Effectiveness of pharmacologically induced histamine release in the treatment of common diseases in dogs

Effectiveness of pharmacologically induced histamine release in the SERGIO DE LA TORRE PÉREZ GUILHOU AND GABRIEL DE ERAUSQUIN
Basophile leukocytes and mastocytes are the main effectors of the hypersensitivity mediated by immunoglobulin E, or f the type I, and they have an important role in protection against viral infections. This form oh hypersensitivity is clinically manifested by means of a series of cardiovascular, respiratory, cutaneous, gastrointestinal and systemic alterations, caused by the release of immunomediators. The mechanism of this reaction has been ascertained mostly by conducting studies on preparations of skin and pulmonary tissue, thus demonstrating the sequential participation of antibodies (E immunoglobulin, typically) ,……. Cells and immunomediators. When the antigen’s way of entry,(or, in experimental preparations of the anti- IgE antibody) is cutaneous, the initial reaction is typically pruritus and erithema, followed later by a poorly delimited edematous and painful area persisting for one or two days. At the histological level, the initial reaction is correlated with mastocyte degranulation and associated superficial edema, while in the subsequent inflammatory reaction ad infiltrate is found, composed of basophiles, neutrophiles, oesinophiles, monocytes and lumphocytes, with associated vascular damage. The antibodies that are responsible for this form of hypersensibility were identified by Prausnitz and Kustner(1921) and were given the name of “ regains”; they may be composed by immunoglobulins of the type G or E. Both these isotypes( Ige and IgG) have opposed regulatory functions, so that the LgE antibodies are responsible for the atypical reactions, while the IgE point to the normal immune response to the allergenic antigens(Blaser, 1996). The production of IgE is controlled genetically, so it varies with the species and the race, buy in all the cases studied, it requires the cooperative action of T Lymphocytes, activated by interleukina 4( Blaser, 1996).The proportion between the production of IgE and antibodies depends on the rate of secretion of interleukina 4 and gamma interferon, which in this turn, is regulated by the concentration of antigen and the degree of activation of T lymphocytes(Mc • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
Hugh et al, 1995; Akdis et al , 1997; Blaser et al 1998). Genetic control of the production of Ige antibodies takes place at this stage, since the signal of activation for T Lymphocytes is generated from the union of the antigen-protein complex(composed by one protein from the major histocompatibility complex and the antigen) with the lymphocyte receptor (TcR) ( Blaser,1996; Blaser et al, Ige is firmly and persistently bound to its cellular receptor (called Fc RI)) located in mastocytes and basophile leukocytesA. second receptor with less affinity ( Fc RII) has been shown in platelets, macrophages and eosinophiles. The mastocytes express the large number of Fc RI receptors with an Ige molecule, resulting in the activation of adenylcyclase and phospholipase, arachydonic acid release, influx of calcium into the mastocyte and eventually, degranulation and release of mediators into the extracellular liquid. Basophile Leukocytes suffer a similar, but slower, process of activation . Besides the activation mediated by IgE, this hypersensitivity process may be activated by some anaphylatoxins (which operate of the specific receptors of the complemental system, C3a and C5a, or, like apitoxin (bee’s poison ?), activate mastocyte degranulation by way of enzymes) and by non immunological stimuli, like certain antibiotics( with molecules of high ionic The degranulation of mastocytes and basophiles results in the release of pre- formed molecules or primary Immunomediators (such as histamine, serotonin or adenosine) and of molecules actively synthesized, or secondary immunomediators (such as prostaglandins and leukotrienus) (?). Besides, the interaction of IgE antibodies with mastocytes results in the release of interleukina 4, that in its turn, promotes the hypersensitivity cycle from very beginning( by activating basophiles) (Dudler et al, 1995). The negative control of the cycle depends on the production of gamma interferon, promoting the synthesis of IgG antibodies that, in their turn, exert a negative modulation on the production of specific IgE( Seeger et al , 1998), and on interleukins release ( • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
The participation of the cellular component of type I immunity in viral diseases is well documented. It has been demonstrated, in particular, that viral infections produce a systemic or local release of histamine in a large variety of species and of clinical or experimental condictions.An incomplete list may comprise the presence of histamine in the blood of guinea pigs experimentally infected with the junin virus (Yanovsky, 1965); of the release of histamine and secondary mediators in the bronchioalveolar washings of dogs (Miura et al, 1989) and humans (Clementsen et al, 1989) with influenza and of human infants with bronchiolitis ( Schoner et al, 1990) and of mastocyte degranulation in the peritoneum of dengue infected mice ( Sanchez- Legran et al, 1986). The release mechanism however, may depend on the type of virus involved. Paramixoviruses release histamine from the basophiles through a mechanism that is independent of IgE, and that is also independent of calcium( that is, the mechanism of exocytosis does not operate) Sanchez – legran and smith, 1989). Besides, the influenza and the syncytial respiratory virus markedle increase the release of histamine brought about by a great variety of immunological and non (Busse et al , 1983; Clementsen Et al, 1990) through the catalytic action of a neuraminidase( Clementsen et al, 1991), A similar increase has also been shown in the leukocytes of patients infected whit HIV (Pedersen at al, 1987; Miadonna et al, 1990), but unlike those viruses, HIV requires IgE to produce an increment in the release of histamine( Pedersen et al, 1989). In spite of all the evidence discussed, the psychopathological meaning of the effect of viral epithelium, dogs do not present either edema of the glottis of bronchosconstriction. This communication summarizes the results of the use if drugs inducing a hypersensitivity reaction of the type I for treatment of common viral diseases in dogs a general veterinary clinic Materials and Methods
• Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
The animals treated are consecutive cases from Dr. de la Torre`s clinic that were examined by one of the three staff veterinarians between may 8, 1991 and October 16, 1998. In all cases the diagnosis was established by the characteristics of the patient and routine lab test, not confirmed by microbiological tests. The results of the active treatments are compared with the means results of 2000 consecutive cases treated in the same center between The diagnosis of canine distemper was arrived at in the presence of bilateral purulent conjunctivitis, mucus in the nose (Fig 1.A), hyperkeratosis of the snout and paw pads, (Fig. 1.B), coughing and sneezing. The typical course of the disease, from the appearance of the conjunctivitis to either resolution or death is between 4 and 8 weeks (with a mean of 42 days). With conventional treatment (penicillin and streptomycin, calcium/ B Complex, cough preventives and antipyretics) the frequency of death is 40 % The progress of the disease is marked by the appearance of compromise of the nervous system, ( convulsions, paraplegia myoclonus), complications due to prostration and The diagnosis of severe viral gastroenteritis was arrived at in the presence of listleness, and exaggerates hydro aerial noises in abdomen accompanied by vomiting and whitish diarrhea of a characteristic smell during the first day, followed by frothy and sanguinolent vomiting, and sanguinolent diarrhea ( Fig 1. C), with dehydration, prostration and death between the second and the fifth day. The frequency of death with conventional symptomatic treatment ( metoclopramide, streptocarbocaftiazol, fluid therapy with saline solution Na=142 mEq/1,K=4.5mEq/1- and penicillin/ streptomycin) is 50 %. The diagnosis of canine papilomatosis was arrived at in the presence of warts in the mouth of dogs between the ages of 4 and 18 moths ( Fig 1. D ), typically during dentition change, and in weak or immunocompromised dogs . The progress of disease is marked by an increment in the number of warts over a period of several weeks( up to three months followed by spontaneous healing. Conventional treatment consists in surgical removal and/or levamizol, or in case the owner expresses this preference, and expectant behavior. • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
Treatments
Apitoxin) (bee’s poison) (with natural bee’s sting) One or two stings were administered in the animals rib cage, after local subcutaneous anesthesia with lidocaine (Fig 2.A), every 5 to 7 days still Amphoteric Oxytetracycline (Ketorolac RM) Was administered in doses ranging from 0.5 to 2 ml subcutaneously, in the rib cage every 96 hours till resolution. Oftalmotrofica vitaminada (Lab. Farve) Was administered in doses of 1cm3/per20 kg., subcutaneously in the rib cage, every 72 hours and not more than three times per patient, in general, one or two injections. The treatment cause a characteristic hypersensitivity reaction of the type 1. A local inflammatory reaction appears in the site of application from 30 to 60 minutes after the injection, ( Fig.2.B), that progresses during 48 hours. In the case of oxytetracycline, the local, reaction is followed by an indurations with a diameter of 3 cm, persisting for three weeks. Systemically the treatment causes marked sedation and appetite loss for 24 to 36 hours. In some cases, and especially with apitoxin, and Oftalmotrofica vitaminada, the treatment causes swelling of the faces, eyes, ears and lips with generalized erithema of the body Analysis of Results
As primary result, the mean duration of each disease, with or without the treatment under study were compared. Secondly, morbidity and mortality rates were studied for each of the diseases in both groups ( the treated and the untreated) and the morbidity corresponding to the adverse effects of each treatment was communicated. Results were statistically compared through the use of the test for the comparison of median populations z(n>400 per group). • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
Viral Respiratory infection (canine distemper) the results of the pro-
histaminergic treatment in dogs with distemper are summarized in Fig. 3. The treatment produced a marked reduction (and highly significant statistically, p<0.001, n=800) of the total duration of the disease. The magnitude of the effect seems to be correlated with the degree of hypersentivity response of the type 1 obtained as a consequence of the treatment Viral Gastroenteritis
Conventionally treated viral gastroenteritis results in a death rate of 50 %. In dogs treated with an induction of a hypersensitivity reaction of the type 1, mortality is reduced to 10 %, and this, in those animals having liver compromise at the time of presentation. And what is more, in these cases a severe hypersensitivity reaction, frequently worsens and complicates the pathology. In those animals responding well to treatment, the duration and severity of the disease are markedly reduced ( Fig.4 p<0.001, n=800). Tabla tolerance to treatment and adverse effects
Amphoteric tetracycline produces an intense local reaction, painful for 24 to 72 hours, but usually well tolerate. It is important to warn the dog owner of this, so as to avoid the concurrent use of anti- inflammatory drugs. Bees poison produces a similar local reaction, but the repeated use of very near sites for stings causes skin necrosis in spots of about 2 to 3 cm in diameter. This complication was present in 5 % of the cases in our universe of around 150 The Hypersensitivity reaction causes moderate systemic effects, consisting • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
The most remarkable adverse effect is local pain, that must not be treated with local anti-inflammatory drugs ( including steroids) or antipyretics. The pet owner should be alerted as regards these predictable secondary effects for him or her Discussion
The results reported here show the marked effect caused by the induction of hypersensitivity of the type 1 in the rates of duration, morbidity and mortality in three viral diseases in dogs. But, given the clinical character of the observation and, particularly the historical character of the controls used, conclusions must be cautious. In spite of this, and considering the weigh of the publications in favor of the role played by the Immunity mediated in this way in viral diseases in diverse species, including dogs, it is useful to consider, heuristically at least, the probable mechanics of operation of the anti-viral effect. As seen in the introduction there is a close relationship between the existence of viral infections and the immunohumoral response mediated by histamine. It would appear reasonable then, to suggest that the agent responsible for the anti viral effect mediated by the hypersensibility reaction of the type 1 is the release Certainly the anti viral effect of histamine, and of several of its metabolic derivates against the vaccine virus has been demonstrated “in vitro “(towianska et al, 1986).In human subjects, too , a cirrekatuib gas been established between the antiviral efficiency of gamma interferon in hepatitis C and blood level of histamine, so that it is only the patients with a high degree of histamine in blood who develop a good therapeutic response ( wejstal, 1998). In vivo, antiviral effect of histamine apparently involves several mechanisms. In the first placve, histamine activates the elimination of infected cells mediated by NK Lymphocytes through H2 receptors (hell strand et al, 1995) On the other hand, in cells infected with the virus of human immunodeficiency (HIV), the mechanism mediated by hypersensitivity of the type 1, results in the elimination of infected cells and the reduction of the viral replication rate (Krauss et, al, 1995)both mediated by the release of histamine in the basophiles. • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,
Thus, it appears likely, that the remarkable beneficial effects derived from the use of anaphylatoxins, or other pharmacological mediators in the hypersensitivity reaction of the type 1 in viral diseases in dog should depend, in part at least of the direct anti viral effect of histamine, in combination with the elimination of the infected cells by way of an H” mechanism. Since the treatment is usually well tolerated and has no significant morbidity either acute or chronic it would seem that an ample and systematic study of this application through controlled clinical tests would be well justified. However in the cases there is evident hepatic compromise, it is prudent to reduce the doses and to use cautious clinical judgment, for the treatment may complicate the course of the disease. Keeping these restrictions in mind, the judious clinical use of the prhistaminergic therapy on empirical bases would appear reasonable, at least in those cases it is justified by the adanger of deats of the animal, or the lack of • Veterinary Surgeon De la Torre Veterinary Clinic Mendoza, Argentina.
• Physician and Doctor of Medicine, Washington University, St Louis MO,

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