Itching for change: Embracing modern flea and tick product development

The development and regulatory approval of ectoparasiticides, including flea and tick control products, involves decades-old methods and the use of large numbers of animals to evaluate toxicity and efficacy. Animals also are used to rear (breed and feed) fleas and ticks for later use in testing. Non-animal methods for regulatory-required testing and rearing currently exist and, with further development, others could soon become available. Here we provide an overview of the state-of-the-science of non-animal methods for rearing and regulatory-required efficacy testing of flea and tick control products. Several remaining challenges as well as recommendations on the steps needed to replace animals in the evaluation of these products are discussed.     

Toxic epidermal necrolysis associated with flea dips.

A 5-y-old intact female Himalayan cat was dipped with an organophosphate-based compound for flea infestation. The animal subsequently died of organophosphate intoxication. Skin lesions present at necropsy were diagnosed microscopically as toxic epidermal necrolysis. A 5-y-old spayed female Corgi dog was dipped with a d-limonene-based compound for flea infestation. The dog subsequently developed a bullous skin disorder which rapidly progressed to severe coalescing necrotizing dermatitis with large areas of skin sloughing. The dog was treated for a tentative diagnosis of toxic epidermal necrolysis with a short course of corticosteroids and extensive supportive care and recovered completely. Flea dip preparations have the potential to induce severe immune-mediated dermatopathies such as toxic epidermal necrolysis.     

Medication error due to ambiguous labelling of a commercial product

Medication errors may involve prescribing, dispensing, preparation and administration of drugs. We report a case in which an administration error occurred due to ambiguous labelling of a commercial drug. Tablets were packed in sets of two tablets per blister with the print on the blister 'Zelitrex 500', making the amount of drug per tablet unclear. A short survey among nurses and pharmacy technicians showed that the majority interpreted the strength of the tablets incorrectly. This case shows that, despite regulations for controlling and accepting labelling before marketing, ambiguous labelling may occur and can lead to medication errors.     

Hypotensive effects of hydroxylamine in intact anesthetized dogs and cats

When given IV in bolus doses to intact anesthetized dogs or cats, hydroxylamine hydrochloride produced transient but precipitous falls in the mean arterial blood pressure in a dose-related manner, as well as a significant methemoglobinemia. The half-time for recovery of the mean arterial pressure was also dose-related. These effects were very similar to those elicited by comparable doses of sodium nitrite, except that the half-recovery time for return to normal blood pressure was somewhat longer with the nitrite. Although hydroxylamine has long been known to relax vascular smooth muscle in vitro, we are not aware of previous demonstrations of hypotensive effects in vivo. Acute poisoning by either nitrite or hydroxylamine is apt to result in both an anemic hypoxia due to methemoglobinemia and a stagnat (hypokinetic) hypoxia due to direct vasodilation. Hydroxylamine, but not nitrite, also appeared to stimulate respiration possibly through an effect on the chemoreceptors of the carotid body.     

Adrenal toxicity in dogs and cats as a contributing cause of hormonal and immune destabilization

The adrenal cortex is regarded as the organ most vulnerable to toxicity within the endocrine system. The production of cortisol, among the many steroidal hormones produced by the cortex, may suffer as a result. In a veterinary clinical practice, household dogs and cats with a wide variety of diseases ranging from allergies to cancer commonly have a cortisol deficiency or defect that triggers endocrine imbalances and immune system destabilization. The causes of deficient cortisol are linked primarily to genetics but also to acquired adrenal damage likely stemming from environmental toxins. An innovative blood test to determine relevant endocrine-immune imbalances in pets and a treatment method based on low-dosage steroidal medication, as a form of cortisol replacement therapy, are described. Despite a prevailing reluctance to use steroidal medications long term because of the fear of side effects, extended and even life-time usage of these medications at low, physiologic dosages has been applied successfully for decades and appears to be gaining wider acceptance. The validity of a combined testing and treatment method for humans based on the veterinary model deserves investigation as a tool with which to identify and correct toxic damage to adrenal function.     

Clinical features and epidemiology of tick typhus in travelers

BACKGROUND: Epidemiologic features of tick typhus among German travelers has not been surveyed recently. METHODS: Clinical features, travel and medical histories in 78 patients with tick typhus who presented to a German outpatient clinic for Infectious and Tropical Diseases were investigated, in order to identify common epidemiological factors and potential strategies of prevention. Diagnosis was confirmed by serological detection of IgG- and IgM-antibodies to Rickettsia conorii by indirect immunofluorescence. RESULTS: The majority of patients (71.8%) had visited southern Africa prior to presentation. All patients presented with fever as the main symptom. An eschar was still present in 68 patients (87.2%) with regional lymphadenitis in 19.2%. However, only a minority of patients (17.9%) remembered a tick bite at the location of the eschar. CONCLUSION: Efforts to reduce the incidence of tick typhus in travelers should focus on preventive measures targeting behavioral changes. Avoiding tick bites during travel to endemic areas appears to be the single most important prophylactic action. Taking this into consideration, it should be possible to decrease the number of travelers returning with tick typhus significantly by adequate pretravel counseling.     

Complement activation associated with polysorbate 80 in beagle dogs

Polysorbate 80 (Tween® 80) is the most extensively used surfactant in parenteral drug formulation. Its application as an adjunct for intravenous drug administration is approved by the Food and Drug Administration. However, severe hypersensitive reactions, which are typical non-immune anaphylactic reactions (pseudoallergy) characterized by the release of histamine and unvaried IgE antibodies, have been associated with Tween® 80. In order to explore the non-immune anaphylactic mechanisms of Tween® 80, we performed in vivo experiments to assess the changes in physiological and hematologic indicators after intravenous injection of Tween® 80 into dogs. Tween® 80 induced the release of histamine, and a 2-fold increase in SC5b-9, 2.5-fold increase in C4d, 1.3-fold increase in Bb, while IgE remained unchanged. It also produced changes in pulmonary pressure, systemic pressure and ECG. In in vitro experiments, Tween® 80 was incubated with dog serum in the presence of an inhibitor of complement activation (EGTA/Mg²⁺). Under these conditions, Tween® 80 increased the contents of C4d and Bb. The results of this study reveal that Tween® 80 can cause cardiopulmonary distress in dogs and activate the complement system through classical and alternative pathways as indicated in both in vivo and in vitro preparations. Moreover, they demonstrate the utility of the beagle dog as an animal model for the study of complement activation-related pseudoallergy. These findings raise concerns with regard to the indiscriminate use of Tween® 80 in clinical applications.     

Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs

Commercial intravenous amiodarone has been reported to have antiarrhythmic actions and to cause only mild hypotension in humans. In the dog, however, amiodarone was observed to cause severe hypotension. Since commercial intravenous amiodarone is amiodarone compound (50 mg/ml) dissolved in water with polysorbate 80 (Tween 80) (100 mg/kg), the effects of amiodarone in ethanol (5 mg/kg) and polysorbate 80 (10 mg/kg) were studied individually, and in combination in anesthetized dogs. Commercial intravenous amiodarone and polysorbate 80 caused at least a 60% drop in mean blood pressure and left ventricular maximum dP/dt for at least 30 min, whereas amiodarone in ethanol did not. The drop in blood pressure was not principally due to peripheral vasodilation. Therefore, in dogs the diluent polysorbate 80 is the major cause of severe hypotension resulting from commercial intravenous amiodarone. These studies show that commercial intravenous amiodarone produces results different in dogs than has been previously reported in humans. Therefore: (a) canine models for studying the antiarrhythmic actions of commercial intravenous amiodarone would produce results complicated by severe hypotension; and (b) polysorbate 80 is not an inert substance, but is a potent cardiac depressant.     

Hippuric acid as a major excretion product associated with black tea consumption

1. Nine habitual tea-drinking volunteers were recruited and asked to follow a low-polyphenol and low-caffeine diet for 6 days and to provide daily 24-h urine samples. On day 4 of the experiment strong black tea brewed under standardized conditions was reintroduced to the volunteers' diet. 2. ¹H-NMR and HPLC profiling of the urine samples indicated that consumption of black tea (6-10 mugs per day) was associated with a significant (p=0.00017) increase in hippuric acid excretion relative to control, increasing from 153-512 to 742-1374?mg day^-1. The excretion of substantial amounts of hippuric acid has not previously been associated with black tea consumption. 3. For some volunteers, the quantity of benzoic acid processed exceeded the acceptable daily intake (ADI), but this is not considered to constitute any hazard. 4. A mass-balance analysis indicated that the necessary quantity of benzoic acid could not be obtained from the contents of gallic acid, flavanols, flavonol glycosides and theaflavins in black tea even if 100% transformation was obtained, suggesting that the thearubigins (the major and chemically ill-defined polyphenols of black tea) may be an important source.