Search

Background: Filarial nematodes cause severe illnesses in humans and canines including limb deformities and disfigurement, heart failure, blindness, and death, among others. There are no vaccines, and current drugs against filarial nematodes infections have only modest effects and are prone to complications. Methodology/principal findings: We identified a gene (herein called DiMT) encoding an S-adenosyl-L-methionine (SAM)-dependent methyltransferase with orthologs in parasite filarial worms but not in mammals. By in silico analysis, DiMT possesses catalytic sites for binding SAM and catecholamines with high affinity. We expressed and purified recombinant DiMT protein and used it as an enzyme in a series of SAM-dependent methylation assays. DiMT acted specifically as a catechol-O-methyltransferase (COMT), catalyzing catabolic methylation of dopamine, and depicted Michaelis Menten kinetics on substrate and co-substrate. Among a set of SAM-dependent methyltransferase inhibitors, we identified compounds that bound with high affinity to DiMT's catalytic sites and inhibited its enzymatic activity. By testing the efficacy of DiMT inhibitors against microfilariae of Dirofilaria immitis in culture, we identified three inhibitors with concentration- and time-dependent effect of killing D. immitis microfilariae. Importantly, RNAi silencing of a DiMT ortholog in Caenorhabditis elegans has been shown to be lethal, likely as a result of excessive accumulation of active catecholamines that inhibit worm locomotion, pharyngeal pumping and fecundity. Conclusions/significance: Together, we have unveiled DiMT as an essential COMT that is conserved in parasitic filarial nematodes, but is significantly different from mammalian COMTs and, therefore, is a viable target for development of novel drugs against filarial nematode infections. Author summary: Parasitic filarial nematodes cause serious illnesses in humans and canines including limb deformities and disfigurement, blindness, heart failure, and death, among others. There are no vaccines, and current drugs in use against filarial nematodes infections have only modest effects and are prone to complications. In this study, we explored a unique enzyme (DiMT), conserved in all parasitic filarial nematodes but not in mammalian species. Using computation, biochemistry and molecular biology approaches, we validated DiMT as a catechol-O-methyltransferase that functions to inactivate catecholamines to prevent their accumulation and hence block their deleterious effects in filarial nematodes, including loss of worm viability, reproduction and survival. Subsequently, we identified DiMT's chemical inhibitors and demonstrated that they possess anti-filarial nematode efficacy through blocking the inactivation of catecholamines. Together, we have unveiled DiMT as a viable molecular target for the development of new drugs for treating filarial nematode infections. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the effects of oral trazodone on echocardiographic variables, heart rate (HR) and blood pressure (BP) in healthy cats. Methods: Client-owned domestic cats between 2 and 8 years of age were recruited. Cats were considered healthy based on physical examination, complete blood count, blood chemistry profile, urinalysis, total thyroxine concentration, non-invasive BP measurement by Doppler method and a screening transthoracic echocardiogram with simultaneous electrocardiogram. Echocardiographic variables assessed pre-trazodone and 90–120 mins post-trazodone (50 mg PO) included left ventricular internal diameter in systole and diastole, interventricular septal and left ventricular free-wall thickness in systole and diastole, left atrial size, left auricular function and left ventricular diastolic function assessed by spectral Doppler transmitral and pulmonary venous flow velocities, and tissue Doppler profiles. Mean echocardiographic and hemodynamic variables were calculated for pre- and post-trazodone examinations for each cat. Pre- and post-trazodone variables were analyzed with a paired t -test with significance set at P <0.05. Results: Twelve healthy cats were evaluated. Trazodone was administered to all cats and a sedative effect was observed. There were no clinically significant differences in any echocardiographic variables post-trazodone administration. Systolic BP was significantly decreased after trazodone (P = 0.001) with no significant change in HR. Conclusions and relevance: Trazodone did not alter echocardiographic variables, in a clinically relevant manner, in this group of healthy cats. Trazodone may aid in obtaining transthoracic echocardiograms without affecting HR or echocardiographic variables but may significantly lower BP in healthy cats. [ABSTRACT FROM AUTHOR]

OBJECTIVE Bearded dragons (Pogona vitticeps), a popular zoological companion species, frequently require sedation for procedures. A novel formulation of alfaxalone with preservatives was FDA approved for 28-day use after the vial is breached. Research has been performed in squamate species using alfaxalone without preservatives at various doses and routes of administration, but it is unknown whether preservatives affect quality of sedation or cardiac function. ANIMALS 10 bearded dragons. PROCEDURES This complete crossover study evaluated the pharmacodynamic effects of alfaxalone with preservatives administered to bearded dragons via intracoelomic (Co; n = 10), SC (10), IM (9), and IV (9) injection at 15 mg/kg. RESULTS Deep sedation was achieved in 9 of 10 1Co, 8 of 10 SC, 8 of 9 IM, and 9 of 9 IV administrations. Heart rate significantly decreased from baseline for ICo (P = ,008; median heart rate, 46), IM (P = .018; 54), and IV (P = .033; 54) routes, but maintained within clinically acceptable limits. Respiratory rate significantly decreased from baseline for ICo (P= .011; median respiratory rate, 30), SC (P= .024; 12), IM (P= .028; 12), and IV (P= .043; 12) routes. Spontaneous ventilation was retained during all events. Timeto first effects was significantly sooner with IV (0 min) administration compared with ICo (P= .02; 5 min) and IM (P = .008; 5 min). Time to loss and recovery of withdrawal, righting reflex, deep pain, and purposeful movement were not significantly different between routes of administration. End-systolic volume was the only echocardiographic parameter significantly affected by IV sedation. CLINICAL RELEVANCE Sedation quality was most consistent via IV administration at 15 mg/kg, and minimal changes in cardiac function were observed. [ABSTRACT FROM AUTHOR]