RESUMEN
BACKGROUND AND AIM: To evaluate the prevalence of goitre by means of urinary iodine excretion, palpatory and ultrasonographic thyroid examinations in a heterogeneous population living by the sea. METHODS AND RESULTS: We used a special self-administered questionnaire to evaluate thyroid size, iodine intake, eating habits and cardiovascular risk factors in 600 subjects with a mean age of 45 +/- 17 years: 253 men (42.3%) and 347 women (57.7%). Urinary iodine excretion was low (72.1 +/- 15.7 microg/L; median 71.2) and associated with ultrasonographic evidence of an enlarged thyroid (16%) or structural thyroid abnormalities (30%), thus allowing us to define the Salerno Gulf as a mild-moderate area of endemic goitre. All of the subjects ate a Mediterranean diet, with a mean of two portions of fish/week. The cardiovascular risk factors considered were obesity, cigarette smoking, hypertension, hypercholesterolemia, hypertriglyceridemia and diabetes, the prevalences of which were in line with those reported in other studies of similar age-matched populations. CONCLUSIONS: The moderate intake of fish and the consumption of a Mediterranean diet did not prevent goitre. Iodine deficiency and subsequent goitre endemia are also present at sea level, probably because of a diet based on local products grown on soil with a low iodine content or possible seawater, soil and air environmental pollution that may interfere with the availability of iodine. The assessment of iodine deficiency should therefore involve the entire population and not only subjects living far from the sea.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Dieta Mediterránea , Bocio/epidemiología , Yodo/deficiencia , Yodo/orina , Tamizaje Masivo , Adulto , Anciano , Femenino , Bocio/diagnóstico , Bocio/diagnóstico por imagen , Bocio Endémico/diagnóstico , Bocio Endémico/diagnóstico por imagen , Bocio Endémico/epidemiología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Palpación , Prevalencia , Factores de Riesgo , Encuestas y Cuestionarios , Glándula Tiroides/diagnóstico por imagen , UltrasonografíaRESUMEN
The medical approach to patients with secreting or clinically non-functioning pituitary adenoma as made considerable progress thanks to the use of new somatostatin analogs. They were first used to treat acromegaly in the mid 1980s and numerous studies have shown a reduction in GH concentration in over 90% of acromegalic patients. Good results were obtained using slow-release analog treatment also in TSH-secreting adenomas, whereas the therapeutic efficacy of these peptides in clinically non-functioning adenomas is still controversial. Treatment with somatostatin analogs improves symptoms, normalises hormone secretion and in some cases may induce a reduction in the volume of pituitary adenomas. Scintigraphy with octreotide may help to select patients who respond to this form of treatment.
Asunto(s)
Adenoma/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Ácido Pentético/análogos & derivados , Péptidos Cíclicos/uso terapéutico , Neoplasias Hipofisarias/tratamiento farmacológico , Somatostatina/uso terapéutico , Acromegalia/tratamiento farmacológico , Adenoma/diagnóstico por imagen , Adenoma/metabolismo , Adolescente , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Adulto , Anciano , Carcinoma/diagnóstico por imagen , Humanos , Radioisótopos de Indio/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Renales/diagnóstico por imagen , Melanoma/diagnóstico por imagen , Persona de Mediana Edad , Ácido Pentético/uso terapéutico , Feocromocitoma/diagnóstico por imagen , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/metabolismo , Valor Predictivo de las Pruebas , Prolactinoma/tratamiento farmacológico , Cintigrafía , Radiofármacos/uso terapéutico , Sensibilidad y Especificidad , Somatostatina/análogos & derivados , Somatostatina/metabolismo , Timoma/diagnóstico por imagen , Neoplasias del Timo/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico por imagen , Tirotropina/metabolismo , Resultado del TratamientoRESUMEN
A cross-sectional study on young dancers and exdancers was performed to evaluate the effects of intense weight-bearing exercise and dietary restriction, started during puberty, on bone mineral density (BMD), menarche age, menstrual function, and gonadotropin structure. Twenty current dancers (group 1) and 9 exdancers (group 2) were compared with a control group of 30 age-matched, regularly cycling women. Body weight, body mass index, total daily caloric intake, and nutritional markers were significantly lower (P < 0.05) in groups 1 and 2 than in controls. Using Quantitative Computed Tomography for the BMD evaluation, 12 dancers and 5 exdancers had Z-scores less than 2.5 SD below the mean of the controls; whereas, in 6 dancers and in 2 exdancers, BMD was between 1 and 2.5 SD. Groups 1 and 2 had a delay of menarche, which correlated positively with years of dance before menarche (r = 0.8; P < 0.001). Dancers had low levels and altered structure of circulating gonadotropins, which improved after GnRH stimulation. In conclusion, ballet training performed by dancers during puberty, dietary restriction, and low body mass index can all be associated with reduction in BMD and altered gonadotropin isoforms, with subsequent delay of menarche, menstrual dysfunctions, and insufficient peak bone mass. A longitudinal study must be conducted to confirm the persistence of low lumbar spine bone density in adult age.
Asunto(s)
Densidad Ósea , Ejercicio Físico , Adulto , Estudios Transversales , Ingestión de Energía , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Hormona Luteinizante/sangreRESUMEN
Neuroendocrine tumours are frequently malignant and have often reached an advanced stage by the time of diagnosis when they are inoperable, accompanied by severe symptoms, sometimes of an endocrine nature. Current therapeutic procedures include surgery, embolisation of hepatic metastases, local radiotherapy, biotherapy and chemotherapy. Over the years somatostatin analogs, of which octreotide is the first form, have become increasingly important in the treatment of patients with neuroendocrine tumours. A major step forward in analog treatment is represented by the development of slow-release formulas which do not require multiple daily injections and reduce the onset of resistance. The treatment of neuroendocrine tumours in the future will be based on the increased use of somatostatin analogs alone or in association with interferon or chemotherapy, and will also include surgery, radiometabolic therapy and targeted irradiation of the tumour.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias Gastrointestinales/terapia , Tumores Neuroendocrinos/terapia , Neoplasias Pancreáticas/terapia , Terapia Combinada , Humanos , Octreótido/uso terapéutico , Receptores de Somatostatina/antagonistas & inhibidoresRESUMEN
This report summarizes the results of a multinational pharmaceutical company survey and the outcome of an International Life Sciences Institute (ILSI) Workshop (April 1999), which served to better understand concordance of the toxicity of pharmaceuticals observed in humans with that observed in experimental animals. The Workshop included representatives from academia, the multinational pharmaceutical industry, and international regulatory scientists. The main aim of this project was to examine the strengths and weaknesses of animal studies to predict human toxicity (HT). The database was developed from a survey which covered only those compounds where HTs were identified during clinical development of new pharmaceuticals, determining whether animal toxicity studies identified concordant target organ toxicities in humans. Data collected included codified compounds, therapeutic category, the HT organ system affected, and the species and duration of studies in which the corresponding HT was either first identified or not observed. This survey includes input from 12 pharmaceutical companies with data compiled from 150 compounds with 221 HT events reported. Multiple HTs were reported in 47 cases. The results showed the true positive HT concordance rate of 71% for rodent and nonrodent species, with nonrodents alone being predictive for 63% of HTs and rodents alone for 43%. The highest incidence of overall concordance was seen in hematological, gastrointestinal, and cardiovascular HTs, and the least was seen in cutaneous HT. Where animal models, in one or more species, identified concordant HT, 94% were first observed in studies of 1 month or less in duration. These survey results support the value of in vivo toxicology studies to predict for many significant HTs associated with pharmaceuticals and have helped to identify HT categories that may benefit from improved methods.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Valor Predictivo de las Pruebas , Pruebas de Toxicidad , Animales , Bases de Datos Factuales , Humanos , Especificidad de la EspecieRESUMEN
Here we describe a subject with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-CAH), in its classical virilizing form, who presented at birth ambiguous genitalia and subsequently was assigned by the parents as male. At the age of 8 years, he underwent a two-step surgical correction of hypospadia and at 22 years old, uterus and ovaries were removed and a bilateral testicular prothesis was surgically placed in scrotum. He refused any chronic glucocorticoid therapy, that was given only acutely to prevent adrenal crises during stress, trauma surgery or severe illness. The patient is now 38 years old, he is genotypically female but phenotypically male, with high endogenous levels of androgen, all of adrenal origin, and with an apparent male sexual life. He had severe osteopenia, probably due to the lack of estrogen/androgen-induced increase in bone mineral density, although periferal estrogen conversion was normal. His skeletal mass, in fact, normally acquired during adolescence and early adult life, could in this case be inefficient, for the precocious pseudopuberty, that caused an inefficient peak bone mass in adolescence period.
Asunto(s)
Hiperplasia Suprarrenal Congénita/complicaciones , Enfermedades Óseas Metabólicas/etiología , Trastornos del Desarrollo Sexual/etiología , Adulto , Andrógenos/sangre , Andrógenos/orina , Densidad Ósea , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Calcio/uso terapéutico , Difosfonatos/uso terapéutico , Femenino , Humanos , Fenotipo , Columna Vertebral , Vitamina D/uso terapéuticoRESUMEN
BACKGROUND AND AIM: The aim of this study was to determine the validity of our previous hypothesis of adrenal 11 beta-hydroxylase (11-OH) dysregulation in "essential" low-renin hypertension. METHODS AND RESULTS: A comparison was made between 30 hypertensive patients and 30 age-matched controls (NC) in basal conditions and after ACTH stimulation (ACTH 1-17) test. The 11-deoxycortisol (S) and deoxycorticosterone (DOC) integrated areas under the curve (AUCs) of stimulus were significantly higher in the hypertensives (p < 0.001) and pointed to adrenal 11-OH dysregulation. CONCLUSIONS: The ACTH 1-17 test detects impairment of 11-OH activity of probable genetic origin. The relative mineralocorticoid excess thus provoked could be an additional cause of "essential" low-renin hypertension.
Asunto(s)
Corteza Suprarrenal/metabolismo , Hipertensión/enzimología , Hipertensión/fisiopatología , Esteroide 11-beta-Hidroxilasa/metabolismo , Corteza Suprarrenal/enzimología , Pruebas de Función de la Corteza Suprarrenal , Hormona Adrenocorticotrópica , Adulto , Área Bajo la Curva , Cortodoxona/sangre , Desoxicorticosterona/sangre , Femenino , Humanos , Masculino , Fragmentos de PéptidosRESUMEN
The occurrence of autoimmune thyroid disorders among patients with coeliac disease (CD) is well documented, but the exact prevalence of CD among patients with autoimmune thyroid diseases (ATD) is as yet unclear. We screened 150 newly diagnosed patients with ATD by serum endomysial antibody detection (EmA). In 5 subjects (3.3%) EmA positivity was found; all underwent jejunal biopsy. On gluten-free diet an excellent clinical and histological response was recorded with an improvement of hypothyroidism and reduction of the thyroxine dosage. Our data suggest a significant high prevalence (3.3%) of CD in patients with ATD, in particular with Hashimoto's thyroiditis.
Asunto(s)
Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/epidemiología , Tiroiditis Autoinmune/complicaciones , Adolescente , Adulto , Enfermedad Celíaca/dietoterapia , Niño , Dieta , Femenino , Glútenes , Humanos , Masculino , Tiroiditis Autoinmune/dietoterapia , Tirotropina/sangre , Tiroxina/sangreRESUMEN
The coexistence of autoimmune endocrine diseases, particularly autoimmune thyroid disease and celiac disease (CD), has recently been reported. We here present a 23-year-old woman with a diagnosis of hypothyroidism due to Hashimoto's thyroiditis, autoimmune Addison's disease, and kariotypically normal spontaneous premature ovarian failure. Considering the close association between autoimmune diseases and CD, we decided to search for IgA anti-endomysium antibodies (EmA) in the serum. The positivity of EmA and the presence of total villous atrophy at jejunal biopsy allowed the diagnosis of CD. On a gluten-free diet the patient showed a marked clinical improvement accompanied, over a 3-month period, by a progressive decrease in the need for thyroid and adrenal replacement therapies. After 6 months, serum EmA became negative and after 12 months a new jejunal biopsy showed complete mucosal recovery. After 18 months on gluten-free diet, the anti-thyroid antibodies titre decreased significantly, and we could discontinue thyroid substitutive therapy. This case emphasizes the association between autoimmune polyglandular disease and CD; the precocious identification of these cases is clinically relevant not only for the high risk of complications (e.g. lymphoma) inherent to untreated CD, but also because CD is one of the causes for the failure of substitute hormonal therapy in patients with autoimmune thyroid disease.
Asunto(s)
Enfermedad de Addison/inmunología , Enfermedades Autoinmunes/complicaciones , Enfermedad Celíaca/complicaciones , Insuficiencia Ovárica Primaria/complicaciones , Tiroiditis Autoinmune/inmunología , Enfermedad de Addison/complicaciones , Enfermedad de Addison/tratamiento farmacológico , Adulto , Autoanticuerpos/sangre , Enfermedades Autoinmunes/diagnóstico , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/dietoterapia , Cortisona/análogos & derivados , Cortisona/uso terapéutico , Estrógenos Conjugados (USP)/uso terapéutico , Femenino , Glútenes/administración & dosificación , Humanos , Acetato de Medroxiprogesterona/uso terapéutico , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Tiroiditis Autoinmune/complicaciones , Tiroiditis Autoinmune/tratamiento farmacológico , Tiroxina/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the presence of a dysregulation in steroid biosynthesis in women from southern Italy. DESIGN: Controlled clinical study. SETTING: Normal and hyperandrogenic women referred to the Endocrinology Unit of Federico II University Medical School of Naples. PATIENT(S): One hundred fifty untreated young hyperandrogenic women and 50 normal age-matched women. INTERVENTION(S): Morning (basal) blood samples obtained in the early follicular phase and after a long (360 minute) ACTH stimulation test. MAIN OUTCOME MEASURE(S): The adrenal maximal response was calculated as stimulus under curve areas (AUCa), and all steroids were assayed using RIA methods. RESULT(S): A dysregulation of 21-hydroxylase was found in 22 patients (14.7%), with a prevalent increase of 17 alpha-hydroxyprogesterone AUC, whereas in 9 hirsute women (6%), there was a prevalent significant increase in 11-deoxycortisol AUC. In 5 women (3.3%), DHEA and DHEAS basal and AUCs plasma levels were increased, suggesting an impaired 3 beta-olo-dehydrogenase activity. The remaining 114 hyperandrogenic women (76%) compose the nonadrenal group, with a probable diagnosis of primitive functional ovarian hyperandrogenism. CONCLUSION(S): Considering the high prevalence of hirsutism and oligomenorrhea in our female hyperandrogenic population, we suggest an adrenal hyperresponsiveness likely due to a dysregulation in enzymes related to androgen adrenal steroidogenesis.
Asunto(s)
Corticoesteroides/biosíntesis , Homeostasis , Hiperandrogenismo/etiología , Esteroide 21-Hidroxilasa/metabolismo , 17-alfa-Hidroxiprogesterona/sangre , Adolescente , Corticoesteroides/sangre , Hormona Adrenocorticotrópica , Adulto , Cortodoxona/sangre , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/sangre , Desoxicorticosterona/sangre , Femenino , Hirsutismo/sangre , Humanos , Italia , Síndrome del Ovario Poliquístico/sangreRESUMEN
BACKGROUND: Aim of this study was to investigate the frequency of association between Myasthenia Gravis (MG) and Graves Ophthalmopathy (GO) using the responses to diagnostic tests for MG (fatigue and neostigmine tests) by measuring horizontal saccadic eye movements (SEM). METHODS: For this paper a random investigation was performed on eleven patients, affected by Graves' disease (GD) at the department of Molecular and Clinical Endocrinology and Oncology and department of Neurology of University of Federico II of Naples, for one year. Eleven patients (11 F), were subjected to endocrinological and ophthalmological examinations (TSH IRMA, TT3-RIA, TT4-RIA, TgAb, TPOAb, orbit ultrasonography or computed tomographic scans) and computerized analysis of saccadic eye movements (SEM); the fatigue and neostigmine tests were performed by means of SEM analysis in seven of this patients. RESULTS: Our results have reported that a positive response to the diagnostic tests for MG is present in 41.6% of hyperthyroid patients with GO, further supporting the hypothesis of a common autoimmune pathogenesis is present between these pathologies. CONCLUSIONS: SEM analysis may be a useful adjunct in the diagnosis of GO.
Asunto(s)
Inhibidores de la Colinesterasa , Fatiga/fisiopatología , Enfermedad de Graves/diagnóstico , Neostigmina , Movimientos Sacádicos/fisiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimientos Sacádicos/efectos de los fármacosRESUMEN
A normal gonadal maturation with normal fertility are some of the major goals of long-term replacement therapy in adult males with Congenital Adrenal Hyperplasia (CAH). We describe here two young men, G.O. (case A, 23 years old) and S.S.(case B, 24 years old), both with a well defined diagnosis of CAH due to 21-hydroxylase deficiency classic homozygote form (21-CAH). In case A the diagnosis of the 21-CAH classic virilizing form was made at 3 years of age. The patient has undergone glucocorticoid therapy and is now 170 cm tall; all his hormonal findings are within the normal range. The semen analysis has shown a good fertility potential, with a slight modification when the patient decided to discontinue the therapy. In case B the diagnosis of the 21-CAH salt wasting form was performed at 9 days of age. The patient was initially treated with i.v. normal saline solution and a daily i.m. injection of hydrocortisone and, subsequently, with mineral and glucocorticoid replacement therapy po. A satisfactory adult stature (165 cm) was attained. The patient is still on therapy, with a good hormonal profile. The semen analysis has shown an apparently normal fertility. In conclusion, our experience in adult males with 21-CAH, who have been administered prompt and adequate replacement therapy, shows that these patients can attain normal quality of life, satisfactory growth and development, normal sexual maturation and activity, and adequate sperm fertilizing ability, thereby supporting the usefulness of continuing this therapy during adult age.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Infertilidad Masculina/prevención & control , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/complicaciones , Adulto , Cortisona/administración & dosificación , Cortisona/análogos & derivados , Cortisona/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Quimioterapia Combinada , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/metabolismo , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Homocigoto , Humanos , Hidrocortisona/administración & dosificación , Hidrocortisona/uso terapéutico , Infertilidad Masculina/sangre , Infertilidad Masculina/etiología , Hormona Luteinizante/sangre , Hormona Luteinizante/efectos de los fármacos , Hormona Luteinizante/metabolismo , Masculino , Prednisona/administración & dosificación , Prednisona/uso terapéuticoRESUMEN
Antithyroid hormone autoantibodies (THBA), described in both humans and animals, result in variable interference when thyroid hormone plasma levels are measured by immunoassays. We previously described a quick chromatographic method to detect circulating THBA in humans. In the present experience, we applied the method on canine sera (10 normal dogs and 3 dogs affected by hypothyroidism) to detect the THBA presence in a dog (no. 13) with clinical evidence of hypothyroidism, in spite of apparently extremely high values of thyroid hormone. After a short incubation of samples with 125I-T3 and 125I-T4 in presence of 8-anilino-1-naphtalenesulfonic acid, samples were eluted and radioactivity values counted. Eluate radioactivity values > 10% and > 30% were considered positive for THBA presence for antiT3 and antiT4 detection, respectively. High radioactivity values were detected in dog serum no. 13 and, therefore, it was considered positive for THBA presence. The Scatchard plot analysis revealed the presence of a monoclonal autoantibody with the highest affinity for T3 and an additional tenfold lower affinity for T4. In conclusion, our chromatographic method allows the detection and the characterization of THBA in species different from humans, with species specific differences in thyroid hormone metabolism; thus, taking into account the rarely availability of canine serum TSH and anti-thyroglobulin antibody immunoassay detection methods, it was possible to correctly diagnose the hypothyroidism in a dog with apparently extremely high values of thyroid hormones due to THBA interference.
Asunto(s)
Autoanticuerpos/sangre , Cromatografía/métodos , Enfermedades de los Perros/inmunología , Hipotiroidismo/veterinaria , Hormonas Tiroideas/inmunología , Naftalenosulfonatos de Anilina , Animales , Perros , Colorantes Fluorescentes , Hipotiroidismo/inmunología , Radioisótopos de Yodo , Tiroxina/sangre , Tiroxina/inmunología , Triyodotironina/sangre , Triyodotironina/inmunologíaAsunto(s)
Glucemia , Insulina/administración & dosificación , Nebulizadores y Vaporizadores , Administración por Inhalación , Animales , Área Bajo la Curva , Glucemia/análisis , Glucemia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Inyecciones Subcutáneas , Insulina/farmacocinética , Pulmón/efectos de los fármacos , Pulmón/ultraestructura , Macaca mulatta , MasculinoRESUMEN
To investigate the relevance of glycoprotein polymorphism to gonadotropin bioactivity in vivo, plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH), 17 beta-estradiol (E2), testosterone and sex hormone binding globulin (SHBG) levels in 17 amenorrheic women affected with anorexia nervosa (14-29 years) and 10 age-matched normally cycling women were evaluated. Plasma FSH and LH levels were assayed using radioimmunoassay (RIA) and immunoradiometric assay (IRMA) methods, before and after concanavalin A-Sepharose (Con A) affinity chromatography. Significant RIA-IRMA differences in FSH and LH plasma values were present only in women with anorexia nervosa (p < 0.005). Moreover, in these patients both FSH and LH showed a reduced binding to the Con A, expressed as a percentage of unbound, suggesting altered glycosylation of these moieties. In conclusion, these findings hypothesize the involvement of glycosylation polymorphism in RIA-IRMA differences; support the usefulness of both RIA and IRMA methods in FSH and LH evaluation, before and after Con A chromatography; and suggest a new pathogenetic pathway to explain amenorrhea in anorexia nervosa.
Asunto(s)
Amenorrea/etiología , Amenorrea/metabolismo , Anorexia Nerviosa/complicaciones , Anorexia Nerviosa/metabolismo , Gonadotropinas/metabolismo , Adolescente , Adulto , Amenorrea/sangre , Anorexia Nerviosa/sangre , Cromatografía de Afinidad , Concanavalina A , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Glicosilación , Gonadotropinas/análisis , Humanos , Ensayo Inmunorradiométrico , Hormona Luteinizante/sangre , Hipófisis/química , Hipófisis/metabolismo , Radioinmunoensayo , Globulina de Unión a Hormona Sexual/análisisRESUMEN
The use of a newly developed head dome system has allowed measurement of pulmonary function in conscious monkeys. Such information is often desired, so that pharmacological or toxicological effects of administered compounds can be measured in the absence of effects from anesthetic agents. The current study was conducted to gain experience with this method and to allow the determination of the effects of sodium pentobarbital anesthesia (30 mg kg-1 i.v.) on the bronchoconstriction seen during i.v. infusion of methacholine in rhesus monkeys. Bronchoconstriction was measured as changes in respiratory resistance using a Buxco LS20 pulmonary mechanics computer. Four male rhesus monkeys (4.2-5.1 kg) were used. For the anesthetized exposures, the animals were intubated with a 4.0-mm cuffed endotracheal tube attached to a size 'O' Fleisch pneumotachograph. For the conscious exposures, the animals sat in restraining chairs with a custom-built head dome attached to the same pneumotachograph. In both cases, transthoracic pressure was monitored with an intrapleural catheter. Each monkey was infused with methacholine in stepwise doses, while anesthetized and conscious, until a 75% increase in respiratory resistance was seen. The ED50 values of 0.134 and 0.180 mg ml-1 methacholine were not significantly different in anesthetized vs conscious monkeys, respectively.
Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Broncoconstricción/efectos de los fármacos , Cloruro de Metacolina/toxicidad , Anestesia , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Infusiones Intravenosas , Macaca mulatta , Masculino , Cloruro de Metacolina/administración & dosificación , Pentobarbital , Pruebas de Función Respiratoria , Programas InformáticosRESUMEN
The acute pulmonary function response to graded levels of a low toxicity dust was studied in guinea pigs. Four groups of five male guinea pigs each were exposed to mean concentrations of 0, 0.25, 1.01 and 5.39 mg Foundry Hill Clay l-1 air with mass median aerodynamic diameters of 2.6, 4.6 and 6.7 microns, respectively. There was a 15-min pre-exposure period to clean air, a 1-h exposure to the test atmosphere and then a 1-h recovery period with exposure to clean air. Concentration-related changes, compared to the pre-exposure period, occurred with a rapid onset in a number of parameters. Generally, the severity of observed effects increased with exposure time and, therefore, with inhaled dose. Statistically significant changes (P < 0.05) were observed in tidal volume, dynamic compliance, dynamic resistance, flow, pressure and minute volume during the last 15 min of exposure. The observed changes were consistent with acute bronchoconstriction. These effects reversed rapidly and there were no significant changes 1 h post-exposure. These results suggest that adverse physiological responses of short duration can occur when animals are exposed via inhalation to low-toxicity materials in the concentration range 0.25-5 mg l-1.
Asunto(s)
Polvo/efectos adversos , Pulmón/fisiología , Administración por Inhalación , Animales , Cobayas , Masculino , Tamaño de la PartículaRESUMEN
This paper reviews technical issues related to the toxicologic testing of inhaled pharmaceuticals. Although there are commonalities between approaches to general and inhalation toxicity testing, there also are specific challenges in the toxicity testing of inhaled pharmaceuticals. A major issue is that of dose; inhaled dose is more difficult to determine than intravenous or oral doses. Also, it is harder to relate dose in laboratory animals to that in man for inhalation exposure than for other routes of administration. Additionally, in the case of inhaled pharmaceuticals, people generally inhale through the mouth, whereas most laboratory animals inhale primarily through the nose. This presents significant challenges in exposure methodology and technology that often need innovative approaches involving alteration to particle size of the agent or dosing procedure. Because the respiratory tract is the site of deposition, local respiratory toxicity and possible damage to lung cells need to be assessed. Systemic toxicity also needs to be evaluated and may be an issue in some cases. Special studies on pulmonary function, mucociliary clearance, or immune response may be needed, depending on the nature of the inhaled pharmaceutical. This review explores the main issues involved in toxicity testing of inhaled pharmaceuticals, the approaches that have been used, and the current and future challenges.
Asunto(s)
Aerosoles/toxicidad , Toxicología/métodos , Administración por Inhalación , Aerosoles/farmacocinética , Animales , Humanos , Nebulizadores y Vaporizadores , Distribución TisularRESUMEN
Inhalation toxicology technology has provided the scientific community with important advances in studies of inhaled toxicants. These advances include new and more efficient exposure systems (e.g., flow-past nose-only exposure systems), and improved approaches to inhalation chamber environmental control (e.g., temperature, humidity, air quality). Practical problems and approaches to testing and operating inhalation exposure systems and the advantages and disadvantages of the major inhalation exposure types (e.g., whole-body, nose-only) are discussed. Important aspects of study design, such as high level particulate exposures resulting in large lung burdens (e.g., greater than or equal to 2 mg/g of lung), slowed pulmonary clearance rates, and nonspecific toxicity are considered, along with practical issues of comparative dosimetry. Regulatory guidelines have continued to present challenges in designing and conducting acute, subchronic, and chronic inhalation studies. The important regulatory issue of performing acute inhalation toxicity studies at high aerosol concentrations and "respirable" particle size distribution is discussed.
Asunto(s)
Cámaras de Exposición Atmosférica , Toxicología/métodos , Administración por Inhalación , Aerosoles , Animales , Relación Dosis-Respuesta a Droga , Humanos , Proyectos de Investigación , Estados Unidos , United States Environmental Protection AgencyRESUMEN
The development of inhalation toxicology as a distinct discipline can be traced back well over one hundred years. The technology has advanced in terms of materials and designs used to construct inhalation chambers and the equipment used to generate controlled test atmospheres of a wide variety of gases, vapors, dusts, and droplets. Consideration of metered dose inhalers, a relatively recent concern, has led to the design of new equipment for administering this unique dosage form. The parameters used to evaluate inhalation toxicity are similar to those used for any other route of administration. In addition, there are some unique procedures for early screening of pulmonary toxicity, especially within a series of related chemicals.