RESUMO
CASE SERIES SUMMARY: Four confirmed cases of xanthinuria in cats, and one suspected case based on pedigree analysis, were identified. Clinical presentations varied and included haematuria, pollakiuria, dysuria, and urethral and ureteral obstruction. All cats had upper urinary tract uroliths. Diagnosis was obtained through infrared mass spectrometry of uroliths or urine. Clinical signs commenced at 3-8 months of age and reduced in all cats in the medium to long term after the introduction of a protein-restricted diet. Four cats were castrated males and one was a spayed female. Cases consisted of four Munchkin pedigree cats and one unrelated domestic shorthair cat. All four affected Munchkin pedigree cats were related, with three cases full siblings and the fourth case a half-sibling. No connection to the Munchkin pedigree could be established for the domestic shorthair cat. A candidate causative genetic variant (XDH p.A681V) proposed for this cat was excluded in the Munchkin family. RELEVANCE AND NOVEL INFORMATION: All affected cats presented diagnostic challenges and routine urinalysis was insufficient to obtain a diagnosis. Cases of feline xanthinuria may be underdiagnosed due to situations where uroliths cannot be retrieved for analysis and there is an inability to make a diagnosis using crystal morphology alone on routine urinalysis. Metabolic screening of urine may provide an effective mechanism to confirm xanthinuria in suspected cases where uroliths are inaccessible or absent. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs and urethral obstruction developing secondary to xanthine urolithiasis. A protein-restricted diet appears to reduce clinical signs as part of long-term management. PLAIN LANGUAGE SUMMARY: Four closely related Munchkin cats and one domestic shorthair cat were found with a suspected genetic disease causing high levels of xanthine in their urine. The case series looks at similarities and differences in their clinical signs, as well as difficulties experienced in obtaining a correct diagnosis. All cats had upper urinary tract stones and required metabolic testing of the stones or urine to diagnose. All cats were young when their clinical signs started and were on a high-protein diet. Four cats were desexed males and one was a desexed female. A genetic variant that may have caused the disease in the domestic shorthair cat was ruled out in the Munchkin family. Cases of high xanthine levels in feline urine may be underdiagnosed as the stones may not be accessed for testing. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs. A protein-restricted diet appears to reduce clinical signs as part of long-term management.
Assuntos
Doenças do Gato , Linhagem , Gatos , Animais , Doenças do Gato/diagnóstico , Doenças do Gato/urina , Doenças do Gato/genética , Masculino , Feminino , Urolitíase/veterinária , Urolitíase/diagnóstico , Urolitíase/urinaRESUMO
We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.
Assuntos
Azirinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Di-Hidropiridinas/química , Inibidores da Fosfodiesterase 4/química , Inibidores de Fosfodiesterase/química , Animais , Azirinas/metabolismo , Azirinas/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Di-Hidropiridinas/metabolismo , Di-Hidropiridinas/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Osteoartrite/tratamento farmacológico , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/uso terapêutico , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.
Assuntos
Azepinas/química , Azirinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Di-Hidropiridinas/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Azepinas/farmacocinética , Azepinas/uso terapêutico , Azirinas/farmacocinética , Azirinas/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Osteoartrite/tratamento farmacológico , Inibidores da Fosfodiesterase 4/química , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
The study sought to examine the effect of long-term meloxicam treatment on the survival of cats with and without naturally-occurring chronic kidney disease at the initiation of therapy. The databases of two feline-only clinics were searched for cats older than 7 years that had been treated continuously with meloxicam for a period of longer than 6 months. Only cats with complete medical records available for review were recruited into the study.The median longevity in the renal group was 18.6 years [95% confidence interval (CI) 17.5-19.2] and the non-renal group was 22 years [95% CI 18.5-23.8]. The median longevity after diagnosis of CKD was 1608 days [95% confidence interval 1344-1919] which compares favourably to previously published survival times of cats with CKD. In both groups the most common cause of death was neoplasia. Long-term treatment with oral meloxicam did not appear to reduce the lifespan of cats with pre-existent stable CKD, even for cats in IRIS stages II and III. Therefore, to address the need for both quality of life and longevity in cats with chronic painful conditions, meloxicam should be considered as a part of the therapeutic regimen.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças do Gato/tratamento farmacológico , Doenças do Gato/epidemiologia , Longevidade , Osteoartrite/veterinária , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Austrália/epidemiologia , Gatos , Testes de Função Renal , Meloxicam , Osteoartrite/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/veterinária , Estudos Retrospectivos , Fatores de Risco , Tiazinas/efeitos adversos , Tiazóis/efeitos adversosRESUMO
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Assuntos
Cicatriz/prevenção & controle , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Pele/efeitos dos fármacos , Animais , Modelos Moleculares , Fosforilação , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
Medical records (2005-2009) of a feline-only practice were searched for cats with degenerative joint disease (DJD) treated using meloxicam. DJD was diagnosed by the presence of at least two of the following: (i) altered mobility (observed by the owner), (ii) abnormal physical findings, (iii) characteristic radiographic changes. The primary study cohort consisted of cats older than 7 years that had received meloxicam for variable intervals in excess of 6 months, and for which complete records were available. These cats were subdivided according to whether detectable chronic kidney disease (CKD) was present ('renal group'), or not ('non-renal group'), and, for the 'renal group', according to the cat's IRIS category. Serum biochemistry, urinalysis (including urine specific gravity [USG]), body mass and condition score were monitored regularly. Progression of CKD in the 'renal group' and 'non-renal group' of cats was compared to two groups of age- and IRIS-matched control cats not receiving meloxicam (from the same clinic, over the same time period). The study was thus a case-control design, with two study groups. Thirty-eight cats with DJD receiving long-term meloxicam therapy met the inclusion criteria. Of these, 22 cats had stable CKD at the start of treatment (stage 1, eight cats; stage 2, 13 cats; stage 3, one cat). No cats initially had an elevated urinary protein to creatinine ratio. The remaining 16 cats initially had normal renal analytes and adequately concentrated urine. The median age of the 'renal' and 'non-renal' meloxicam groups was 15.5 and 13.4 years, respectively. The median treatment duration was 467 days in the 'renal group' and 327 days in the 'non-renal group'. After titration (to the lowest effective dose), the median maintenance dose was 0.02 mg/kg/day in both groups (range 0.015-0.033 mg/kg/day). There was no difference in sequential serum creatinine concentration or USG measurements between the 'non-renal group' treated with meloxicam compared to control cats not treated with meloxicam. There was less progression of renal disease in the 'renal group' treated with meloxicam compared to the age- and IRIS-matched cats with CKD not given meloxicam. These results suggest that a long-term maintenance dose of 0.02 mg/kg of meloxicam can be safely administered to cats older than 7 years even if they have CKD, provided their overall clinical status is stable. Long-term meloxicam therapy may slow the progression of renal disease in some cats suffering from both CKD and DJD. Prospective studies are required to confirm these findings.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças do Gato/tratamento farmacológico , Doenças do Gato/epidemiologia , Osteoartrite/veterinária , Insuficiência Renal Crônica/veterinária , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Estudos de Casos e Controles , Doenças do Gato/patologia , Gatos , Feminino , Testes de Função Renal , Masculino , Meloxicam , New South Wales/epidemiologia , Osteoartrite/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos , Tiazinas/efeitos adversos , Tiazóis/efeitos adversosRESUMO
A total of 38 cases of naturally occurring intestinal tritrichomoniasis in Australian cats are described. Detailed information was available for 13 cases diagnosed in two veterinary hospitals, one in Victoria and one in New South Wales (NSW). In all instances, presumptive microscopic diagnoses were confirmed by polymerase chain reaction (PCR) testing. Affected cats were generally young (median age 8 months) and of a pedigree breed (12/13 cats; 92%). Diarrhoea was observed in 10 cats (77%); the remaining three cats were asymptomatic and detected by screening undertaken because these cats cohabited with symptomatic cases. Concurrent infections with Giardia species (7/13 cats; 54%), and Toxocara species and Eucoleus species (2/13 cats; 15%) were identified. Treatment of tritrichomoniasis with ronidazole at a dose of 30mg/kg once or twice a day, in concert with appropriate therapy of concurrent gastrointestinal infections, resolved diarrhoea in all cats treated. Limited case details of a further 25 infected cats were obtained from a commercial laboratory offering a real-time PCR assay for Tritrichomonas foetus, and compared with findings from the 13 cats presenting to the contributing veterinary hospitals. All samples submitted to this laboratory returning a positive PCR result were from pedigree cats maintained in multi-cat facilities. Most of the samples were derived from Victoria (4/8 catteries tested; 50%), although positive samples were also identified from cats in NSW (1/4 catteries tested; 25%), Queensland (1/4 catteries; 25%), Tasmania (1/4 catteries; 25%) and South Australia (1/4 catteries; 25%). Our impression is that intestinal tritrichomoniasis is an emerging infectious disease of Australian cats. Tests to detect T foetus should be a routine component of the work-up of chronic diarrhoea in cats, especially young purebred cats.
Assuntos
Doenças do Gato/parasitologia , Doenças Transmissíveis Emergentes/veterinária , Intestinos/parasitologia , Infecções Protozoárias em Animais/parasitologia , Tritrichomonas foetus/isolamento & purificação , Criação de Animais Domésticos , Animais , Austrália , Doenças do Gato/diagnóstico , Gatos , Diarreia/veterinária , Fezes/parasitologia , Feminino , Masculino , Linhagem , Reação em Cadeia da Polimerase/veterinária , Infecções Protozoárias em Animais/diagnósticoRESUMO
This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Antineoplásicos/química , Benzamidas/química , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Humanos , Ácidos Hidroxâmicos/química , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-AtividadeRESUMO
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Assuntos
Amidas/síntese química , Compostos de Anilina/síntese química , Antineoplásicos/síntese química , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Piridonas/síntese química , Amidas/química , Amidas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase 1/química , MAP Quinase Quinase 2/química , Masculino , Camundongos , Modelos Moleculares , Transplante de Neoplasias , Fosforilação , Piridonas/química , Piridonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Molgula pacifica (Huntsman) is a recently rediscovered ascidian that occupies shallow subtidal rocks on wave-swept coasts of British Columbia. Individuals occur most abundantly at sites with intermediate exposure at or near 4 m depth. On a scale of centimeters, they are highly aggregated. Molgula pacifica is hermaphroditic, self-fertile, and oviparous. Embryos develop on the bottom without passing through a typical tadpole stage. Each of the egg follicle cells contains a single large adhesive vacuole that occupies most of the cell volume. Shortly after spawning these vacuoles rupture, causing the follicle cells to secrete a sticky mucus coat that adheres the egg to the substratum. Juveniles hatch and move away from the chorion using epidermal ampullae, as reported for other anural molgulids. Adhesive eggs may be an adaptation that permits anural development in high-energy hard-bottom habitats. Egg adhesion may also explain the small-scale distribution of the species.