[Assessment of hypersensitivity to honey-bee venom in beekeepers by skin tests]. / Valoración mediante pruebas cutáneas de la hipersensibilidad al veneno de abeja en apicultores.

BACKGROUND: Beekeepers are exposed to frequent honey-bee stings, and have the risk to develop hypersensitivity to bee venom, but long-term exposure can induce immune tolerance in them. Up to 30% of beekeepers show positive skin tests with honey-bee venom. The prevalence of systemic reactions to bee stings in beekeepers is from 14% to 42%. OBJECTIVE: To know the prevalence of hypersensitivity to honeybee venom in Mexican beekeepers and non-beekeepers by the use of skin tests. MATERIAL AND METHODS: A group of 139 beekeepers and a group of 60 non-beekeeper volunteers had a history and physical related to age, sex, family and personal atopic history and time of exposure to bee stings. Both groups received intradermal skin tests with honey-bee venom, 0.1 mcg/mL and 1 mcg/mL, and histamine sulphate 0.1 mg/mL and Evans solution as controls. The skin tests results of both groups were compared by chi-squared test. RESULTS: Of the group of beekeepers, 116 were men (83%) and 23 women, average age was 39.3 years, had atopic family history 28% and personal atopy 13%, average time of exposure to bee stings was 10.9 years, skin tests with honey-bee venom were positive in 16.5% and 11% at 1 mcg/mL and 0.1 mcg/mL, respectively. In the non-beekeepers group venom skin tests were positive in 13.3% and 6.7% at 1 mcg/mL and 0.1 mcg/mL. We did not find significant differences between the two venom concentrations tested in both groups, neither in the number of positive skin tests between the two groups. CONCLUSIONS: We found hypersensivity to honey-bee venom slightly higher in the beekeepers than in the group apparently not exposed. Both honey-bee venom concentrations used did not show difference in the results of the skin tests. The similarity of skin tests positivity between both groups could be explained by immune tolerance due to continued exposure of beekeepers.

ANTECEDENTES: los apicultores están expuestos frecuentemente a picaduras de abejas y tienen el riesgo de volverse hipersensibles al veneno de abejas, pero la exposición a largo plazo puede inducir tolerancia inmunológica. Hasta 30% de los apicultores tienen pruebas cutáneas positivas con veneno de abeja. La prevalencia de reacciones sistémicas por picaduras de abejas en los apicultores es de 14 a 42%. OBJETIVO: conocer la prevalencia de hipersensibilidad al veneno de abeja en apicultores mexicanos y no apicultores, mediante la aplicación de pruebas cutáneas. MATERIAL Y MÉTODOS: estudio transversal que se incluyeron 139 apicultores y 60 voluntarios no apicultores se les elaboró su historia clínica con referencia a la edad, sexo, antecedentes familiares y personales atópicos y tiempo de exposición a picaduras de abejas. A los dos grupos se les aplicaron pruebas cutáneas intradérmicas con veneno de abeja con 0.1 y 1 mcg/mL, y como testigos sulfato de histamina 0.1 mg/mL y solución de Evans. Los resultados de las pruebas cutáneas se compararon entre los dos grupos mediante chi cuadrada. RESULTADOS: del grupo de apicultores 116 fueron hombres (83%) y 23 mujeres, la edad promedio fue de 39.3 años; refirieron atopia familiar 28% y atopia personal 13%; el tiempo de exposición promedio a picaduras de abejas fue de 10.9 años; las pruebas cutáneas con veneno de abeja fueron positivas en 16.5 y 11% a concentraciones de 1 y 0.1 mcg/mL, respectivamente. En el grupo de no apicultores las pruebas cutáneas con veneno resultaron positivas en 13.3 y 6.7% a concentraciones de 1 y 0.1 mcg/mL, respectivamente. No se observaron diferencias significativas entre las dos concentraciones de veneno probadas en ambos grupos, ni en el número de pruebas cutáneas positivas entre los dos grupos. CONCLUSIONES: se encontró hipersensibilidad al veneno de abeja ligeramente mayor en los apicultores que en el grupo aparentemente no expuesto. Las dos concentraciones de veneno de abeja probadas no mostraron diferencia en los resultados de las pruebas cutáneas.

Antihistamine treatment for allergic rhinitis: different routes, different outcomes?

Allergic rhinitis is one of the most common chronic disorders in the United States, causing patients significant discomfort and interfering with quality of life and functioning. Histamine is the primary mediator in the development of allergic rhinitis symptoms and is a primary therapeutic target. Guidelines, both in the United States and globally, recommend antihistamines as first-line therapy of allergic rhinitis. This article discusses the outcomes associated with intranasal versus oral administration of antihistamines. Both oral and intranasal antihistamines are approved for the first-line treatment of allergic rhinitis and both formulations result in a reduction in symptoms and an improvement in quality of life. Intranasal agents may be preferred in patients in whom nasal congestion is particularly bothersome or in cases where a more rapid onset of action is desired. Oral agents would be a better choice in young children (especially children who are at risk of developing asthma), in cases of poor medication compliance, and in patients who are bothered most by histamine-associated symptoms, such as itching or red and watery eyes. Both oral and intranasal antihistamines are safe and well tolerated and meet the needs of patients with allergic rhinitis, especially those with mild to moderate disease.

Histamine in Macaca mulatto monkey cardiac sympathetic nerve system: a morphological and functional assessment.

Our previous study demonstrated the co-localization of histamine with norepinephrine (NE) within superior cervical ganglia (SCG), and the release of histamine from sympathetic nerve endings of guinea pig evoked by stimulations. We have now further investigated that whether the histamine can be synthesized, stored and released from the sympathetic nerve systems of Macaca mulatto monkey, and investigated the modulation of the sympathetic endogenous histamine release through histamine H(3) receptor in the monkey cardiac sympathetic nerve system. Double-labeled immunofluorescence technique was applied to investigate co-localization of histamine and NE in SCG of Macaca mulatto monkey. The cardiac sympathetic nerve terminals (synaptosomes) of Macaca mulatto monkey was prepared and depolarized with 50 mmol/L K(+). Histamine released from synaptosomes was detected by spectrofluorometer and regulations of histamine release through Ca(2+), Ca(2+)-channel blockers, H(3)-receptor agonist (R)-alpha-methylhistamine and histamine H(3)-receptor antagonist, thioperamide were observed. Co-localization of histamine and NE was identified within the same neuron of SCG. Release of histamine was Ca(2+)-dependent and inhibited by N-type Ca(2+)-channel blocker omega-conotoxin, but not affected by the L-type Ca(2+)-channel blocker lacidipine. Compound 48/80, a mast cell releaser, did not affect cardiac synaptosome histamine exocytosis. Cardiac synaptosome histamine release was augmented by the enhanced synthesis of histamine or the inhibition of histamine metabolism. Histamine H(3)-receptor activation by (R)-alpha-methylhistamine inhibited high K(+)-evoked histamine release and thioperamide blocked the effects of (R)-alpha-methylhistamine. These results firstly showed that histamine co-existed with NE within sympathetic neurons of monkey and the exocytosis of histamine from sympathetic terminals could be regulated by presynaptic histamine H(3) receptors. Sympathetic histamine may act as a neurotransmitter to modulate sympathetic neurotransmission.

Dermal microdialysis in the dog: in vivo assessment of the effect of cyclosporin A on cutaneous histamine and prostaglandin D2 release.

Dermal microdialysis, a relatively noninvasive technique, allows investigation of the changes in cellular mediators released during cutaneous allergic responses. This technique was used to evaluate the effect of cyclosporin A, an immunosuppressive drug used for treatment of canine atopic dermatitis, on the cutaneous release of two pro-inflammatory mediators following intradermal allergen challenge. Four beagle dogs spontaneously sensitized to Ascaris suum were treated for 1 month with oral cyclosporin A. At days 0, 15 and 30 of the treatment, dialysis probes were inserted into the skin of the back, and 20 microL of A. suum antigen was injected intradermally at each site. At timed intervals, dialysate was collected and assayed for histamine and prostaglandin D(2) and the wheal area was measured. Mean histamine concentration and wheal area were significantly lower at days 15 and 30 of treatment, compared with day 0. However, prostaglandin D(2) concentration was not significantly reduced. The inhibition in histamine release after intradermal challenge, by cyclosporin, confirms its anti-inflammatory action in the dog. Dermal microdialysis provides a useful tool for investigating canine allergic reactions and their modulation by drugs.

Biochemical and clinical assessment of histamine blockade.

The effects of antihistamines on biochemical stress indicators and on psychomotor and physiological functions were studied in 60 healthy patients receiving in a randomized, double-blind study either 25 mg promethazine, 150 mg ranitidine, both drugs or placebo (n = 15 in each group). Different aspects of the premedications were evaluated by determining various hormone, neurotransmitter and neurotransmitter metabolite levels in blood and cerebrospinal fluid, and subjectively using questionnaires concerning the quality of the preoperative night's sleep and visual analogue scales, and objectively by measuring changes in blood pressure and heart rate, impairment of vigilance with the Maddox wing apparatus and the critical flicker fusion threshold test. The relationships between the subjective assessments and the biochemical stress indicators were also investigated. There were no differences between the study groups in the quality of the preoperative night's sleep, estimated fear, apprehension or dizziness, or in the various physiological stress indicators. Only few statistically significant correlations were found between the subjective and biochemical assessments. It is concluded that histamine receptor antagonists used in clinical doses do not interfere with the biochemical, clinical preoperative, and physiological responses.

Pharmacological assessment of spantide II analogues.

We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5-7.5 at the NK1 receptor and of 5.9-7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than spantide II in causing histamine release from rat peritoneal mast cells.

Assessment of histamine release from basophils in whole blood by benzylpenicilloyl poly-L-lysine in penicillin-sensitized patients.

Histamine release from basophil granulocytes in whole blood by benzylpenicilloyl poly-L-lysine (PPL) was investigated in 7 patients with penicillin allergy. All patients presented with systemic immediate hypersensitivity reactions after i.v. administration of penicillin G. Total histamine (of 7 patients) ranged from 27.5 ng/ml to 62.1 ng/ml (mean 43.2 ng/ml). The spontaneous histamine release ranged from 0.15% to 5.1% (mean 1.8%) of the total content. Addition of PPL in various concentrations resulted in values between 0.8 and 9.6%. Although PPL is a reliable allergen for prick- and intradermal testing in the diagnosis of penicillin allergy--demonstrating a histamine liberation in the skin--the in vitro experiment using the same allergen showed no histamine release above 10%. Using a threshold of 5% out of 7 patients, 4 (57%) would show a positive histamine release. Therefore it might indicate that in penicillin allergy a threshold of 5% must be used. In addition, basophils in whole blood and skin mast cells may be activated differently.

[Occupational hypersensitivity to spiramycin. Report of a case]. / Hipersensibilidad ocupacional a espiramicina. A propósito de un caso.

A case report of occupational hypersensitivity to Spiramycin. Rhinoconjunctivitis and spasmodic cough are reported in a 34 year-old female handling spiramycin powder in a pharmaceutical factory. The symptoms appeared within the first few hours of coming into contact with the drug and continued for several hours after leaving her place of work. The patient had no personal case history of atopy. Results for prick-test with extracts using a concentration of 1/100 (w/v) were positive, as were results por intradermical tests with a solution using a concentration of 1/10.000 (w/v). The diagnostic was confirmed with the application of a nasal provocation test. Our criteria to determine positivity to this test was according to Bachman (1) and the European Committee of Rhinomanometry. On our suggestion the patient was transferred to another section of the pharmaceutical company whereupon all symptoms disappeared immediately and no further allergic reactions to drugs were registered. This case suggest that reactions to a chemical product may involve immunological mechanisms.

Evaluation of cutaneous responses and lung function from exposure to opiate compounds among ethical narcotics-manufacturing workers.

We recently demonstrated morphine-6-hemisuccinate-human serum albumin conjugate (M-6-HS-HSA)-specific IgG in serum from ethic narcotics-manufacturing workers. In this article, we present results of epicutaneous tests to opiate compounds and lung-function studies in these same workers. Thirty-nine workers, exposed to opiates, were evaluated for possible work-related changes in lung function and were administered a questionnaire concerning opiate exposure and health history in February 1988. In December 1988, 33 employees with occupational exposure to opiates, six other workers (New Jersey referent) employed at the same factory with minimal exposure to opiate compounds, and 17 nonexposed individuals from Cincinnati, Ohio, were subjected to epicutaneous threshold testing with a panel of six opiate compounds and nine common aeroallergens. In opiate-exposed workers, significantly lower epicutaneous threshold concentrations were detected (compared to New Jersey referent and Cincinnati control subjects) for dihydrocodeine (p less than 0.01), hydrocodone (p less than 0.05), codeine (p less than 0.01), and morphine (p less than 0.05). Significant associates existed among epicutaneous threshold concentrations between the agents tested; that is, individuals with a positive morphine skin test would generally have a positive codeine skin test, etc. Atopic status (positive cutaneous test results to two or more of nine common aeroallergens) was not significantly associated (p greater than 0.05) with positive opiate skin sensitivity. Although the mean cross-shift decrements in FEV1 for all workers were nonsignificant, five opiate-exposed individuals demonstrated cross-shift decrements in FEV1 of greater than 10%. Daily maximum-minus-minimum changes in workweek PEFR (PEFRmax-min) were significantly reduced for Monday through Thursday (p less than 0.05) compared to PEFRmax-min changes during a nonwork, nonexposure 3-day weekend. Ten exposed workers demonstrated daily PEFRmax-min changes of greater than 20%, suggesting acute airway obstruction. Increased cutaneous reactivity to opiate compounds among opiate-exposed workers may reflect development of pharmacologic hyperresponsiveness to opiate compounds.

Pharmacokinetics, effect on clotting tests and assessment of the immunogenic potential of hirudin after a single subcutaneous or intravenous bolus administration in man.

The pharmacokinetics and the anticoagulant effects of hirudin were investigated in 12 healthy volunteers after single subcutaneous or intravenous bolus administrations. Hirudin concentrations in citrated plasma and urine were determined with a radioimmunobioassay, which detects the inhibitor by its thrombin-binding capacity. Plasma profiles could be adequately described by the equation for an open two-compartment model (intravenous route) and by the Bateman equation (subcutaneous route), respectively. Within 24 h half of the administered hirudin dose was recovered in the urine in biologically active form. The prolongation of clotting times (activated partial thromboplastin and thrombin time) was dependent on the hirudin plasma concentration. All test subjects tolerated the hirudin injection without visible or measurable side effects. No hirudin-specific antibodies were found after single parenteral administrations.

Regulation of histamine turnover via muscarinic and nicotinic receptors in the brain.

To clarify the regulation of central histaminergic (HAergic) activity by cholinergic receptors, the effects of drugs that stimulate the cholinergic system on brain histamine (HA) turnover were examined, in vivo, in mice and rats. The HA turnover was estimated from the accumulation of tele-methylhistamine (t-MH) during the 90-min period after administration of pargyline (65 mg/kg, i.p.). In the whole brain of mice, oxotremorine, at doses higher than 0.05 mg/kg, s.c., significantly inhibited the HA turnover, this effect being completely antagonized by atropine but not by methylatropine. A large dose of nicotine (10 mg/kg, s.c.) also significantly inhibited the HA turnover. This inhibitory effect was antagonized by mecamylamine but not by atropine or hexamethonium. A cholinesterase inhibitor, physostigmine, at doses higher than 0.1 mg/kg, s.c., significantly inhibited the HA turnover. This effect was antagonized by atropine but not at all by mecamylamine. None of these cholinergic antagonists used affected the steady-state t-MH level or HA turnover by themselves. In the rat brain, physostigmine (0.1 and 0.3 mg/kg, s.c.) also decreased the HA turnover. This inhibitory effect of physostigmine was especially marked in the striatum and cerebral cortex where muscarinic receptors are present in high density. Oxotremorine (0.2 mg/kg, s.c.) and nicotine (1 mg/kg, s.c.) also decreased the HA turnover in the rat brain. However, these effects showed no marked regional differences. These results suggest that the stimulation of central muscarinic receptors potently inhibits the HAergic activity in the brain and that strong stimulation of central nicotinic receptors can also induce a similar effect.

Mast cells in the guinea pig superior cervical ganglion: a functional and histological assessment.

We have previously found that antigenic stimulation of mast cells in the guinea pig superior cervical ganglion leads to membrane depolarization of principal neurons and a long-term increase in the efficacy of ganglionic transmission. In this study experiments were conducted to discern the histological, immunological and pharmacological characteristics of the mast cells within the superior cervical ganglion. Mast cells within the superior cervical ganglion could be stained with toluidine blue or berberine sulfate, the latter indicating that heparin-like molecules were present in the granules. Stainable mast cells were distributed throughout the ganglion with no gross evidence of regional localization. The number of mast cells stained with toluidine blue was reduced significantly (P less than 0.01) in contralateral ganglia that had been exposed to the sensitizing antigen (ovalbumin), indicating antigen-induced degranulation. The superior cervical ganglion contained 208 +/- 6 picomole of histamine (mean +/- SEM, n = 66). Ovalbumin evoked the release of histamine from the superior cervical ganglion in a concentration-dependent fashion. At maximally effective concentrations, ovalbumin released 33 +/- 2% of the total histamine stores (mean +/- SEM, n = 61). Similar values were obtained with antigen-challenged stellate ganglia. A temperature of 37 degrees C and an extracellular calcium concentration of 1 mM was required to elicit optimal antigen-induced responses. In addition to releasing histamine, antigenic stimulation of the ganglion resulted in a 3- to 5-fold increase in the synthesis and release of arachidonic acid metabolites including peptidoleukotriene, thromboxane B2, prostaglandins (PG) E2, F2 alpha, D2, the PGD2 metabolite 9 alpha 11 beta-PGF2, and the prostacyclin metabolite 6-keto PGF1 alpha. Various putative mast cell secretagogues were examined for their ability to activate the superior cervical ganglion mast cell, as indicated by evoked histamine release. In contrast to rat peritoneal mast cells, high concentrations of substance P, compound 48/80, and nerve growth factor failed to stimulate the ganglion mast cells. Preganglionic nerve stimulation, electrical field stimulation of axons and cell bodies, or depolarizing concentrations of potassium chloride also failed to activate the superior cervical ganglion mast cells. These results suggest that substances released by membrane depolarization do not influence the function of the resident mast cells. The results demonstrate that the mast cells within sympathetic ganglia can be actively sensitized to respond to specific antigen. These mast cells are similar to lung parenchymal mast cells with respect to histological, immunological and pharmacological characteristics...

Allergic and pseudo-allergic reactions caused by penicillins, cocoa and peppermint additives in penicillin factory workers examined by basophil histamine release.

Allergic and pseudo-allergic reactions were examined in penicillin factory workers exposed to the dust of preparations of pivampicillin and pivmecillinam. Among 14 workers basophils from five persons showed histamine release by challenge with penicillins, whereas no release was observed in controls of non-atopic individuals not working with the manufacturing of penicillin. Positive skin response was obtained in four workers by path testing and in three persons by scratch test revealing late but no immediate response. All the eight workers who were also exposed to flavour additives used in the penicillin preparations showed histamine release by cocoa and peppermint. The release was not changed by removal of immunoglobulins from the basophil cell surface and the additives caused a similar release in the controls. The histamine release caused by cocoa and peppermint therefore depend on non-immunological mechanisms, i.e. pseudo-allergic reactions which might contribute to the symptoms in penicillin factory workers.

Oxatomide: in vivo assessment of antagonistic activity, and effects on histamine release and enzymatic histamine degradation in skin.

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 H1 activity in a dose-dependent but non-competitive manner. It also shows some 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 subjects.