RESUMEN
The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed the presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology after nodul-ectomy at four months post-therapy showed that 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, although it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Sequential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/kg twice daily post-prandially for three consecutive days) was well absorbed with predictable plasma levels, macro- and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.
Asunto(s)
Filaricidas/uso terapéutico , Onchocerca/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Piperazinas/uso terapéutico , Administración Oral , Adulto , Animales , Disponibilidad Biológica , Esquema de Medicación , Tolerancia a Medicamentos , Ojo/parasitología , Femenino , Filaricidas/administración & dosificación , Filaricidas/farmacocinética , Filaricidas/farmacología , Guatemala , Humanos , Masculino , Microfilarias/efectos de los fármacos , Oncocercosis/diagnóstico por imagen , Oncocercosis/parasitología , Oncocercosis Ocular/diagnóstico por imagen , Oncocercosis Ocular/tratamiento farmacológico , Oncocercosis Ocular/parasitología , Piperazinas/administración & dosificación , Piperazinas/farmacocinética , Piperazinas/farmacología , Piel/parasitología , UltrasonografíaRESUMEN
The objective of this multidisciplinary clinical investigation was to test whether amocarzine was absorbed effectively and safely in patients of two races and either sex infected with Onchocerca volvulus while living in the holoendemic area of Esmeraldas Province, Ecuador. The prerequisite for a systemic onchocercacidal effect is the regular absorption of orally administered amocarzine. Single dosing after overnight fasting proved to produce irregular absorption of amocarzine, although some microfilaricidal effect was achieved. A pilot study with repeated low dose and postprandial administration of amocarzine showed a regular and predictable absorption with acceptable tolerability and a microfilaricidal effect lasting up to one year post-therapy. Since amocarzine and its major N-oxide metabolite are coloured agents, urine colorimetry was used to assess the urinary excretion of the N-oxide qualitatively. For the postprandial drug regimens plasma concentrations of amocarzine and its metabolite were determined at two selected time points in patients of two races and either sex; the results showed no major differences. Excision of onchocercal nodules was performed four months post-therapy. The pooled results of the histologic analysis of 100 patients with the same drug regimen read under blinded condition showed that 65% of the adult female worms were dead, 20% necrobiotic and 15% alive. The male worms were fewer and mainly necrobiotic. Control worm populations in Esmeraldas without chemotherapy showed that on the average 81.5% were alive and 18.5% dead. Amocarzine was also microfilaricidal producing a reduction of skin dwelling microfilariae to about 10% of the initial value within the first week after start of therapy and lasting for half a year at a 20% level. The reduction of ocular microfilarial was slower and reached 35-40% after one year. The general tolerability was acceptable to good. Reversible dermal reactions were usually mild and peaked as a rash in 57% of the patients on day 6. No prohibitive ocular intolerance was observed. Mild and reversible dizziness peaked on day 4 in 74% of patients. A positive reversible Romberg sign was found in 12 patients on day 4. Amocarzine, the first oral micro- and macrofilaricidal agent administered as a low dose repeat regimen (3 mg/kg twice daily and postprandial for three consecutive days) can be recommended for oral onchocercacidal therapy in adult patients. Clinical trials in juveniles should be encouraged.
Asunto(s)
Filaricidas/uso terapéutico , Onchocerca/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Piperazinas/uso terapéutico , Absorción , Adulto , Animales , Población Negra , Colorimetría , Esquema de Medicación , Tolerancia a Medicamentos , Ecuador , Femenino , Filaricidas/farmacocinética , Filaricidas/farmacología , Humanos , Indígenas Sudamericanos , Masculino , Microfilarias/efectos de los fármacos , Oncocercosis/parasitología , Oncocercosis Ocular/tratamiento farmacológico , Oncocercosis Ocular/parasitología , Piperazinas/farmacocinética , Piperazinas/farmacología , Piel/parasitologíaRESUMEN
Skin punch biopsies were performed in 54 selected patients with onchocerciasis participating in a clinical trial with amocarzine (CGP 6140) in Ecuador and Guatemala. Skin snipping for counting microfilariae of Onchocerca volvulus was done before treatment (day 0) and day 4 and 8 following start of the therapy which consisted of 3 mg/kg amocarzine postprandially twice daily for three consecutive days. The mean microfilarial skin density has been reduced by 45% on day 4 and 95% on day 8. Skin punch biopsies were taken on day 5, within 1 cm from the snip site on the iliac crest. Histopathologic examination revealed that the vast majority of the microfilariae in the upper as well as in the deeper dermis were degenerated or necrotic, surrounded often (57%) by minute foci of fibrinoid change of the collagen. There was usually slight, less frequently moderate eosinophilic, lympho-plasmocytic and initial histocytic inflammatory reaction in the vicinity. Microfilariae were frequently (69%) found at the dermal-epidermal junction and in the epidermis. Occasionally (7%) intra-epidermal microabscesses were noted. Microfilariae were detected also in the lumen of some dermal lymphatic vessels. Therefore it is concluded that amocarzine showed marked microfilaricidal effects in the skin of patients with onchocerciasis as evidenced histologically by mainly destroyed or moribund microfilariae which induced a mild to moderate inflammatory cell reaction.
Asunto(s)
Onchocerca/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Piperazinas/uso terapéutico , Piel/parasitología , Adulto , Animales , Biopsia con Aguja , Ecuador , Epidermis/parasitología , Femenino , Guatemala , Humanos , Masculino , Microfilarias/efectos de los fármacos , Oncocercosis/parasitología , Piperazinas/farmacologíaRESUMEN
Ultrasonography of onchocercal skin nodules was performed with an ophthalmologic real time linear scanner with a B probe of 10 MHz. A clinical trial in Guatemala with amocarzine (CGP 6140)--a new oral macrofilaricidal compound--investigated three repeat dose regimens and one placebo control group, each group consisting of six patients. Onchocercal nodules were scanned before treatment and on day 10, 30 and 60 after start of amocarzine. A total of 28 treated and 8 additional untreated nodules were analysed and compared with the histologic findings following nodulectomy at day 60. Of the 28 treated nodules, 21 were of onchocercal origin and seven were lymph nodes. The correlation between ultrasonography and histology was good in 25 patients, but did not match in three. In 20 out of 21 treated nodules a progressive ultrasonographic change over two months was seen. Of the eight additional untreated nodules, five were of onchocercal origin, one was a lymph node, one an epidermoid cyst and in one only fibrous tissue was detected. The ultrasonography correlated well to histology in seven nodules but not in one. In five onchocercal nodules no change was observed over two months. For initial control purposes six nodules were excised around day 10, four were of onchocercal origin and two were lymph nodes. The correlation was good in four. The present results indicate that an ophthalmologic real time linear scanner can be used in the bidimensional mode as a non-invasive method to assess sequentially the events in superficial onchocercal nodules following chemotherapy with amocarzine. This is the first objective non-invasive method permitting sequential assessment of the content of onchocercal nodules and it is far superior than subjective sequential manual palpation.
Asunto(s)
Filaricidas/uso terapéutico , Onchocerca/efectos de los fármacos , Oncocercosis/diagnóstico por imagen , Piperazinas/uso terapéutico , Piel/diagnóstico por imagen , Animales , Filaricidas/administración & dosificación , Filaricidas/farmacología , Estudios de Seguimiento , Guatemala , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Masculino , Onchocerca/aislamiento & purificación , Oncocercosis/tratamiento farmacológico , Oncocercosis/parasitología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piel/parasitología , UltrasonografíaRESUMEN
An open clinical trial of amocarzine was carried out in onchocerciasis patients in Ecuador and Guatemala. Administration after food was more effective than that during fasting. The most effective and best tolerated regimen, 3 mg/kg twice daily after food for 3 days (in 312 patients), killed 73% of 1477 female worms at nodulectomy 4 months after treatment. The mean microfilarial skin count was greatly reduced within a week (6-11% Of day 0 value on day 8) and it remained low at least 6 months (14-18% on day 180). Follow-up of a higher dose 3 day regimen taken while fasting showed microfilaridermia of 7-9% of the day 0 value 2 years after treatment.
Asunto(s)
Filaricidas/uso terapéutico , Onchocerca/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Piperazinas/uso terapéutico , Adulto , Animales , Estudios de Cohortes , Terapia Combinada , Esquema de Medicación , Evaluación de Medicamentos , Ecuador , Femenino , Filaricidas/administración & dosificación , Filaricidas/efectos adversos , Estudios de Seguimiento , Guatemala , Humanos , Oncocercosis/cirugía , Proyectos Piloto , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piel/parasitologíaRESUMEN
A portable ophthalmologic real-time ultrasound linear scanner (Ophthascan) was used to determine the optic resolution of excised onchocercal nodules of Onchocerca volvulus and O. gibsoni origin. Fresh, thawed and fixed nodules were used. Following macroscopic and histologic examination it became apparent that the Ophthascan could clearly distinguish between echogenic worm coils and non-echogenic areas of necrosis. The fibrotic nodular capsule was more echogenic than the worm coils inside the nodule. The optic resolution did not permit to distinguish the internal organ structures within a worm segment. This in vitro determination of the visual resolution of an opthalmologic real-time ultrasound linear scanner is in accordance with in vivo results of an ongoing trial with a new macrofilaricide. Thus sonography can be used to visualise the interior of superficial onchocercal nodules in vivo and to follow their evolution with or without chemotherapy. The non-invasive diagnostic and sequential assessment of onchocercal nodules by sonography will be a valuable contribution in onchocerciasis, especially for the assessment of macrofilaricides.
Asunto(s)
Onchocerca/anatomía & histología , Oncocercosis/diagnóstico , Ultrasonografía , Animales , Bovinos , Femenino , Humanos , Masculino , Oncocercosis/parasitología , Oncocercosis/patologíaRESUMEN
Routine autopsy studies of hearts with coronary thrombosis, collected over a period of eleven years, showed unique morphologic features of rupture of soft atheromatous plaques. These features include: (1) irregular luminar outline: angulation, invagination, upheaval, and/or wrinkles, (2) wavy outline of atheromatous cavity, (3) volcano-like rupture with seepage or gushing of semiliquid atheromatous contents into lumen, (4) cholesterol crystals arranged in rheologic vector direction, (5) rupture of deeper intimal fibrous tissue, (6) one or multiple intimal upheavals, (7) focal thickening of contracted media, (8) vestige of volcano-like eruption with organized thrombus, and (9) old thrombotic occlusion with wavy appearance of thick intimal fibrous tissue. The authors present a dynamic model of vasoconstriction or artery spasm that accounts for these features and the rupture of soft atheromatous plaques.
Asunto(s)
Enfermedad de la Arteria Coronaria/patología , Vasoespasmo Coronario/patología , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , Trombosis Coronaria/patología , Vasoespasmo Coronario/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Infarto del Miocardio/patología , Rotura EspontáneaRESUMEN
The features of 39 cases of spontaneous endomyocardial disease occurring in the rat heart are discussed and the condition is compared with endomyocardial fibrosis occurring in man. Rat endomyocardial disease is an age-related change characterized by subendocardial proliferation of spindle cells that may progress to a lesion histologically similar to fibrosarcoma. Human endomyocardial fibrosis, on the other hand, is not age-related and shows essentially fibrohyaline changes of low cellularity preceded by the occurrence of acid mucopolysaccharides in the subendocardial region; no evidence of malignant change has ever been reported.
Asunto(s)
Cardiomiopatías/patología , Endocardio , Fibrosis Endomiocárdica/patología , Ratas/anatomía & histología , Animales , Cardiomiopatías/inducido químicamente , Cardiopatías/inducido químicamente , Cardiopatías/patología , Humanos , Ratas EndogámicasRESUMEN
The carcinogenic potential of a technical-grade epoxy resin, Araldite GY 250, of which the diglycidyl ether of bisphenol A (DGEBPA) is the main component, was investigated in CF1 mice. Groups of 50 male and 50 female mice were treated for 2 yr by repeated epidermal application of a 1 or 10% (v/v) solution in acetone. The controls, 50 mice of each sex, were treated with acetone alone. The treatment had no effect on survival and no excess incidence of skin tumours occurred. A positive control group of 50 male and 50 female CF1 mice was treated by epidermal application of 2% (v/v) beta-propiolactone in acetone. In this group there was a high incidence of malignant skin tumours at the site of application and, consequently, increased mortality. Treatment with neither DGEBPA technical nor beta-propiolactone induced systemic neoplasia.
Asunto(s)
Carcinógenos , Compuestos Epoxi/toxicidad , Éteres Cíclicos/toxicidad , Neoplasias Cutáneas/inducido químicamente , Acetona/administración & dosificación , Acetona/toxicidad , Administración Tópica , Animales , Compuestos de Bencidrilo , Peso Corporal/efectos de los fármacos , Compuestos Epoxi/administración & dosificación , Femenino , Masculino , Ratones , Propiolactona/administración & dosificación , Propiolactona/toxicidad , Neoplasias Cutáneas/patologíaRESUMEN
Light microscopic and immunocytologic investigation revealed focal or diffuse pituitary gonadotroph hyperplasia in 3/27 male and 3/39 female Sprague-Dawley rats over 2 years of age. Three male and 2 female rats exhibited proliferation of morphologically abnormal gonadotrophs which were described as nodules, and 4 male and 5 female rats possessed gonadotroph adenomas which contained both immunoreactive beta-LH and beta-FSH. On plastic sections at the ultrastructural level, a further female rat was found to possess focal gonadotroph hyperplasia, 2 male and 2 female rats, gonadotroph nodules and 2 male and 2 female rats gonadotroph adenomas. While extensive gonadotroph and thyrotroph hyperplasia was observed in the nontumorous portion of the 2 pituitaries harboring thyrotroph adenoma, widespread gonadrotroph hyperplasia was noted in only 2 of 13 pituitaries with gonadotroph adenoma. Gonadotroph adenomas appeared to develop from discrete foci of morphologically altered gonadotrophs. These foci probably then progressed to form nodules and subsequently adenomas. Gonadotrophs within the nodules were often similar in morphology to adenomatous gonadotrophs whereas the earlier, smaller lesions were pleomorphic or more commonly trabecular in appearance. Serum LH levels were measured in some animals. As a group, rats displaying changes in gonadotroph morphology had a higher mean serum LH level than those without these changes, however, the values ranging from 23-249 ng/ml were well within the normal serum LH levels reported in aging rats. Gonadotroph adenomas in human patients have only recently been identified with accuracy and are relatively uncommon. As in the case of rats, they do not appear to arise from a pre-existing end organ hypofunction or pre-existing gonadotroph hyperplasia. A suitable animal model, in the form of spontaneously occurring gonadotroph adenomas in aging rats, might be useful in establishing the etiology, biochemical properties and appropriate therapy for these tumors.
Asunto(s)
Adenoma/ultraestructura , Envejecimiento , Neoplasias Hipofisarias/ultraestructura , Adenoma/análisis , Adenoma/fisiopatología , Animales , Femenino , Hormona Folículo Estimulante/análisis , Gonadotropinas Hipofisarias/metabolismo , Técnicas para Inmunoenzimas , Hormona Luteinizante/análisis , Masculino , Microscopía Electrónica , Adenohipófisis , Neoplasias Hipofisarias/fisiopatología , Radioinmunoensayo , Ratas , Ratas EndogámicasRESUMEN
A 34-year-old native women presented as an acute abdominal emergency at the Surgery Department, Missionary Hospital "Ad Lucem" in Banka-Bafang, Cameroon. She complained of colicky, epigastric abdominal pain, nausea, vomiting, constipation, and retention of flatus. At laparotomy, numerous small cystic nodules (3-8 mm in diameter) were noted in the mesentery and under the intestinal and parietal peritoneum. Histological examination of two of them revealed slightly enlarged mesenteric lymph nodes containing several parasitic pseudocysts. The parasites were diagnosed as well-preserved, encysted, Armillifer armillatus nymphs. Neither degenerative nor inflammatory granulomatous reactions were observed in the adjacent tissue. Two and a half years later, a similar attack of acute abdominal symptoms recurred. A radiological examination revealed several C-shaped or circular, dense opacities characteristic of calcified pentastomid nymphs. At laparotomy, local findings similar to those at the previous surgical examination were noted. Additionally, a few firm, whitish, calcified nodules were found in the mesentery and under the fibrous capsule of the liver.
Asunto(s)
Abdomen Agudo/etiología , Artrópodos , Enfermedades Parasitarias/complicaciones , Adulto , Femenino , Humanos , Enfermedades Parasitarias/etiología , Enfermedades Parasitarias/patologíaRESUMEN
Bordetella pertussis adheres specifically to the cilia of respiratory epithelial cells. This ability to adhere is characteristic of virulent organisms. In order to define the contribution of various virulence factors of B. pertussis to the process of adherence, mutants deficient in single virulence factors were tested for the ability to adhere to rabbit cilia in vitro and in vivo. Two protective antigens were found to be critical to the process of adherence: filamentous hemagglutinin and pertussis toxin.
Asunto(s)
Bordetella pertussis/fisiología , Cilios/microbiología , Hemaglutininas/inmunología , Toxina del Pertussis , Factores de Virulencia de Bordetella/inmunología , Animales , Antígenos Bacterianos , Técnicas In Vitro , Pulmón/microbiología , Pulmón/patología , Conejos , Tráquea/microbiología , Tos Ferina/microbiología , Tos Ferina/patologíaRESUMEN
Fifty-five adenomas were identified and characterized in the anterior pituitaries of 27 male and 39 female SD rats, over 24 months of age, by histology, ultrastructural morphology, and immunocytochemistry. Adenomas were found in 85% of male and 79% of female rats; all known adenohypophysial hormones were represented in various tumors. Prolactin (PRL)-containing adenomas were the most common (47.2%); luteinizing hormone-(LH)-containing adenomas (16.3%), immunonegative adenomas (12.7%), PRL- and growth hormone (GH)-containing adenomas (10.9%), thyroid-stimulating hormone (TSH)-containing adenomas (3.6%), adrenocorticotropin hormone (ACTH)-containing adenomas (3.6%), and GH-containing adenomas (1.8%) were also identified. Unexpected combinations were observed in 3 tumors (5.4%); a GH-LH-containing adenoma, a PRL-ACTH-containing adenoma, and a PRL-LH-TSH-containing adenoma were noted. One intermediate lobe adenoma and 1 metastatic plasmacytoma were diagnosed. It can be concluded that spontaneous pituitary adenomas in aging SD rats are potential models of the human disease because of diversity of hormone content and morphologic appearance.
Asunto(s)
Adenoma/patología , Hipófisis/crecimiento & desarrollo , Neoplasias Hipofisarias/patología , Adenoma/ultraestructura , Hormona Adrenocorticotrópica/análisis , Envejecimiento , Animales , Femenino , Hormona del Crecimiento/análisis , Inmunoensayo , Hormona Luteinizante/análisis , Masculino , Microscopía Electrónica , Neoplasias Hipofisarias/ultraestructura , Prolactina/análisis , Radioinmunoensayo , Ratas , Ratas Endogámicas , Especificidad de la Especie , Tirotropina/análisisRESUMEN
Two cases of primary renal carcinoidal tumor are reported. One was discovered in a 32-year-old pregnant woman. The other tumor was retrospectively diagnosed 3 years after nephrectomy in a 65-year-old woman who was hospitalized with a metastatic lesion in her lumbar spine. Both tumors are compared with 5 other cases previously reported in the literature, and hypotheses about the cause of renal localization of this tumor are reviewed.