RESUMEN
SURGIFOAM (Absorbable Gelatin Sponge, USP), a new absorbable hemostatic sponge, GELFOAM (Absorbable Gelatin Sponge, USP) or Avitene (microfibrillar collagen hemostat) were evaluated in a three-month tissue reaction and absorption study in rabbits. Bilateral craniotomy was followed by subdural implantation of each hemostatic device. A sham control group was treated in a similar way except that no material was implanted. Implantation of these hemostatic devices for 15, 43, or 92 days did not result in any deaths or clinical neurobehavioral abnormalities, changes in cerebrospinal fluid, or significant macroscopic observations at necropsy. The tissue reaction to SURGIFOAM sponge was characterized by transient granulomatous inflammation that was slightly less intense than that observed for GELFOAM sponge which correlated to slightly longer absorption. In contrast, the tissue reaction to Avitene hemostat was characterized by moderate to marked granulomatous inflammation with an acute inflammatory component indicating a greater degree of tissue irritancy. Sequelae of this reaction were still observed at 92 days post-implantation. The tissue reaction in humans to SURGIFOAM sponge used as a hemostatic agent for neurologic surgical procedures is expected to be comparable to that observed with GELFOAM sponge, resulting in no significant adverse reactions for patients. This animal model was useful to assess the tissue reaction and absorption of biomaterials implanted in contact with the central nervous system, and it was able to differentiate between materials of biologic origin.
Asunto(s)
Pérdida de Sangre Quirúrgica/prevención & control , Encefalitis/inducido químicamente , Meningitis/inducido químicamente , Procedimientos Neuroquirúrgicos/instrumentación , Espacio Subdural/cirugía , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Encefalitis/patología , Encefalitis/fisiopatología , Esponja de Gelatina Absorbible/efectos adversos , Esponja de Gelatina Absorbible/metabolismo , Meninges/efectos de los fármacos , Meninges/patología , Meninges/fisiopatología , Meningitis/patología , Meningitis/fisiopatología , Procedimientos Neuroquirúrgicos/métodos , Proyectos Piloto , Conejos , Resultado del TratamientoRESUMEN
Dura-Guard Dural Repair Patch, PRECLUDE Dura Substitute, and Codman ETHISORB Dura Patch were evaluated in a six-month dural tissue reaction study in rabbits. Bilateral craniotomy was followed by subdural implantation for each dura mater substitute. The surgical procedure for the sham control group was the same except that no material was implanted. Implantation of all of these dura mater substitutes for 28, 91, or 182 days post-implantation did not result in any deaths or clinical neurobehavioral abnormalities, changes in cerebrospinal fluid, or significant macroscopic changes at necropsy. However, histomorphologic evaluation of the implantation sites revealed some differences in the tissue response to these materials. For Dura-Guard Dural Repair Patch, a nonabsorbable material derived from bovine pericardium, the implantation site was characterized by fibrosis of the overlying area with islands of osseous metaplasia and adhesions to the brain surface. Over time, infiltrative fibrosis of the implant resulted in separation of the collagenous layers of the implant and compression of the underlying brain. Fibrosis of the overlying area that incorporated this material formed a 'replacement' dura mater. Adhesions to the brain surface observed initially were still present at six months post-implantation. Implantation of PRECLUDE Dura Substitute, a nonabsorbable material comprised of expanded polytetrafluoroethylene, resulted in virtually no early reaction, and few adhesions to the brain surface at any time period. Although this material was eventually incorporated by fibrosis, islands of osseous metaplasia were also observed in this 'replacement' dura mater. The tissue reaction to Codman ETHISORB Dura Patch, an absorbable material comprised of polyglactin 910 and polydioxanone, was generally characterized by low-grade granulomatous inflammation and initial adhesions to the brain surface. The three-dimensional structure of this implant acted as a scaffold to guide the development and integration of a 'replacement' dura mater. The absorption of the material was associated with complete resolution of the inflammatory reaction, a lack of cerebral adhesions, and restoration of the normal architecture of this region. In conclusion, subdural implantation of Dura-Guard Dural Repair Patch, PRECLUDE Dura Substitute, or Codman ETHISORB Dura Patch in rabbits for up to six months resulted in the eventual restoration of the dura mater without significant adverse effects. However, osseous metaplasia associated with nonabsorbable Dura-Guard Dural Repair Patch and PRECLUDE Dura Substitute, and the infiltration of Dura-Guard Dural Repair Patch by fibrosis suggests that long-term follow-up may be needed after the use of these materials in patients. An advantage of Codman ETHISORB Dura Patch was that it was completely absorbed after guiding the restoration of the dura mater without any morphological sequelae.
Asunto(s)
Materiales Biocompatibles , Encéfalo/cirugía , Duramadre/cirugía , Implantes Absorbibles , Animales , Encéfalo/patología , Duramadre/patología , Fibrosis , Inflamación , Modelos Animales , Polidioxanona , Poliglactina 910 , Politetrafluoroetileno , Conejos , Adherencias Tisulares , Cicatrización de HeridasRESUMEN
The effects of the steroidal androgen receptor antagonist zanoterone (WIN 49596) and the steroidal 5 alpha-reductase inhibitor finasteride (MK-906) either alone or in combination on prostatic size, histomorphology, and biochemistry were determined in the intact male dog. Additionally, the effects of treatment with zanoterone and/or finasteride on testicular size, serum testosterone and LH levels, and spermatogenesis were determined in the same dogs. Daily oral treatment for 16 weeks with either zanoterone alone at 10 mg/kg.day or finasteride alone at 1.0 mg/kg.day reduced (P < 0.05) the size of the prostate, resulted in mild to moderate diffuse glandular atrophy of the prostate, and decreased prostatic DNA and prostatic arginine esterase (the primary canine prostatic protein) levels compared to those in intact controls. These changes occurred with no effect on testicular weight, testicular histomorphology, daily sperm production, or serum LH levels. Serum testosterone concentrations were increased (P < 0.05) approximately 3-fold in the 10 mg/kg.day zanoterone treatment group compared to those in intact controls. Combination treatment of male dogs for 16 weeks with zanoterone (10 mg/kg.day) plus finasteride (1.0 mg/kg.day) orally also reduced (P < 0.05) prostate size, resulted in moderate to marked diffuse prostatic glandular atrophy, and decreased prostatic DNA and arginine esterase levels more than either drug alone, without affecting testicular size, testicular histomorphology, serum LH concentrations, or serum testosterone concentrations compared to those in intact controls. The effects of combination treatment with zanoterone and finasteride on prostatic size; histomorphology; and DNA, arginine esterase protein, and arginine esterase mRNA levels were similar to those observed in castrate controls. In addition, in situ estimates of prostatic size using transrectal ultrasonography indicated that the median time to 70% prostatic regression in dogs administered combination zanoterone plus finasteride was similar to that in castrate controls (9.6 and 9.3 weeks, respectively), indicating that the combination was more effective in causing prostatic regression than either drug alone. Finally, at the dosages used, no adverse effects of combination treatment with zanoterone plus finasteride on testicular or other major body organ weights were observed. Based on these results, combination therapy using zanoterone and finasteride for the treatment of human androgen-dependent disorders such as benign prostatic hyperplasia and prostate cancer has potential utility.
Asunto(s)
Androstenos/farmacología , Azaesteroides/farmacología , Pregnanos/farmacología , Próstata/efectos de los fármacos , Pirazoles/farmacología , Testículo/efectos de los fármacos , Androstenos/administración & dosificación , Animales , Azaesteroides/administración & dosificación , Secuencia de Bases , Hidrolasas de Éster Carboxílico/genética , Hidrolasas de Éster Carboxílico/metabolismo , ADN/metabolismo , Perros , Epidídimo/anatomía & histología , Finasterida , Inmunohistoquímica , Hormona Luteinizante/sangre , Masculino , Datos de Secuencia Molecular , Tamaño de los Órganos , Pregnanos/administración & dosificación , Próstata/anatomía & histología , Próstata/metabolismo , Pirazoles/administración & dosificación , ARN Mensajero/metabolismo , Testículo/anatomía & histología , Testículo/metabolismo , Testosterona/sangreRESUMEN
Ipazilide fumarate (WIN 54177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. The compound is being developed as oral and iv therapy for ventricular and supraventricular arrhythmias. Since ipazilide therapy may require long-term use, a 1-year oral gavage study (daily dosages of 20, 80, or 160 mg/kg) was conducted in rats. Controls received the purified water vehicle. Treatment-related clinical signs were limited to post-dosing salivation. Increased relative liver weight (females, at 80 and 160 mg/kg) was correlated with centrilobular hypertrophy, but was not associated with significant increased serum liver enzymes activities. These liver weight changes were interpreted as an adaptive metabolic response and were not considered toxicologically significant. An increased incidence of centrilobular hepatocellular vacuolation representing lipid accumulation over that observed for male controls occurred for males in all ipazilide-treated groups. This observation, however, was not correlated with elevated hepatic enzyme activities. Hepatocellular basophilic foci were observed for females only (80 and 160 mg/kg groups); however, the significance of this lesion is unclear. Transient dosage-related duodenal villous atrophy/sloughing was observed for males from the 80 and 160 mg/kg groups. Mild increases in hemoglobin, hematocrit, urea, and creatinine (160 mg/kg), attributed to treatment, were considered of minor toxicologic importance. Likewise, no clinical or anatomical pathologic observations that may indicate cardiac toxicity were determined. It is concluded that a dosage of 20 mg/kg (two to three times the clinical efficacious dosage) was considered a no-effect dosage level since it did not produce any effects of toxicological significance.
Asunto(s)
Antiarrítmicos/toxicidad , Pirazoles/toxicidad , Administración Oral , Animales , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Atrofia/inducido químicamente , Esquema de Medicación , Duodeno/efectos de los fármacos , Duodeno/patología , Femenino , Hemoglobinas/análisis , Hipertrofia/inducido químicamente , Recuento de Leucocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Pirazoles/sangre , Pirazoles/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Recombinant human interleukin 4 (rhuIL-4) is a candidate for the treatment of refractory cancer based on its potential to enhance immune function. Recombinant human IL-4 was administered subcutaneously at 0, 1, 5, or 25 micrograms/kg/day for 28 days with a 14-day recovery to male and female cynomolgus monkeys as part of the preclinical safety evaluation. Clinical pathologic changes related to treatment with rhuIL-4 were evidence of consumptive coagulopathy, erythrocyte fragmentation, lymphocytosis, and lymphocyte morphologic changes indicative of marked antigenic or mitogenic stimulation, mild eosinophilia and neutrophilia, hypoalbuminemia, hypocholesterolemia, and hypertriglyceridemia. Based on data obtained after the 14-day recovery period, the clinical pathologic changes associated with rhuIL-4 administration were considered to be reversible.
Asunto(s)
Interleucina-4/toxicidad , Animales , Atrofia/inducido químicamente , Coagulación Sanguínea/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Recuento de Eritrocitos/efectos de los fármacos , Femenino , Granulocitos/efectos de los fármacos , Granulocitos/patología , Hematócrito , Hemoglobinas/efectos de los fármacos , Humanos , Hiperplasia/inducido químicamente , Inyecciones Subcutáneas , Recuento de Leucocitos/efectos de los fármacos , Macaca fascicularis , Masculino , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Tiempo de Protrombina , Proteínas Recombinantes/toxicidad , Túbulos Seminíferos/efectos de los fármacos , Túbulos Seminíferos/patología , Vasculitis/inducido químicamente , Vasculitis/patologíaRESUMEN
Recombinant human IL-4 (rhuIL-4) is primate-specific and produces multiple biologic effects on lymphoid cells involved in protection against cancer. RhuIL-4 was evaluated in the cynomolgus monkey to support clinical studies for the immunotherapy of cancer. Administration of rhuIL-4 to monkeys by SC injection of 0, 0.5, 2.5 or 12.5 micrograms/kg BID for one-month (with two-week recovery) resulted in alterations in clinical chemistry and hematology (CCH) parameters consistent with a consumptive coagulopathy. Histomorphologic evaluation revealed increased granulopoiesis, testicular atrophy, and proliferative and inflammatory vascular lesions (VL). IVL principally affected the arterial tree with some proliferation of medial smooth muscle. During the latter part of the treatment and recovery period. CCH parameters approached or returned to pretreatment values, the former finding attributed to the production of antibody to rhuIL-4. At final necropsy, bone marrow appeared normal, and IVL decreased in incidence and severity. ELISA studies of serum indicated 50-90% of the monkeys developed antibody titers > 1000 by Day 22 (not observed in man). The frequency and severity of adverse effects due to rhuIL-4 in the clinic appear to be does-related and reversible with few objective responses to therapy observed. Common toxicities included milk to moderated fever and fatigue and an occasional change in hematopoietic, hepatic and renal function. The monkey predicted hematologic findings, but not all target organ effects.
Asunto(s)
Interleucina-4/toxicidad , Animales , Anticuerpos/análisis , Evaluación Preclínica de Medicamentos , Femenino , Interleucina-4/inmunología , Macaca fascicularis , Masculino , Tamaño de los Órganos/efectos de los fármacos , Proteínas Recombinantes/toxicidad , Albúmina Sérica/análisisRESUMEN
Ipazilide fumarate (Win 54, 177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. Subchronic (29 days) nonclinical safety evaluation of ipazilide was conducted following oral and iv administration in Sprague-Dawley rats (20-320 mg/kg oral and 1.25-10 mg/kg iv) and 14 and 28 days in beagle dogs (3-30 mg/kg oral and 2.5-20 mg/kg iv). The pharmacokinetic parameters of ipazilide indicate that ipazilide is absorbed (tmax less than or equal to 1 hr) in fasted rats and dogs following single and repeated oral administrations. The apparent elimination half-life in the two species is approximately 1 hr (except in rats at a dosage of 320 mg/kg), suggesting rapid clearance. Increases in liver weights (rats 320 mg/kg) accompanied by the observation of centrilobular hypertrophy of hepatocytes were considered an expression of an adaptive metabolic response of the liver to ipazilide and may be associated with the induction of microsomal enzymes. Duodenal villous atrophy and epithelial hyperplasia (rats, 80 and 320 mg/kg) were interpreted to represent an irritant response to the drug. Local irritation was also observed at the injection site in rats and dogs. Dogs tolerated the oral and the iv administration of ipazilide at dosages of up to 30 and 20 mg/kg, respectively. Despite emesis (oral dogs), which was reduced in frequency following repeated treatment over several weeks, plasma levels in treated dogs (i.e., Cmax 4-5 micrograms/ml) were approximately twice that required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antiarrítmicos/farmacocinética , Pirazoles/farmacocinética , Administración Oral , Animales , Antiarrítmicos/toxicidad , Peso Corporal/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Femenino , Inyecciones Intravenosas , Masculino , Pirazoles/toxicidad , Ratas , Ratas EndogámicasRESUMEN
The purpose of this presentation was to review issues and findings in the pre-clinical development and evaluation of recombinant human protein therapeutics. Since human cytokines and lymphokines are endogenous proteins, their pre-clinical development and evaluation would seem straightforward and their toxicities minimal. Unfortunately, the pre-clinical development of this class of agents has been problematic and confounding. Some of the clinical toxicities and pharmacodynamics have been predicted by the pre-clinical evaluation and others have not. Some molecules are species specific which limits species selection for pre-clinical evaluation. Other confounding issues include: route of exposure, synergy of toxicity with other lymphokines, length of study design, immunogenicity, predictiveness of pre-clinical evaluation and iatrogenic toxicities. An approach used by SWPRD in the evaluation of this class of molecules was discussed. Insight gained during the pre-clinical and clinical development of these molecules should simplify the further development of protein therapeutics that follow. Specific studies with recombinant human interleukin-4 (rhuIL-4) were reviewed in detail as part of a pre-clinical safety evaluation. Native IL-4 has properties that exemplify many of the immune recognition-induced lymphokines and is produced principally by activated T-lymphocytes CD4+. It is a co-factor in B-cell proliferation and enhances ex vivo B-cell expansion and is believed to be a candidate for the treatment of refractory cancer based on this immune enhancement ability. rhuIL-4 is a 15,400 molecular weight cytokine produced in a yeast expression system.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hematopoyesis/efectos de los fármacos , Inflamación/etiología , Interleucina-4/toxicidad , Animales , Evaluación Preclínica de Medicamentos , Femenino , Interleucina-4/inmunología , Masculino , Proteínas Recombinantes/toxicidad , Especificidad de la EspecieRESUMEN
Recombinant human interleukin-4 (rhuIL-4) is a candidate for the treatment of refractory cancer based on its potential to enhance the function of the immune system. Total daily dosages of 0 (placebo control), 1, 5, or 25 micrograms/kg of rhuIL-4 were given as divided (b.i.d.) subcutaneous dosages to male and female cynomolgus monkeys (5/sex/group) for 1 month followed by a 2-week recovery. Histomorphologic evaluation of 3/sex/group at 1 month revealed vascular lesions, granulocytic hyperplasia, and seminiferous tubular atrophy attributed to treatment with rhuIL-4. Dosage-dependent proliferative and inflammatory vascular lesions with eosinophil infiltration affected principally the arterial tree. After 2 weeks of recovery, these lesions, including chronic endarteritis and chronic and/or obliterative arteritis, occurred with an overall lower incidence, and were not observed for monkeys from the 1.0 micrograms/kg/day group. Granulocytic hyperplasia in bone marrow observed for monkeys from all groups given rhuIL-4 at 1 month was not present after 2 weeks of recovery. Seminiferous tubular atrophy was observed for monkeys from the 5 and 25 micrograms/kg/day groups at 1 month and after 2 weeks of recovery.
Asunto(s)
Interleucina-4/administración & dosificación , Animales , Vasos Sanguíneos/citología , Vasos Sanguíneos/efectos de los fármacos , Femenino , Genitales Masculinos/citología , Genitales Masculinos/efectos de los fármacos , Sistema Hematopoyético/citología , Sistema Hematopoyético/efectos de los fármacos , Humanos , Tejido Linfoide/citología , Tejido Linfoide/efectos de los fármacos , Macaca fascicularis , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Enfermedades Vasculares/inducido químicamente , Enfermedades Vasculares/patologíaRESUMEN
An intestinal schwannoma (neurilemmoma) was found in an aged female rhesus monkey culled from a research colony. The neoplasm was characterized principally by palisades of spindle-shaped cells (Antoni type A) surrounded by thick argyrophilic fibres, while plump cells with areas of vacuolation (Antoni type B) were observed to a lesser extent. Thick hyalinized perivascular cuffs were prominent and multifocal thromboses were present in cavernous vascular channels. Electron microscopic examination of the intercellular matrix between Antoni type A cells revealed long-spacing (100 to 120 nm) collagen fibrils. Although the mass had expanded beyond the confines of the muscularis externa, the cytological features of the neoplasm appeared benign.
Asunto(s)
Neoplasias Intestinales/veterinaria , Enfermedades de los Monos/patología , Neurilemoma/veterinaria , Animales , Femenino , Neoplasias Intestinales/patología , Neoplasias Intestinales/ultraestructura , Macaca mulatta , Microscopía Electrónica , Neurilemoma/patología , Neurilemoma/ultraestructuraRESUMEN
Brain tissue sections from control male and female Fischer 344 (F344) rats from ten National Toxicology Program (NTP) Bioassays were histomorphologically reviewed for non-neoplastic lesions of the hippocampus. Unilateral segmental hippocampal neuronal necrosis, which has not been reported in normal rats, was observed in 9 of 433 (2.1 per cent) males and 1 of 454 (0.2 per cent) females. Significant coexisting lesions were left-sided atrial and/or valvular thrombosis, metastatic mesothelioma, and large lymphocyte leukaemia. These data suggest that this naturally occurring lesion of predominantly aged male rats may result from an impairment of cerebral perfusion secondary to vascular obstruction by thrombotic emboli or leukaemic cells and haemolytic anaemia concomitant with large lymphocyte leukaemia, which commonly occurs in F344 rats.
Asunto(s)
Hipocampo/patología , Animales , Ratones , Necrosis , Neuronas/patología , Ratas , Ratas Endogámicas F344RESUMEN
The effect of the steroidal androgen receptor antagonist Win 49,596 on the prostate and testis was studied in beagle dogs and was compared to the effects of the nonsteroidal androgen receptor antagonist ICI 176,334 and the steroidal 5 alpha-reductase inhibitor MK-906. Win 49,596 was shown to bind to the androgen receptor from normal canine prostate with a Ki of 2.2 microM. After 16 weeks of treatment, prostate size, as estimated by transrectal ultrasonography, was unchanged in intact controls and was 26% of the initial size in castrate controls. Oral doses of Win 49,596 from 0.625-40 mg/kg.day for 16 weeks caused dose-dependent prostatic regression and a dose-related increase in both the incidence and severity of glandular atrophy of the prostate. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at 40 mg/kg.day on prostatic weight, total DNA, histomorphology, and secretory function were similar to those of castration, while the effects of Win 49,596 at 10 mg/kg.day were similar to those of ICI 176,334 at 0.25 mg/kg.day and MK-906 at 1.0 mg/kg.day. No effects on testicular weight, daily sperm production, or spermatogenesis were observed; however, mild Leydig cell hyperplasia was observed in two dogs treated with 40 mg/kg.day Win 49,596. In addition, at 10 and 40 mg/kg.day Win 49,596, moderate but variable increases in serum testosterone levels were observed. In summary, Win 49,596 caused regression of the hypertrophic canine prostate without effects on spermatogenesis and/or sexual function, supporting its possible use in the treatment of human benign prostatic hypertrophy/hyperplasia.
Asunto(s)
Antagonistas de Andrógenos , Pregnanos/farmacología , Próstata/efectos de los fármacos , Hiperplasia Prostática/tratamiento farmacológico , Pirazoles/farmacología , Receptores Androgénicos/efectos de los fármacos , Testículo/efectos de los fármacos , Inhibidores de 5-alfa-Reductasa , Antagonistas de Andrógenos/metabolismo , Androstenos/metabolismo , Androstenos/farmacología , Anilidas/metabolismo , Anilidas/farmacología , Animales , Azaesteroides/metabolismo , Azaesteroides/farmacología , ADN/metabolismo , Perros , Finasterida , Hipertrofia , Masculino , Nitrilos , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Pregnanos/metabolismo , Pregnanos/uso terapéutico , Próstata/patología , Próstata/fisiopatología , Pirazoles/metabolismo , Pirazoles/uso terapéutico , Receptores Androgénicos/fisiología , Semen/metabolismo , Espermatogénesis/efectos de los fármacos , Testículo/fisiopatología , Testosterona/sangre , Compuestos de Tosilo , UltrasonografíaRESUMEN
A series of experiments were conducted to investigate the regulation of the primary secretory protein of the canine prostate, arginine esterase, by androgens and/or new antiandrogen under development. In the first experiment, castration decreased (P less than 0.05) prostatic arginine esterase levels relative to intact controls (0.26 +/- 0.1 and 17.0 +/- 0.1 mumole/min/mg protein, respectively). Treatment of castrate dogs with either 5, 10, or 20 silastic capsules (8 cm length) containing the androgen 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) plus 1 capsule containing estradiol-17 beta (E2) or the i.m. injection of 25 mg 3 alpha-diol and 0.25 mg E2 for 12 weeks resulted in a dose-dependent increase (P less than 0.05) in prostatic arginine esterase activity (6.8 +/- 1.7, 19.0 +/- 3.6, 21.3 +/- 0.9, and 14.2 +/- 0.7 mumole/min/mg protein, respectively). In the second experiment, steroid treatment (10 3 alpha-diol plus 1 E2 silastic capsules) of castrate dogs for 12 weeks resulted in prostatic arginine esterase activity of 17.8 +/- 2.3 mu mole/min/mg. Co-administration of the steroidal androgen receptor antagonist. Win 49,596 (WIN) at doses of 0.625, 2.5, 10, or 40 mg/kg/day p.o., dose-dependently inhibited (P less than 0.05) prostatic arginine esterase activity (14.9 +/- 1.1, 14.3 +/- 1.3, 3.4 +/- 1.9, and 0.21 +/- 0.1 mumole/min/mg, respectively) to levels similar to that observed in castrate controls (0.14 +/- 0.03 mumole/min/mg). Administration of the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day p.o. to steroid-induced dogs also inhibited (P less than 0.05) arginine esterase activity (0.07 +/- 0.02 mumole/min/mg). In the last experiment, treatment of intact dogs with WIN at 0.625, 2.5, 10, and 40 mg/kg/day for 16 weeks dose-dependently reduced (P less than 0.05) arginine esterase levels (17.0 +/- 1.0, 16.3 +/- 1.5, 10.2 +/- 1.2, and 3.9 +/- 2.5 mumole/min/mg, respectively) compared to intact controls (14.4 +/- 1.2 mumole/min/mg). Histomorphologic and ultrastructural evaluation of prostates from dogs indicated that antiandrogen treatment resulted in glandular epithelial atrophy as well as a reduction in the number of secretory granules. The results of these experiments support that canine prostatic arginine esterase activity is under androgenic control, can be inhibited by antiandrogen treatment and may serve as a functional marker of the androgenic state of the prostate. Whether the effects of androgen and antiandrogens on prostatic arginine esterase is direct or indirect due to a general inhibitory effect on secretory epithelial cell function requires additional study. Furthermore, subject to further evaluation, the steroidal androgen receptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Antagonistas de Andrógenos/farmacología , Andrógenos/farmacología , Hidrolasas de Éster Carboxílico/metabolismo , Próstata/efectos de los fármacos , Inhibidores de 5-alfa-Reductasa , Androstano-3,17-diol/farmacología , Androstenos/farmacología , Anilidas/farmacología , Animales , Azaesteroides/farmacología , Cápsulas , Perros , Relación Dosis-Respuesta a Droga , Estradiol/farmacología , Finasterida , Flutamida/farmacología , Hiperplasia/tratamiento farmacológico , Inyecciones Intramusculares , Masculino , Nitrilos , Pregnanos/farmacología , Próstata/citología , Próstata/enzimología , Prostatectomía , Pirazoles/farmacología , Compuestos de TosiloRESUMEN
The effects of the steroidal androgen receptor antagonist Win 49,596 on steroid-induced prostatic growth, histomorphology, and secretory function were studied in the castrate male beagle dog. At oral doses ranging from 0.625 to 40 mg/kg/day for 12 weeks, Win 49,596 inhibited prostatic growth in terms of both weight and total DNA in a dose-dependent manner. In addition, both the incidence and severity of diffuse glandular hyperplasia/hypertrophy were dose-dependently inhibited by Win 49,596, resulting in diffuse glandular atrophy. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at a dosage of 40 mg/kg/day were similar to that observed for the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day. Oral administration of Win 49,596 to castrate dogs at a dosage of 40 mg/kg/day for 12 weeks failed to produce any evidence of agonist activity. These results demonstrate that Win 49,596 prevented the experimental induction of benign prostatic hyperplasia in dogs and suggest that on further evaluation this compound may be efficacious in the treatment of the human disease.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Pregnanos/farmacología , Hiperplasia Prostática/prevención & control , Pirazoles/farmacología , Andrógenos/sangre , Animales , ADN/análisis , Perros , Masculino , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Pregnanos/uso terapéutico , Próstata/metabolismo , Próstata/patología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Pirazoles/uso terapéutico , UltrasonografíaRESUMEN
A model for the dose-dependent hormonal induction of benign prostatic hyperplasia (BPH) in castrated dogs has been established using subcutaneously implanted Silastic capsules containing 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) and estradiol-17 beta. In vivo release rates per capsule approximated 122.0 +/- 4.2 micrograms 3 alpha-diol and 22.7 +/- 0.8 micrograms estradiol per day based on in vitro studies and resulted in dose-dependent increases in serum 3 alpha-diol and dihydrotestosterone concentrations. The implantation of castrated dogs with either 10 or 20 Silastic capsules containing 3 alpha-diol and one capsule containing estradiol or the intramuscular injection of 3 alpha-diol (75 mg/week) and estradiol (0.75 mg/week) for 99 days significantly increased (P less than .01) prostatic weights and total prostatic DNA over intact controls. These treatments also resulted in a histomorphological pattern similar to that observed in dogs with the glandular form of spontaneous BPH. In addition, normal prostatic secretory function as determined by semen volume was maintained in these dogs. Although subcutaneous implantation of five Silastic capsules containing 3 alpha-diol and one capsule containing estradiol into castrated dogs resulted in prostatic weights and total prostatic DNA that were similar (P less than .10) to intact controls, these prostates were characterized histomorphologically by glandular atrophy and squamous metaplasia. Furthermore, prostatic secretory function was decreased (P less than .05) in these animals compared with intact controls at 3 months of treatment. This study has led to the development of a model of steroid-induced BPH that will facilitate the evaluation of competitive androgen-receptor antagonists in the dog.
Asunto(s)
Androstano-3,17-diol/toxicidad , Androstanoles/toxicidad , Estradiol/toxicidad , Hiperplasia Prostática/inducido químicamente , Animales , Cromatografía Líquida de Alta Presión , Dihidrotestosterona/sangre , Perros , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos , Estradiol/análisis , Masculino , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Semen/análisis , Testosterona/sangreRESUMEN
Oral administration of ciprofibrate, a potent hypolipidemic compound, to rats for 2 or more weeks at doses of 20 mg/kg/day or more resulted in hypertrophy and increased eosinophilia of the oxyntic cells in the gastric mucosa. Ultrastructural evaluation revealed small secretory canaliculi with small microvilli in these cells, changes consistent with the inhibition of acid secretion. After longer administration (e.g., greater than 2 months at 20 mg/kg/day), hyperplasia of the neuroendocrine cells (in particular, the enterochromaffin-like cells) was present in the fundic mucosa of the stomach. After life-time (2-year) administration at 10 mg/kg/day, neuroendocrine cell hyperplasia was accompanied by formation of malignant carcinoid tumors in the fundus of 5 of 59 male and 1 of 60 female rats. In contrast, administration of ciprofibrate to mice at 20 mg/kg/day for 2 months was not associated with oxyntic or neuroendocrine cell changes, a finding consistent with the lack of gastric carcinoid tumors in a 2-year mouse study. Similarly, no significant changes were induced in the marmoset stomach by doses as high as 100 mg/kg/day for 6 months. These findings are consistent with the hypothesis that the formation of gastric carcinoid tumors following ciprofibrate administration is a phenomenon that occurs specifically in those species such as the rat where this compound has significant gastric antisecretory activity.
Asunto(s)
Tumor Carcinoide/inducido químicamente , Clofibrato/análogos & derivados , Ácido Clofíbrico/análogos & derivados , Hipolipemiantes/toxicidad , Neoplasias Gástricas/inducido químicamente , Animales , Callitrichinae , Tumor Carcinoide/patología , Ácido Clofíbrico/toxicidad , Ácidos Fíbricos , Mucosa Gástrica/patología , Gastrinas/sangre , Masculino , Ratones , Microscopía Electrónica , Ratas , Ratas Endogámicas F344 , Neoplasias Gástricas/patologíaRESUMEN
During a toxicology study in cynomolgus (long-tailed or crab-eating) monkeys (Macaca fascicularis), a randomly distributed incidence of significantly increased hepatic enzyme activity was observed. Premedication hepatic enzyme activity in all monkeys of this study was normal, but increased alanine aminotransferase (ALT) activity was found in 4 of the 24 animals 2 weeks after initiation of the study and in 10 of 24 at 4 weeks. A drug-related effect was considered unlikely initially because the increases were not doserelated, and a 3-year review of 655 cynomolgus monkeys revealed a 15-20% incidence of increased hepatic enzyme activity. Good correlation was subsequently established between increased hepatic enzyme activity, active hepatitis A virus (HAV) infection, and histomorphologic confirmation of hepatitis (chronic periportal inflammation). Follow-up viral serodiagnostic screening of resident macaques revealed an overall incidence of anti-HAV IgG in 80% (155/193) of cynomolgus and in 70% (14/20) of rhesus monkeys. Serial screening demonstrated that several initially negative monkeys became seropositive for anti-HAV IgG, and a few acquired active infection (anti-HAV IgM). Among newly acquired cynomolgus monkeys, 2.5% (2/80) had an acute HAV infection, and 35% (28/80) eventually tested positive for anti-HAV IgG while quarantined in the primate facility. The characterization of an enzootic HAV infection in incoming monkeys posed a significant risk for the primate colony and handlers. Rigorous sanitation, isolation, and quarantine procedures, including personnel training and additional protective clothing for personnel working in the primate colony, reduced tho potential for transmission and arrested the outbreak. Experimenters should be cautious in ascribing toxicity to a test article based solely on increased hepatic enzyme activity associated with chronic periportal inflammation.
RESUMEN
A non-ionic diagnostic medium, iohexol, was administered by subarachnoid injection to groups of six cynomolgus monkeys and compared with the vehicle, physiologically normal saline, and/or saline of equal osmolality to determine its potential for increasing total protein and leucocyte levels in cerebrospinal fluid. Also investigated was the effect of repeated spinal taps not subsequently followed by the intrathecal injection of test or control articles. In the monkey, unlike man, low-level leucocyte counts were consistently observed following initial withdrawal of spinal fluid. Elevated leucocyte and total protein levels were observed in the present investigations one day to a week after intrathecal injection of radiopaque, vehicle or saline solution. Total protein returned to normal levels earlier than did leucocyte counts. However, repeated needle puncture alone was found to be sufficient to cause an elevation of leucocytes 3 to 4 times the baseline level, while inflammatory effects were observed histologically only when autopsy was performed soon after the final spinal tap.
Asunto(s)
Medios de Contraste/administración & dosificación , Yodobenzoatos/administración & dosificación , Ácidos Triyodobenzoicos/administración & dosificación , Animales , Proteínas del Líquido Cefalorraquídeo/análisis , Medios de Contraste/efectos adversos , Inyecciones Espinales , Yohexol , Recuento de Leucocitos , Macaca fascicularis , Vehículos Farmacéuticos/efectos adversos , Cloruro de Sodio/administración & dosificación , Ácidos Triyodobenzoicos/efectos adversosRESUMEN
Five different pharmacologic agents were examined for their effects upon edema, hemorrhage, and vascular infiltration by neutrophils in the reverse passive Arthus reaction (RPAR) in guinea pigs. Two agents, colchicine (3.0 mg/kg p.o.) and ibuprofen (100 mg/kg p.o.) significantly inhibited all three parameters of RPAR. Cobra venom factor (100 units/kg i.p.) inhibited edema and hemorrhage but it did not inhibit neutrophil infiltration. Aminophylline and sulfinpyrazone (100 mg/kg p.o.) inhibited only hemorrhage; they did not inhibit edema or neutrophil infiltration. The results from these studies with five chemically or biologically unrelated pharmacologic agents suggest that the RPAR in guinea pigs can be separated into its basic components (edema, hemorrhage, and neutrophilic infiltration) by selective inhibitors. Inhibition of edema and hemorrhage, or hemorrhage alone of the two-hour RPAR in guinea pigs is not dependent upon inhibition of neutrophilic infiltration.
Asunto(s)
Antiinflamatorios/farmacología , Reacción de Arthus/prevención & control , Aminofilina/farmacología , Animales , Colchicina/farmacología , Edema/prevención & control , Cobayas , Hemorragia/prevención & control , Ibuprofeno/farmacología , Masculino , Neutrófilos/efectos de los fármacos , Sulfinpirazona/farmacología , Factores de TiempoRESUMEN
A spontaneous ameloblastic odontoma was found in an 86-week-old male Fischer 344 rat. Radiographic and histopathologic characteristics confirmed the diagnosis as a true benign neoplasm.