RESUMEN
OBJECTIVE: To determine whether histopathologic changes are detectable in grossly normal medial menisci from dogs with rupture of the cranial cruciate ligament (CCL). DESIGN: Case series. SAMPLE POPULATION: 40 medial menisci from dogs with rupture of the CCL and 20 medial menisci from control dogs without stifle joint disease. PROCEDURE: Data evaluated included age, duration of clinical signs, and whether rupture of the CCL was complete or incomplete. Three groups (n = 20/group) were also compared on the basis of 5 histologic criteria; group-1 menisci appeared grossly normal and were obtained from dogs with naturally occurring rupture of the CCL, group-2 menisci were grossly abnormal and were also obtained from dogs with naturally occurring CCL ruptures, and group-3 menisci were collected at postmortem from dogs without stifle joint disease that were of similar age and weight as dogs in groups 1 and 2. RESULTS: Group-2 menisci were significantly different from group-1 and -3 menisci in all histologic criteria. Group-1 menisci were significantly different from control menisci in only 1 of the 5 histologic criteria (cartilage differentiation). Dogs that were > or =3 years old had significantly more surface cellularity than did dogs that were < 3 years old. A significant difference was not detected between groups 1 and 2 with regard to completeness of rupture. CONCLUSIONS AND CLINICAL RELEVANCE: Histologic changes in meniscal cartilage correlate with gross appearance of the cartilage at time of surgery for rupture of the CCL. On the basis of minimal histologic changes, routine removal of grossly normal menisci does not appear to be warranted.
Asunto(s)
Lesiones del Ligamento Cruzado Anterior , Perros/lesiones , Meniscos Tibiales/patología , Factores de Edad , Animales , Ligamento Cruzado Anterior/cirugía , Rotura/patología , Rotura/veterinariaRESUMEN
Compared with the in vitro activities of itraconazole (geometric mean MIC [GM], 0.56 microg/ml) and amphotericin B (GM, 0.66 microg/ml), the in vitro activity of terbinafine was inferior against Aspergillus fumigatus (GM, 19.03 microg/ml) (P < 0.05) and superior against A. flavus (GM, 0.10 microg/ml), A. terreus (GM, 0.16 microg/ml), and A. niger (GM, 0.19 microg/ml). Clinical correlation is required, as trailing endpoints are problematic.
Asunto(s)
Anfotericina B/farmacología , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Itraconazol/farmacología , Naftalenos/farmacología , Pruebas de Sensibilidad Microbiana , TerbinafinaRESUMEN
The in vitro activity of BMS-207147 against 80 clinical isolates of Aspergillus was compared with that of itraconazole and amphotericin B, using a validated microtiter method. Geometric mean MICs (in microg/ml) were as follows: 1.71 for BMS-207147, 0.67 for itraconazole, and 0.63 for amphotericin B. The range of concentrations of each drug was 0.125 to >16 microg/ml. Aspergillus fumigatus was significantly more susceptible to BMS-207147 (P < 0. 05) than A. terreus and A. flavus. No BMS-207147-resistant A. fumigatus isolates were identified, though eight itraconazole-resistant (MIC, >8 microg/ml) isolates were. BMS-207147 is active against Aspergillus spp. at slightly high concentrations compared with itraconazole and amphotericin B.
Asunto(s)
Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Tiazoles/farmacología , Triazoles/farmacología , Anfotericina B/farmacología , Farmacorresistencia Microbiana , Humanos , Itraconazol/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Interleukin-5 (IL-5) is essential for the formation of eosinophils, which are thought to have a major role in the pathogenesis of asthma and other allergic diseases. We aimed to assess the effects of monoclonal antibody to IL-5 on blood and sputum eosinophils, airway hyper-responsiveness, and the late asthmatic reaction to inhaled allergen in patients with mild asthma. METHODS: We did a double-blind randomised placebo-controlled trial, in which a single intravenous infusion of humanised (IgG-K) monoclonal antibody to IL-5 (SB-240563) was given at doses of 2.5 mg/kg (n=8) or 10.0 mg/kg (n=8). The effects of treatment on responses to inhaled allergen challenge, sputum eosinophils, and airway hyper-responsiveness to histamine were measured at weeks 1 and 4 with monitoring of blood eosinophil counts for up to 16 weeks. FINDINGS: Monoclonal antibody against IL-5 lowered the mean blood eosinophil count at day 29 from 0.25x10(9)/L (95% CI 0.16-0.34) in the placebo group to 0.04x10(9)/L (0.00-0.07) in the 10 mg/kg group (p<0.0001), and prevented the blood eosinophilia that follows allergen challenge. After inhaled allergen challenge, 9 days after treatment, the percentage sputum eosinophils were 12.2% in the placebo group and lowered to 0.9% (-1.2 to 3.0; p=0.0076) in the 10 mg/kg group, and this effect persisted at day 30 after the dose. There was no significant effect of monoclonal antibody to IL-5 on the late asthmatic response or on airway hyper-responsiveness to histamine. INTERPRETATION: A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosinophils at 4 weeks, which has considerable therapeutic potential for asthma and allergy. However, our findings question the role of eosinophils in mediating the late asthmatic response and causing airway hyper-responsiveness.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Asma/terapia , Eosinófilos/metabolismo , Interleucina-5/antagonistas & inhibidores , Adulto , Análisis de Varianza , Pruebas de Provocación Bronquial , Método Doble Ciego , Histamina/sangre , Humanos , Infusiones Intravenosas , Recuento de Leucocitos , Masculino , Esputo/citologíaRESUMEN
This study determined the effect of the polypeptide growth factors transforming growth factor-beta (TGF-beta), insulin-like growth factor-I (IGF-I), and growth hormone (GH) alone and in combination with dietary L-Arginine HCL (ARG) on skin flap survival in rats. Caudally based dorsal skin flaps were created in 110 Sprague-Dawley rats. The rats were randomly assigned into three treatment groups, based on drinking water supplementation. Group 1 (n = 50) received ARG in their drinking water, group 2 (n = 50) received tap water alone, and group 3 (n = 10) received N-omega-nitro-L-arginine (L-NA) and hydralazine. Groups 1 and 2 were divided into subgroups of 10 rats each based on treatment with either: TGF-beta, IGF-I, GH, or IGF-I + GH. All subgroups that received GH had significantly greater (P < .0001) median body weight gains when compared with subgroups not receiving GH. L-arginine HCL when added to IGF-I negated the positive effects of IGF-I on both flap survival and weight gain. Although the rats in all subgroups from groups 1 and 2 had an increase in mean percent skin flap survival when compared with the water alone subgroup, only rats receiving IGF-I, or the combination of ARG with either TGF-beta or GH, had statistically significant enhanced skin flap survival. Rats in group 3 did not show an increase in skin flap survival when compared with the control subgroup.
Asunto(s)
Arginina/uso terapéutico , Supervivencia de Injerto , Sustancias de Crecimiento/uso terapéutico , Isquemia/terapia , Complicaciones Posoperatorias/terapia , Colgajos Quirúrgicos , Animales , Quimioterapia Combinada , Hormona del Crecimiento/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Isquemia/patología , Masculino , Complicaciones Posoperatorias/patología , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta/uso terapéuticoRESUMEN
1. 14C-Bemitradine (50 mg) was rapidly and efficiently absorbed (approximately 89%) in man following a single oral dose, as a solution in gelatine capsules. Peak 14C levels of 895 +/- 154 ng equiv./ml (mean +/- S.E.M.) were reached within 2 h, and declined with half-lives of 1.07 +/- 0.25 and 13.0 +/- 5.6h. 2. No bemitradine was detected in plasma, but peak concn. (124 +/- 29 ng/ml) of its desethyl metabolite were reached at 1.05 +/- 0.28 h, and declined with a half-life of 1.32 +/- 0.08 h. 3. Desethylbemitradine was rapidly metabolized to its ether glucuronide, a phenol and a dihydrodiol which were also present as glucuronide conjugates. The glucuronides were the major compounds in plasma from 2 h after drug administration. 4. Excretion in 5 days amounted to 88.8 +/- 2.3% and 10.4 +/- 2.1% dose in urine and faeces respectively. No bemitradine or desethylbemitradine were excreted unchanged. 8-(2-Hydroxyethyl)-7-(3,4- dihydroxycyclohexa-1,5-dienyl)-1,2,4-triazolo-1,5c-pyrimidin e-5-amine (E; 17% dose); 8-(2-hydroxyethyl)-7-(4-hydroxyphenyl)-1,2,4-triazolo-1,5c- pyrimidine-5-amine (F; 4% dose), their glucuronides (A, 19% dose and B, 6% dose respectively), desethylbemitradine glucuronide (D, 25% dose) and an unidentified metabolite (C, 12% dose) were excreted in urine. Compound F was the major faecal metabolite.
Asunto(s)
Diuréticos/farmacocinética , Pirimidinas/farmacocinética , Triazoles/farmacocinética , Vasodilatadores/farmacocinética , Absorción , Administración Oral , Adulto , Biotransformación , Diuréticos/administración & dosificación , Diuréticos/metabolismo , Glucuronatos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/metabolismo , Circulación Renal/efectos de los fármacos , Triazoles/administración & dosificación , Triazoles/metabolismo , Vasodilatadores/administración & dosificación , Vasodilatadores/metabolismoRESUMEN
The disposition and metabolism of a 5-nitroimidazole compound (SC 28538) was investigated in the rat, beagle dog and rhesus monkey. The absorption of [14C]-SC 28538 was rapid and essentially complete after oral dosage in male animals, and also after intravaginal dosage in the female rat. Peak plasma levels of radioactivity occurred within 2 h of dosage. In the rat and dog the radioactivity was excreted predominantly in the faeces (greater than 60%) but in the monkey more than 60% was excreted in the urine. In both the male and pregnant female rat radioactivity was concentrated in the gastro-intestinal tract, liver and harderian gland and the concentrations of radioactivity in other tissues was generally lower than in plasma. Radioactivity was cleared more rapidly from plasma than from the majority of tissues. SC 28538 was extensively metabolised to form glucuronide and amino acid conjugates. The half-life of SC 28538 was of the order of 1 h in the dog and 3.7 h in the monkey.
Asunto(s)
Nitroimidazoles/farmacocinética , Animales , Sistema Digestivo/metabolismo , Perros , Heces/análisis , Femenino , Haplorrinos , Hígado/metabolismo , Masculino , Embarazo , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
The disposition of [14C]pranolium chloride, a dimethyl quaternary derivative of propranolol, has been studied in rats, mice and hamsters after oral parenteral dosage. 2. Elimination of 14C occurred largely via the kidneys after parenteral dosage, but biliary excretion was significant. Pranolium chloride was excreted unchanged and as a conjugate, and was also metabolized to 1-naphthol which was conjugated. 3. The radiolabel was localized in the liver, kidneys, heart, lungs and gastro-intestinal tract of the rat, but did not pass the placental or blood-brain barriers to any appreciable extent. Unchanged pranolium chloride was localized in rat cardiac tissue for at least 6 h after i.v. dosage. 4. Pranolium chloride was poorly and variably absorbed from the gastro-intestinal tract of animals. Peak plasma levels occurred between 10 min and 1 h. The absorption of the pranolium cation was marginally increased after prolonged fasting, but was not affected by the presence of alternative anions.
Asunto(s)
Propranolol/análogos & derivados , Animales , Bilis/análisis , Cricetinae , Masculino , Ratones , Propranolol/metabolismo , Ratas , Distribución TisularRESUMEN
The stable isotope co-administration technique for estimating the bioavailability of drugs has been investigated in a series of experiments using rhesus monkeys. The compound chosen for study was disopyramide phosphate. A cross-over study was designed whereby the animals received disopyramide phosphate (administered intravenously at 5 mg kg-1) and [13C, 15N]disopyramide phosphate (administered orally at 5 mg kg-1), with a wash-out period between doses. A co-administration study was carried out whereby both the oral and intravenous doses were administered together. The co-administration study was repeated. The results from the cross-over study showed [13C, 15N]disopyramide to have an oral availability of 4.9 +/- 0.9% (by comparing areas under the plasma concentration versus time curves). The bioavailability was estimated to be 5.7 +/- 0.3% comparing totals excreted in urine over 48 h. The bioavailability of the oral dose was calculated as 8.2 +/- 2.5% (comparing areas under plasma concentration versus time curves) and 9.3 +/- 3.0% (comparing totals excreted in urine) after co-administration. The differences between these results and the cross-over results were examined in a further study, using oral administration only. The animals were dosed orally with a solution containing both disopyramide phosphate (5 mg kg-1) and [13C, 15N]disopyramide phosphate (5 mg kg-1). No differences were observed between the plasma concentration versus time curves or urinary excretion for either isotope. It is unlikely that the discrepancy in bioavailability is due to absorption, metabolism or exretion of the oral dose. It is probable that the high concentration of disopyramide obtained after the intravenous dosage affects the disposition of the oral dose, and this gives the higher figure.