Antifungal agents of use in animal health--practical applications.

The purpose of this paper is to provide an overview of antifungal agents currently in use in veterinary medicine. The practical applications and the therapeutic regimens that have proved successful in the treatment and prevention of fungal infections in dogs and cats, cattle and sheep, horse, pig, poultry and other birds, rodents, rabbits and fur animals are summarized.

Antifungal agents of use in animal health--chemical, biochemical and pharmacological aspects.

A limited number of antifungal agents is licensed for use in animals, however, many of those available for the treatment of mycoses in humans are used by veterinary practitioners. This review includes chemical aspects, spectra of activity, mechanisms of action and resistance, adverse reactions and drug interactions of the antifungals in current use.

Sensitization to triglycidylisocyanurate (TGIC) with cutaneous and respiratory manifestations.

The case is presented of a man with allergic contact dermatitis and occupational asthma due to triglycidylisocyanurate (TGIC), which is used as a hardener in thermosetting powder paint. The contact dermatitis was confirmed by patch testing (TGIC 0.5% and 5% in petrolatum), and the occupational asthma was confirmed by bronchial provocation testing: two challenges to an aerosol of lactose containing TGIC (0.05% and 0.1%, w/w, each for 0.5+1+2+4 min) led to a maximal decrease in FEV1 of 22% and 31% after 6 and 4 h, respectively. Skin prick tests with unconjugated TGIC were possibly positive. This case confirms that exposure to TGIC in powder paints may cause not only contact dermatitis, but also occupational asthma.

Micturitional disturbances are associated with impaired breathing control in multiple sclerosis.

STUDY OBJECTIVES: To investigate whether the localization of multiple sclerosis (MS), the duration of the disease, and the level of neurologic functioning in patients with MS predispose them to disturbed breathing control. DESIGN: Case-control study. SETTING: Outpatient pneumology department of a university hospital. PATIENTS: Twenty-three MS patients and 51 healthy control subjects. MEASUREMENTS AND RESULTS: Resting mouth occlusion pressure at 0.1 s after onset of inspiratory effort (P0.1) was measured during the hypercapnic response (HCR) and the hypoxic response (HR) in all subjects. The Kurtzke expanded disability status scale and the functional system score were used to describe the level of neurologic functioning of the MS patients. Predictors of HCR and HR were assessed by multiple regression analysis. Low maximal inspiratory pressure (MIP) values correlated with low resting P0.1 values (r = 0.44; p = 0.05), although in neuromuscular diseases, high resting P0.1 values are usually found to compensate for low MIPs. Detrusor-sphincter dyssynergia (DSD) was the only predictor for lower ventilatory HCR (p = 0.006; r2 = 0.52), lower P0.1 HCR (p = 0.004; r2 = 0.47), lower ventilatory HR (p = 0.04; r2 = 0.28), and lower P0.1 HR (p = 0.04; r2 = 0.10); low MIPs and pyramidal tract involvement had no role. CONCLUSIONS: (1) Impaired control of breathing in some MS patients is related mainly to central defects. (2) DSD is the most important predictor of disturbed ventilatory control, presumably because the micturition and pneumotaxic center are closely related and located in the rostral pons. (3) No relationship with the duration of the MS disease could be demonstrated, which can be explained by the variable course of MS itself.

Occupational asthma caused by palladium.

Occupational exposure to complex platinum salts is a well-known cause of occupational asthma. Although there is evidence that platinum refinery workers may also be sensitized to other precious metals, such as palladium or rhodium, no instances of occupational asthma due to an isolated sensitization to palladium have been reported. A case is reported of occupational rhinoconjunctivitis and asthma in a previously healthy worker exposed to the fumes of an electroplating bath containing palladium. There was no exposure to platinum. Sensitization to palladium was documented by skin-prick tests. The skin-prick test was positive with Pd(NH3)4Cl2, but not with (NH4)2PdCl4. Corresponding salts of platinum were all negative. A bronchial provocation test with Pd(NH3)4Cl2 (0.0001% for a total of 315 s, followed by 0.001% for a total of 210 s) led to an early decrease in forced expiratory volume in one second (-35%). A similar exposure (0.001% for a total of 16 min) in an unrelated asthmatic gave no reaction. This case shows that an isolated sensitization to palladium can occur and that respiratory exposure to palladium is a novel cause of metal-induced occupational asthma.

Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma.

Endogenously released nitric oxide (NO) has been detected in the exhaled air of humans. Exhaled NO (NOexh) levels have been significantly increased in patients with inflammatory airways disorders such as asthma, and NOexh has been suggested to be a usable marker of airway inflammation. In the present study, NOexh levels were measured both in steroid-treated and untreated subjects with mild asthma, and were correlated with the degree of airway hyperresponsiveness (AHR), measured as the dose of histamine that produced a 20% decrease in FEV1 (PC20histamine). NOexh levels, which were significantly increased in steroid-naive patients (Group A1: NOexh = 21 +/- 11 ppb; n = 56) in comparison with levels in control subjects (Group B: NOexh = 10 +/- 2 ppb; n = 20; p < 0.001), correlated significantly with the PC20histamine (r = -0.65; p < 0.0001). The NOexh level was significantly lower in patients with chronic cough of other causes than bronchial asthma (Group A2: NOexh = 11 +/- 3 ppb; n = 18) when compared with the level in subjects with mild asthma (Group A1: p < 0.001). Therefore, the noninvasive measurement of NOexh allowed us to discriminate, among patients with respiratory complaints, between those with and without AHR. In asthmatic subjects treated with inhaled steroids, the NOexh levels were significantly lower (Group A3: NOexh = 13 +/- 5 ppb; n = 25) than in untreated subjects (Group A1; p < 0.01), and there was no relationship with the PC20histamine (r = -0.18, p = NS). These findings confirm that NOexh reflects AHR in patients with mild asthma who have not already been treated with inhaled steroids. Patients treated with inhaled steroids had an NOexh level comparable to levels in control subjects, although AHR could still be demonstrated.

Respiratory dysfunction in multiple sclerosis: a prospective analysis of 60 patients.

This study aimed to determine the relationship between pulmonary function, respiratory muscle function and neurological function in multiple sclerosis (MS). Sixty patients (27 males and 33 females) aged 27-75 yrs (mean +/- SD 48 +/- 12 yrs) were prospectively studied. The Kurtzke Expanded Disability Status Scale (EDSS; range 0-10) score was 6.5 +/- 1.5; and the different Functional Systems Scores (FSS; ranges 0-5 and 0-6) were: pyramidal 3.4 +/- 1.1; brain stem 1.9 +/- 1.2; mental 1.3 +/- 0.9; cerebellar 2.2 +/- 1.0; sphincter 1.8 +/- 1.5; visual 1.4 +/- 1.4; and sensory 2.0 +/- 1.5. Results of lung function tests were: vital capacity (VC) 80 +/- 23% of predicted; single-breath transfer factor of the lung for carbon monoxide (TL, CO, sb) 83 +/- 17% pred; maximal static expiratory mouth pressure (MEP) 30 +/- 16% pred; and maximal static inspiratory mouth pressure (MIP) 47 +/- 23% pred, indicating a marked respiratory muscle dysfunction, with a minor restrictive defect. In 70% of the patients, a transcutaneous oxygen saturation (Stc, O2) of less than 92% at night was found. Comparison of lung function and disability scores showed that the abnormalities in both tended to be correlated to each other, and that this was significant for EDSS versus lung volumes, for most FSS with VC, and also for some FSS with MEP and/or MIP. Duration of disease was significantly correlated with the EDSS, but not with the different FSS scores (with the exception of mental status) and not with lung function. Multiple sclerosis leads to lung function abnormalities attributable to respiratory pump dysfunction.

Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma.

Montelukast, a new specific oral cysteinyl LT3-receptor antagonist was evaluated for its activity in attenuating inhaled leukotriene D4 (LTD4) bronchoconstriction in patients with asthma. In two double-blind, placebo-controlled, randomized crossover studies, patients with mild asthma (forced expiratory volume in 1 second [FEV1] > or = 70%) were studied. In trial A, LTD4 challenge began 4 hours (peak plasma concentration) after a single dose of placebo or 5, 20, 100, and 250 mg montelukast. In trial B, and LTD4 challenge was started 20 hours after administration of placebo, 40 mg montelukast, or 200 mg montelukast. During each challenge, twofold increasing concentrations of LTD4 were inhaled until specific airways conductance (sGaw) decreased by at least 50% (PC50) or the highest concentration of LTD4 was inhaled. In trial A with all doses and in trial B with the 200 mg dose, bronchoconstriction was attenuated (50% fall in sGaw was not observed) up to the highest dose of LTD4 administered. In trial B, during the 40 mg period, only two of six patients exhibited a 50% fall in sGaw; PC50 ratios (montelukast 40 mg/placebo) were 18 and 45 in these two patients. These results indicate that montelukast is a highly potent and long-lasting antagonist of LTD4-induced bronchoconstriction in patients with asthma.

Ventilatory effects of acetazolamide in cats during hypoxemia.

In normoxemic cats, acetazolamide (ACTZ) has been shown to cause a large rise in ventilation (VE) but a decrease in peripheral chemoreceptor activity. The relative contribution of the peripheral chemoreceptors to ventilation is higher during hypoxemia than during normoxemia. Therefore, what are the effects of ACTZ during steady-state hypoxemia? The aims of this study in anesthetized cats were 1) to study the effect of ACTZ (50 mg/kg iv) on mean hypoxemic [arterial PO2 (PaO2) approximately 6 kPa] ventilation and 2) to study the effect of ACTZ on the isocapnic hypoxic ventilatory response. In the first study, in six cats with an inspiratory CO2 fraction of 0, ACTZ led to an insignificant rise in mean VE of 119 ml.min-1.kg-1 after 1 h. In five other cats maintained at an inspiratory CO2 fraction of 0.015, ACTZ resulted in a significantly larger response in VE (268 and 373 ml.min-1.kg-1 after 1 and 2 h, respectively). In the second study, before infusion in five cats, an isocapnic fall in mean PaO2 from 13 to 4.7 kPa led to a significant rise in mean VE of 385 ml.min-1.kg-1; 1 h later, the response (at the same mean alveolar PCO2) was reduced to an insignificant rise of 38 ml.min-1.kg-1. Before infusion four other cats showed a significant rise in mean VE of 390 ml.min-1.kg-1 when mean PaO2 was lowered isocapnically from 12.4 to 6.8 kPa; 2 h after infusion, an isocapnic fall in mean PaO2 from 13.9 to 7.2 kPa led to an insignificant rise of 112 ml.min-1.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic tests of hyperventilation syndrome.

In 90 patients referred to the pulmonary function laboratory for evaluation of hyperventilation syndrome (HVS) and in whom somatic causes of the complaints had been excluded, we investigated the degree of concordance between three widely applied diagnostic methods: 1) the standardized Nijmegen questionnaire on major daily complaints; 2) the reproduction of the same symptoms during the hyperventilation provocation test (HVPT); and 3) the responses of end-tidal CO2 fraction (FETCO2) during the HVPT. In 86% of the patients a concordance was found between Nijmegen questionnaire (i.e. score of 24/64 or more) and symptom reproduction during HVPT (i.e. recognition of at least 2 major daily complaints). Based on these combined data we made a definite diagnosis of HVS in 37 patients, of non-HVS in 40 patients, and we retained only a possible HVS in 13 patients. Each of the 16 complaints in the questionnaire contributed significantly to the distinction between HVS and non-HVS patients, and a striking similarity in rank order of daily complaints and reproduced symptoms was found. The responses in FETCO, during HVPT had little additional diagnostic value. A spontaneous fall of at least 0.25% FETCO2 during the 5 min adaptation period before the HVPT, was most reliably correlated with the aforementioned diagnostic criteria of HVS: specificity 83%, sensitivity 57%, and accuracy 70%. Neither the 3 min FETCO2 ratio nor the 5 min FETCO2 ratio during recovery after the HVPT showed a good correlation with the other diagnostic criteria. The response of FETCO2 during HVPT did especially not provide additional useful diagnostic information in the 13 patients with only possible HVS.

Evaluation of the clinical usefulness of capnography curves during a hyperventilation provocation test in the diagnosis of hyperventilation syndrome.

We evaluated the diagnostic usefulness of capnography curves during and following a hyperventilation provocation test (HVPT) in the hyperventilation syndrome (HVS). The diagnosis of HVS was based on the Nijmegen questionnaire and on the reproduction of symptoms during HVPT. Capnography curves of 40 HVS patients, 40 non-HVS patients with psycho-somatic complaints and 26 healthy controls were analyzed. There was no difference in baseline end-tidal CO2-level (FETCO2) between the 3 groups. The spontaneous fall of FETCO2 during the adaptation phase was clearly different in HVS patients versus non-HVS patients or controls: -0.12 mmol/l (95% confidence limits -0.18 to -0.06) versus +0.01 mmol/l (95% confidence limits -0.04 to +0.16) (p = 0.002). The 3 minutes FETCO2 recovery ratio and the 5 minutes ratio were not significantly different between the groups. In conclusion, in this study the spontaneous fall of FETCO2 during the adaptation phase of the HVPT was the only valuable part of the capnography test to discriminate between HVS and non-HVS patients.

Effects of acetazolamide on medullary extracellular pH and PCO2 and on ventilation in peripherally chemodenervated cats.

The responses of ventilation and of medullary extracellular fluid (ECF) pH and PCO2, to an intravenous (i.v.) infusion of 50 mg/kg acetazolamide (an inhibitor of carbonic anhydrase), were measured in cats anaesthetized with chloralose and urethane, in which both bilateral vagotomy and carotid nerve section had been performed. After 2 h, it was observed that: acetazolamide caused an acidosis in medullary ECF which was still developing after 2 h, reflected by a progressive fall in pH (mean = 0.215 pH units in 2 h), while ECF PCO2 showed an insignificant rise of about 1 kPa; acetazolamide caused a considerable rise in ventilation, which largely developed in the first 15 min after drug infusion; the direction of the ECF acid-base responses in the first 15 min varied, whereas that of the ventilatory response did not. Furthermore, the time course of the former developed quite differently from the latter. It was therefore concluded that the observed changes in medullary ECF pH and PCO2 can not explain the large and fast ventilatory response of acetazolamide.

Ventilatory response to carbonic anhydrase inhibition in cats: effects of acetazolamide in intact vs peripherally chemodenervated animals.

Hyperventilation induced by red cell carbonic anhydrase inhibition (CAI) has been observed frequently; its mechanism, however, is still obscure. In the present study in anaesthetized cats, we have investigated the effect of 50 mg/kg acetazolamide, a carbonic anhydrase inhibitor, on ventilation. In order to determine the role of the peripheral chemoreceptors, we compared the response in peripherally chemodenervated and intact cats. Furthermore, in cats with intact peripheral chemoreceptors, we determined hypoxic sensitivity before and 2 h after i.v. infusion of the drug. In all animals, acetazolamide caused a large increase in ventilation. However, the peripherally chemodenervated animals developed a significantly larger response than the intact animals (respectively about 200 and 100% increases in ventilation). The first group also showed a significantly larger fall in PACO2. In the intact animals studied, acetazolamide virtually abolished the hypoxic sensitivity which existed before infusion of the drug. We conclude that acetazolamide, at the dose studied, causes a decrease in activity of the peripheral chemoreceptors, and also a decrease (c.q. removal) of their sensitivity to PaO2 changes. The increase in ventilation by acetazolamide is probably caused by an action of the drug on the central nervous system, possibly on the central chemoreceptors.

Mechanism of pulmonary function changes after surgical correction for funnel chest.

In 24 subjects with pectus excavatum we evaluated whether the previously detected unfavourable effects of corrective surgery on the ventilatory capacity were attributable to pulmonary or to chest wall factors. We found that 12.2 +/- 3.7 yrs postoperatively (i.e. at the age of 23.3 +/- 5.4 yrs) the vital capacity was decreased from 89 +/- 10% predicted (pred) preoperatively to 64 +/- 6% pred (p less than 0.001) and forced expiratory volume in one second from 88 +/- 17 to 66 +/- 11% pred (p less than 0.001). At total lung capacity (TLC; 69 +/- 5% pred) we found an obvious reduction in transpulmonary pressure (59 +/- 23% pred) and in transdiaphragmatic pressure (30 +/- 17 cmH2O) postoperatively. This indicated an extrapulmonary cause of the restrictive defect, attributable to abnormal chest wall mechanics secondary to the extensive surgery on the sternum and parasternal zones.

Hypocapnic hyperventilation versus isocapnic hyperventilation with ambient air or with dry air in asthmatics.

The effects of three types of hyperventilation challenge tests (free hypocapnic, ambient air; controlled isocapnic, ambient air; controlled isocapnic, dry air), on FEV1 and on Raw were compared in 12 asymptomatic asthmatics. Controlled isocapnic hyperventilation of dry air as well as of ambient air caused bronchoconstriction lasting for more than 8 min, but the degree of bronchoconstriction was significantly greater with the former. Free hypocapnic hyperventilation of ambient air caused peak bronchoconstriction after 1 min, followed by a steady functional improvement; the values after 1 min were similar to those following isocapnic dry air hyperventilation, and values after 8 and 15 min were similar to those following isocapnic ambient air hyperventilation. The changes in Raw induced by the three types of hyperventilation were not influenced by a preceding full inspiration. In the eight subjects in whom the lung function had returned to within 10% of control after 30 min, identical duplicate hyperventilation challenge tests performed at that time demonstrated a significant, partial refractoriness for all tests. Thus the simple, free hypocapnic, hyperventilation test with ambient air was found to be as reliable as the more sophisticated controlled isocapnic tests.

Pulmonary function in moderate neuromuscular disease without respiratory complaints.

Pulmonary function studies were carried out in 29 patients with moderate neuromuscular disease who had virtually no respiratory complaints. The earliest and most pronounced abnormalities were decreased transrespiratory pressures. Next a restrictive pulmonary defect with increased residual volume and a proportional decrease of maximal expiratory flows occurred, together with a decrease in static lung compliance. Because of a decrease in transpulmonary pressure at total lung capacity and often an increase in diffusing capacity per unit lung volume the above mentioned restrictive defects were attributed to muscular weakness and interstitial lung disease was excluded. Finally, some ventilation inequality could be found, probably originating in the poorly ventilated supradiaphragmatic regions.