RESUMEN
BACKGROUND AND PURPOSE: Rho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine). EXPERIMENTAL APPROACH: Pharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo. KEY RESULTS: This compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate. CONCLUSIONS AND IMPLICATIONS: Azaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Diaminas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Administración Oral , Animales , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Sitios de Unión/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Células Cultivadas , Simulación por Computador , Proteínas Quinasas Asociadas a Muerte Celular , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Ratones , Modelos Animales , Modelos Moleculares , Técnicas de Cultivo de Órganos , Fosforilación , Reacción en Cadena de la Polimerasa/métodos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Conejos , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores de Tiempo , Vasodilatadores/administración & dosificación , Vasodilatadores/química , Vasodilatadores/farmacología , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismoRESUMEN
The pK(a) values of the CXXC active-site cysteine residues play a critical role in determining the physiological function of the thioredoxin superfamily. To act as an efficient thiol-disulphide oxidant the thiolate state of the N-terminal cysteine must be stabilised and the thiolate state of the C-terminal cysteine residue destabilised. While increasing the pK(a) value of the C-terminal cysteine residue promotes oxidation of substrates, it has an inhibitory effect on the reoxidation of the enzyme, which is promoted by the formation of a thiolate at this position. Since reoxidation is essential to complete the catalytic cycle, the differential requirement for a high and a low pK(a) value for the C-terminal cysteine residue for different steps in the reaction presents us with a paradox. Here, we report the identification of a conserved arginine residue, located in the loop between beta5 and alpha4 of the catalytic domains of the human protein disulphide isomerase (PDI) family, which is critical for the catalytic function of PDI, ERp57, ERp72 and P5, specifically for reoxidation. An examination of the published NMR structure for the a domain of PDI combined with molecular dynamic studies suggest that the side-chain of this arginine residue moves into and out of the active-site locale and that this has a very marked effect on the pK(a) value of the active-site cysteine residues. This intra-domain motion resolves the apparent dichotomy of the pK(a) requirements for the C-terminal active-site cysteine.
Asunto(s)
Arginina , Secuencia Conservada , Proteína Disulfuro Isomerasas/química , Sitios de Unión , Catálisis , Cisteína , Proteínas de Choque Térmico/química , Humanos , Concentración de Iones de Hidrógeno , Isomerasas/química , Cinética , Glicoproteínas de Membrana/química , Mutación , Oxidación-Reducción , Conformación Proteica , Proteína Disulfuro Isomerasas/genética , Alineación de SecuenciaRESUMEN
Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 A, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureus protected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents.
Asunto(s)
Amidohidrolasas , Aminopeptidasas/antagonistas & inhibidores , Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Cristalografía por Rayos X , Farmacorresistencia Microbiana , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacocinética , Pruebas de Sensibilidad Microbiana , Mutación/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
OBJECTIVE: To test the simultaneous effect of various established predictors of breast and cervical cancer screening (breast self-examination, clinical breast examination by a physician, Papanicolaou [Pap] smear, and pelvic examination) in a low-income, Mexican-American sample. MATERIAL AND METHODS: A total of 188 Mexican-American women participated in a face-to-face structured interview in their preferred language. We tested a model with four established predictors of breast and cervical cancer screening--communication skills, knowledge of cancer, access to health care (finances and availability of care), and anxiety about cancer. Simultaneous structural equations analysis was used to form latent variables and to control for the effect of all predictors concurrently. RESULTS: Screening behavior was inversely associated with anxiety about cancer when all other predictors were statistically controlled. In addition, anxiety substantially affected the relationship between communication skills and screening behavior. Unexpectedly, knowledge of cancer was positively, rather than negatively, associated with anxiety about cancer. Predictors in the model demonstrated an excellent fit of the proposed model to the data. CONCLUSION: Successful cancer screening programs for Mexican-American women must address not only access barriers but also communication skills, knowledge, and, perhaps most importantly, anxiety.
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Neoplasias de la Mama/prevención & control , Conductas Relacionadas con la Salud , Tamizaje Masivo , Americanos Mexicanos/estadística & datos numéricos , Neoplasias del Cuello Uterino/prevención & control , Salud de la Mujer , Ansiedad , Neoplasias de la Mama/psicología , Comunicación , Femenino , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud , Humanos , Encuestas y Cuestionarios , Neoplasias del Cuello Uterino/psicologíaRESUMEN
PURPOSE: To evaluate the ability of thin overlying bismuth radioprotective shielding to reduce the x-ray dose to radiosensitive superficial organs during diagnostic computed tomography (CT). MATERIALS AND METHODS: A variety of patient and phantom studies were performed with four thicknesses of bismuth radioprotective latex over the breast. Dose savings were determined with thermoluminescent dosimeters. A prototype and then a final manufactured radioprotective brassiere was constructed and tested for radiation dose savings to the breast during diagnostic chest CT. Preliminary studies were also performed to evaluate shielding of the thyroid, orbit, and testes. RESULTS: The use of bismuth radioprotective latex saved an average 57% of the radiation dose to the breast from thoracic CT, decreasing the radiation level from an average 2.2 rad (0.022 Gy) to 1.0 rad (0.010 Gy) (P < .001). Preliminary tests of shielding other superficial radiosensitive organs frequently included at diagnostic CT (eyes, thyroid gland, and testes) were performed with the same thickness of overlying bismuth radioprotective latex, with similar results. Radiation to the thyroid gland was reduced by 60% (from 0.0573 to 0.0229 Gy) and radiation to the eye and testes was reduced by 40% (from 0.0256 to 0.0154 Gy) and 51% (from 0.0463 to 0.0229 Gy), respectively. CONCLUSION: The use of in-plane overlying bismuth radioprotective latex manufactured into form-fitting garments did not affect the diagnostic CT image but reduced the amount of radiation to radiosensitive superficial structures.
Asunto(s)
Bismuto , Mama/efectos de la radiación , Ropa de Protección , Protección Radiológica/instrumentación , Radiografía Torácica , Tomografía Computarizada por Rayos X , Adulto , Neoplasias de la Mama/prevención & control , Ojo/efectos de la radiación , Femenino , Humanos , Látex , Masculino , Neoplasias Inducidas por Radiación/prevención & control , Fantasmas de Imagen , Dosis de Radiación , Testículo/efectos de la radiación , Glándula Tiroides/efectos de la radiaciónRESUMEN
Homoharringtonine (HHT) has been reported to induce hyperglycemia. This report describes a study conducted to characterize the effect of HHT on insulin production and action. Our data indicate that HHT-induced hyperglycemia results from the development of insulin resistance. A review of the literature suggests that patients receiving HHT continuous infusions of 5 mg/m2/d or greater and patients greater than 10 years of age may be at increased risk for the development of HHT-induced hyperglycemia. We recommend that patients with these risk factors, as well as diabetic patients and patients concurrently receiving asparaginase and/or prednisone, have their blood glucoses routinely monitored for hyperglycemia.
Asunto(s)
Alcaloides/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Harringtoninas/efectos adversos , Hiperglucemia/inducido químicamente , Enfermedad Aguda , Antineoplásicos Fitogénicos/administración & dosificación , Glucemia/análisis , Péptido C/orina , Evaluación de Medicamentos , Harringtoninas/administración & dosificación , Homoharringtonina , Humanos , Hiperglucemia/metabolismo , Infusiones Intravenosas , Insulina/sangre , Resistencia a la Insulina , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Factores de Riesgo , Factores de TiempoRESUMEN
A nonanemic chronic lymphocytic leukemia patient with nearly 500,000 lymphocytes/microL underwent leukapheresis when she presented with CNS symptoms and retinal vascular engorgement. Respiratory distress developed during the cell separator run, which led us to ask whether the procedure could have changed the adhesive properties of her cells. C5a desarginine, N-f-Met-Leu-Phe, adenosine diphosphate, and collagen all failed to aggregate her lymphocytes in vitro, but arachidonic acid, excess free calcium, and 4 mumol/L epinephrine did aggregate the cells. Arachidonate-induced aggregation appeared to be a toxic phenomenon: the ED50 for aggregation was statistically indistinguishable from that for cytotoxicity, and aspirin only mildly blunted the response. In contrast, epinephrine-induced aggregation was not associated with lactic dehydrogenase release or the loss of trypan blue exclusion and was blunted by propranolol; radiopindolol-binding studies confirmed the presence of a beta-adrenergic receptor. There were approximately 3,000 receptors/cell, with no statistically significant difference between normal and chronic lymphocytic leukemia B cells or between B cells and T cells (separated by rosetting techniques). The Kd for the B cells' receptor, however, was less than that for T cells by a factor of ten (P less than .01). We conclude that B cells may aggregate when stimulated and that they--like T cells--have beta-adrenergic receptors. Adrenergically mediated changes in B cell adhesiveness may play a role in regulating lymphocyte traffic; in the rare patient with truly enormous B cell counts, we postulate that they may be an occasional cause of morbidity.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Agregación Celular/efectos de los fármacos , Leucemia Linfoide/patología , Linfocitos/efectos de los fármacos , Receptores Adrenérgicos beta/efectos de los fármacos , Adenosina Difosfato/farmacología , Antagonistas Adrenérgicos beta/farmacología , Ácido Araquidónico , Ácidos Araquidónicos/farmacología , Aspirina/farmacología , Calcimicina/farmacología , Citratos/farmacología , Ácido Cítrico , Disnea/etiología , Femenino , Humanos , Leucaféresis/efectos adversos , Linfocitos/patología , Persona de Mediana Edad , N-Formilmetionina Leucil-Fenilalanina/farmacologíaRESUMEN
Based on a 6 1/2-year study of 284 consecutive adult patients with primary myelodysplastic syndrome (MDS) and and acute myelogenous leukaemia (AML), we have found that refined chromosome analysis can be used as an independent prognostic indicator in the great majority of patients with MDS and AML. In MDS, the FAB subtype was also found to have prognostic value and this was enhanced when the chromosomal findings were taken into consideration. In AML, the age of the patient correlated more closely with the chromosomal changes in predicting prognosis in most patients than did the FAB classification. Previously we reported that refined chromosome analysis of bone marrow specimens from 161 adult patients with primary or non-therapy related MDS and AML identified three prognostic chromosomal categories in each disease, representing 40% of all patients (Yunis et al, 1984, 1986). By extending our study to 284 patients, as well as a longer follow-up, it was possible to determine the prognostic implications of two additional chromosomal categories in MDS and five in AML. Since 73% of all patients are now represented in well-defined chromosomal subgroups with prognostic significance, refined chromosome analysis emerges as a tool that could have considerable impact in protocols.
Asunto(s)
Aberraciones Cromosómicas , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Médula Ósea/ultraestructura , Humanos , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/mortalidad , PronósticoRESUMEN
This article documents that hydroxyurea (HUR) is excreted into human breast milk, and it reviews the literature describing similar evaluations for other antineoplastic agents.
Asunto(s)
Hidroxiurea/farmacocinética , Leche Humana/metabolismo , Adulto , Femenino , Humanos , Hidroxiurea/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , EspectrofotometríaRESUMEN
High-dose cytarabine (HDARAC) therapy is an effective regimen in treating refractory leukemias. A typical regimen is cytarabine 3 g/m2 iv over one to three hours q 12h for a total of 8 to 12 doses. This case report illustrates the neurotoxicity unique to HDARAC. The patient received two cycles of HDARAC over the course of a ten-week period. During the first treatment, dysarthria and ataxia were seen after completion of the patient's eighth and final dose of HDARAC. These symptoms resolved over a period of five days. Six weeks later a more severe syndrome of dysarthria and ataxia developed during a second cycle of treatment. These symptoms worsened over 24 hours despite discontinuation of therapy, then gradually decreased in severity but persisted until his death two months later. The neurotoxicity seen with HDARAC is dose-related and has occurred in up to 60 percent of treated patients. The incidence of cerebellar toxicity approaches 30 percent, with irreversible ataxia reported in up to 16.7 percent. Because the cerebellar toxicity may be worsened by continuation of therapy after initial onset of symptoms, prompt termination of HDARAC is recommended.
Asunto(s)
Enfermedades Cerebelosas/inducido químicamente , Citarabina/efectos adversos , Citarabina/uso terapéutico , Humanos , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
In a study of 56 consecutive adult patients with de novo myelodysplastic syndromes (MDS), all cases were successfully analyzed with two refined chromosome banding techniques. Most patients (44 of 56, 79%) were found to have a chromosome defect. The majority of these patients had a recurrent loss of chromosomal material rather than a reciprocal translocation or inversion, as commonly found in acute leukemia. The three largest chromosomal categories found were associated with a wide range of survival. Twelve patients (21%) had normal chromosomes, a stable clinical course, and long survival (median follow-up time of 49 months, with all patients alive). Nine patients had in common a single chromosome defect resulting in either monosomy 7 or deletion 7q. They had a median survival of 12 months, and four died of acute nonlymphocytic leukemia (ANLL). Of 12 patients with complex defects, 11 had a complete or partial loss of a chromosome 5 and a complete or partial loss of the long arm of a chromosome 7 or 20. They had a poor median survival of four months, and six patients died of ANLL. Although the French-American-British (FAB) classification was also found to have some prognostic value, FAB subgroups were chromosomally heterogeneous and showed less dramatic differences in median survival than the larger chromosomal subgroups. We have shown, for the first time, that a refined chromosomal analysis is an independent prognostic indicator in de novo MDS and may be helpful in establishing therapeutic approaches in this difficult group of heterogeneous disorders.
Asunto(s)
Mapeo Cromosómico , Síndromes Mielodisplásicos/genética , Adulto , Anciano , Aberraciones Cromosómicas/diagnóstico , Bandeo Cromosómico , Trastornos de los Cromosomas , Cromosomas Humanos 6-12 y X , Femenino , Humanos , Masculino , Métodos , Persona de Mediana Edad , Pronóstico , TrisomíaAsunto(s)
Agranulocitosis/inducido químicamente , Enfermedades de la Médula Ósea/inducido químicamente , Hematopoyesis/efectos de los fármacos , Ibuprofeno/efectos adversos , Leucocitos , Adulto , Anciano , Agranulocitosis/inmunología , Anticuerpos/inmunología , Artritis Reumatoide/tratamiento farmacológico , Enfermedades de la Médula Ósea/inmunología , Proteínas del Sistema Complemento/inmunología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Técnicas In Vitro , Leucocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , MasculinoAsunto(s)
Leucemia/diagnóstico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Humanos , Lactante , Leucemia Linfoide/diagnóstico , Persona de Mediana EdadRESUMEN
Using high-resolution chromosomes of bone-marrow specimens from 105 consecutive adult patients with de novo acute nonlymphocytic leukemia, we found an unusually high degree of complexity in this disorder, which may explain previous difficulties in identifying useful prognostic indicators. Specimens from 99 of the 105 patients were successfully analyzed, and 92 (93 per cent) had a chromosomal defect. Seventeen categories were identified, 12 representing a specific recurrent defect. Three of them have been found to have independent prognostic importance. Patients with an inversion 16 (9 per cent), diagnosed as having M2, M4, or M5b disease according to the morphologic classification of the French-American-British Acute Leukemia Cooperative Study Group, had a uniform and sustained complete remission and a median survival of 25 months. In contrast, 14 patients (14 per cent) with complex chromosomal abnormalities and a diagnosis of M1, M2, M4, M5a, or M6 disease had a very poor prognosis. In 12 of the 14 patients efforts to achieve induction of remission failed, and the group had a median survival of 2.5 months. A third group with a trisomy 8 as the single defect (11 per cent) had an intermediate prognosis and a median survival of 10 months. With the different types of treatment for acute nonlymphocytic leukemia that are now available, we suggest that high-resolution chromosome analysis will become an important tool in selecting specific types of therapy for groups of patients with differing prognoses.
Asunto(s)
Aberraciones Cromosómicas , Leucemia/mortalidad , Enfermedad Aguda , Adolescente , Adulto , Factores de Edad , Anciano , Médula Ósea/patología , Inversión Cromosómica , Femenino , Humanos , Cariotipificación , Leucemia/genética , Masculino , Persona de Mediana Edad , Pronóstico , Translocación Genética , TrisomíaRESUMEN
A 24-year-old woman experienced grand mal seizures temporally related to cisplatin, vinblastine, and bleomycin (CVB) administration. A second episode of seizures occurred when the patient's phenytoin level was estimated to be in the range of 15 micrograms/ml. Her plasma phenytoin level at the time had dropped to 2 microgram/ml despite a recent dosage increase. To evaluate the cause of the subtherapeutic phenytoin levels, daily plasma phenytoin levels and 24-h urine collections were obtained during her next CVB cycle. Data revealed a mean phenytoin absorption of 32% (normal greater than 80%), establishing that phenytoin malabsorption occurred. The disruption of phenytoin absorption at a cellular level by CVB therapy is the proposed mechanism. Frequent monitoring of plasma phenytoin levels is recommended for patients receiving CVB.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fenitoína/metabolismo , Convulsiones/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Disponibilidad Biológica , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Femenino , Humanos , Fenitoína/sangre , Fenitoína/uso terapéutico , Fenitoína/orina , Embarazo , Convulsiones/inducido químicamente , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/análogos & derivados , VindesinaRESUMEN
A 3-year-old girl had the typical features of visceral larva migrans syndrome, including hypereosinophilia, recurrent pulmonary infiltrates, and elevated serum IgG, IgE, and isohemagglutinin titers. A marked mitogenic response of her cultured lymphocytes to Toxocara antigen but not to Ascaris antigen was found. A neutrophil chemotactic abnormality ot Escherichia coli culture filtrates and zymosan-activated sera was also demonstrated, which partially corrected after she was treated with diethylcarbamazine citrate.
Asunto(s)
Antígenos , Quimiotaxis de Leucocito , Larva Migrans Visceral/diagnóstico , Activación de Linfocitos , Toxocara/inmunología , Preescolar , Escherichia coli/inmunología , Femenino , Humanos , Larva Migrans Visceral/inmunología , NeutrófilosRESUMEN
Lead interferes with heme synthesis in erythrocytes and has a deleterious effect on red cell membranes. We measured myeloperoxidase (MPO) enzyme activity in the granulocytes of dogs fed increasing quantities of lead. Concurrently, iodination capability and in vitro bactericidal activity were measured. Blood lead levels were monitored. Three of 4 dogs poisoned with lead developed significant decreases in MPO enzyme activity in their granulocytes. The decline in MPO activity correlated with cumulative lead toxicity as judged by blood lead levels and clinical signs of lead poisoning. Iodination ability in all 4 dogs decreased with cumulative lead toxicity. After discontinuation of lead administration, recovery of granulocyte MPO activity preceded recovery of iodination ability. This observation suggests the possibility of separate effects of lead on iodination ability and MPO activity. Moderate impairment of bactericidal capacity developed in 3 of 4 dogs with severe lead poisoning. Clinical infections were not observed during the course of the study.