stimulation.

1 Atropine is shown to impair responses of the vas deferens of the mouse to field stimulation by acting at a site proximal to the smooth muscle cells. 2 The inhibitory effect of atropine is prevented by desmethylimipramine and reversed by dexamphetamine, and appears similar to the adrenergic-neurone blockade of guanethidine. 3 Electronmicroscopical studies show the presence in vas of presumptive noradrenergic axons which have acetylcholinesterase reaction product associated with their axolemmae. 4 These results are discussed in relation to the controversial hypothesis of a 'cholinergic link' in noradrenergic transmission.

Noradrenaline and motor transmission in the vas deferens of the mouse.

1. A comprehensive investigation of the innervation of the vas deferens of the mouse was made using pharmacological, histochemical and electronmicroscopical techniques. 2. Guanethidine inhibited the response of the vas to transmural stimulation and potentiated the response to noradrenaline (NA). Phentolamine abolished responses to NA and to transmural stimulation. 3. After chemical sympathectomy degenerative changes were seen in presumptive noradrenergic axons; histochemical fluorescence due to catecholamines was absent. The vas failed to respond to transmural stimulation, and a 10-fold increase in sensitivity of the vas to exogenous NA was observed. 4. NA is shown to diffuse slowly through this tissue whose muscle cells are densely packed. This is disscussed in relation to the apparent "insensitivity" of the vas to exogenous NA. 5. A cholinergic component was identified histochemically which did not contribute significantly to the motor response of the vas as chemical sympathectomy abolished completely the motor response elicited by transmural stimulation. 6. It is concluded that NA is the motor trnasmitter for the smooth muscle of the vas deferens of the mouse.

3 H-noradrenaline-accumulating ability of cholinergic nerve terminals in cat sympathetic ganglia.

1. After incubation of pieces of cat posterior mesenteric ganglion in [(3)H]-noradrenaline solution, the localization of the isotope was assessed by electron-autoradiography.2. Significantly higher concentrations of [(3)H]-noradrenaline were found over acetylcholinesterase-positive axons terminal on ganglion cells than in adjacent background areas.3. [(3)H]-Noradrenaline was not accumulated by ganglion cells under these circumstances.4. The significance of these findings in relation to previous physiological and pharmacological investigation is discussed.