RESUMEN
BACKGROUND: Netherton syndrome (NS) is a rare disease caused by SPINK5 mutations, featuring variable skin and hair involvement and, in many cases, allergic manifestations with a risk of lethality, particularly in infants. The clinical management of NS is challenging. OBJECTIVES: To analyse the clinical manifestations of a cohort of infants with NS managed in a reference centre and to draw up recommendations for management. METHODS: We conducted a monocentric analysis of patients with NS. The inclusion criteria were management in our reference centre, a histologically or molecularly confirmed diagnosis of NS and available epidemiological, clinical and laboratory data. RESULTS: A total of 43 patients with NS were included. Hypernatraemia was reported in 23 cases (54%) and associated with a greater likelihood of enteral and/or parenteral nutritional support (P < 0.001). Moreover, hypernatraemia was more frequent in patients with skin manifestations at birth (P = 0.026) and in patients bearing the c.153delT mutation in SPINK5 exon 3 (P = 0.014). The need for enteral and/or parenteral nutritional support was associated with a history of hypernatraemic dehydration (P < 0.001). Several unexpected extracutaneous complications were recorded, and new mutations were reported. The death rate (9% overall) was higher among the subset of patients bearing the c.153delT deletion. CONCLUSIONS: Our data emphasize that neonatal NS is a severe and sometimes lethal multisystem disorder. Patients have a high risk of variable metabolic anomalies (i.e. lethal hypernatraemia) and therefore have major nutritional needs. Cases of NS associated with c.153delT are particularly severe. Unexpected clinical manifestations broadened the phenotypic spectrum of NS. We provide recommendations on the management of the life-threatening manifestations of NS in neonates based on our multidisciplinary experience.
Asunto(s)
Síndrome de Netherton , Cabello , Humanos , Lactante , Recién Nacido , Mutación , Síndrome de Netherton/genética , Síndrome de Netherton/terapia , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Inhibidor de Serinpeptidasas Tipo Kazal-5RESUMEN
BACKGROUND: Generalized recessive dystrophic epidermolysis bullosa (RDEB) is often complicated by high nutritional difficulties with risks of malnutrition. OBJECTIVES: To provide information regarding the benefits of enteral feeding by gastrostomy (GTF), energy and protein requirements, tolerance, growth and pubertal development in children with RDEB. METHODS: Twenty-four patients were referred over a 7-year period in a retrospective study. Gastrostomy placement was decided in patients unable to feed orally and/or presenting loss in weight and height of at least 1 SD compared with their best growth level, despite regular nutritional advice. Weight and height were expressed as Z-scores. Catch-up growth following GTF onset was studied. RESULTS: Gastrostomies were performed in 11 children (aged 9·0±5·8years), and one young man aged 18years. The body weight Z-score was -2·3±1·0, height Z-score 1·1±1·1, weight-for-height was 81±11% and height-for-age 95± 4%. At onset, GTF provided 74±21% and 180±81% of the recommended dietary allowance (RDA) for energy and proteins, respectively. At study update (53±20months), GTF provided 91±29% and 205±100% of RDA for energy and proteins, respectively. Weight-for-height reached 92±15% and height-for-age 98±5%. A normal puberty was obtained when GT was performed before the age of 10years. Skin was not improved. CONCLUSION: Malnutrition was observed in 50% of the children with generalized RDEB. Protein and energy needs are particularly high. GTF is well tolerated and helps with catch-up growth and puberty. It must be considered before malnutrition onset, and, if necessary, before puberty.
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Nutrición Enteral/métodos , Epidermólisis Ampollosa Distrófica/terapia , Gastrostomía/métodos , Adolescente , Niño , Preescolar , Ingestión de Energía , Femenino , Trastornos del Crecimiento/terapia , Humanos , Masculino , Estado Nutricional , Satisfacción del Paciente , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Aumento de PesoRESUMEN
POLG-related mitochondrial disease is a rare mitochondrial disorder that is potentially associated with anaesthetic complications such as propofol-related infusion syndrome. A 19-year-old man with mitochondrial DNA deletions and POLG-related disorders presented for an elective robotic Heller-Dor myotomy for the treatment of oesophageal pseudo-achalasia associated with severe gastro-oesophageal reflux. The fasting period was minimised to reduce the risk of metabolic stress. The anaesthetic technique included a rapid sequence induction with propofol and rocuronium, a remifentanil and sevoflurane-based general anaesthesia with multimodal monitoring and peri-operative lactate-free intravenous fluids with added dextrose. The patient did not experience propofol-related infusion syndrome but did have delayed tracheal extubation due to residual neuromuscular blockade requiring a second dose of sugammadex. This report demonstrates the safety of single-use, low-dose propofol in this patient group. Patients with POLG-related mitochondrial disease may be at risk of prolonged neuromuscular blockade, and appropriate dosing of neuromuscular blocking agents with monitoring of neuromuscular blockade is strongly encouraged.
RESUMEN
INTRODUCTION: Severe epidermolysis bullosa simplex (EBS sev) is a rare genodermatosis characterized by congenital generalized blistering and mucosal involvement. Increased needs and decreased intake quickly lead to nutritional imbalance. Enteral nutrition support is proposed, but classical nasogastric tubes are not well tolerated in these patients and gastrostomy is preferred. OBJECTIVE AND METHODS: To report the experience with EBS sev in neonatal units of French reference centers for gastrostomy. In this retrospective multicentric study, we included all patients with EBS sev who had gastrostomy placement before age 9 months during neonatal care hospitalization. RESULTS: Nine infants (5 males/4 females) with severe skin and mucosal involvement were included. A gastrostomy was decided, at an early age (mean 3.7 months, range 1.4 to 8 months) in infants with mean weight 4426 g (range 3500 to 6000 g). Techniques used were endoscopy with the pull technique for 5 infants and surgery under general anesthesia for 4. Main complications were local but resolved after treatment. All infants gained weight after gastrostomy. The mean withdrawal time (n = 7) for the gastrostomy was 35.8 months (range 10.5 months to 6.5 years). Seven children had persistent oral disorders. CONCLUSIONS: Gastrostomy in infants with EBS sev can be necessary in neonatal intensive care units. Both surgical and endoscopic pull techniques seem efficient, with good tolerance.
Asunto(s)
Epidermólisis Ampollosa Simple , Epidermólisis Ampollosa , Niño , Nutrición Enteral , Femenino , Gastrostomía , Humanos , Lactante , Recién Nacido , Cuidado Intensivo Neonatal , Masculino , Estudios RetrospectivosRESUMEN
The origin of contamination in pertussis of young infants is generally the close relatives. From 2000 to 2004, only serology and culture were available in our hospital. The families of 16 young infants (age below one year) hospitalized for pertussis were screened using serological tests: 21/48 contacts were positive. After 2004, PCR was available for exploration of index cases and families: 35/85 contacts were positive. Of the mothers tested 23/46 were positive compared to 14/41 fathers. Only one parent presented with a typical paroxystic pertussis cough, 60% presented with a nonparoxystic cough having lasted for more than five days and 40% of positive adults did not present with cough. Despite official recommendations, none of these young parents had received an antipertussis booster vaccination. This study shows the high frequency of atypical or nonsymptomatic pertussis in adults in the close family of infected young infants. These adults contribute to spreading the disease.
Asunto(s)
Tos Ferina/diagnóstico , Tos Ferina/transmisión , Tos/epidemiología , Padre , Femenino , Humanos , Lactante , Masculino , Madres , Núcleo Familiar , Reacción en Cadena de la Polimerasa , HermanosRESUMEN
This study investigated 41 infants, aged <4 months, who were hospitalised with symptoms compatible with pertussis. Of these, 16 had Bordetella pertussis infection confirmed by real-time PCR. For four of these 16 patients, the initial sample was PCR-negative, but samples collected 5-7 days after the onset of infection were PCR-positive. PCR was also positive with samples from 15/16 families and 20/41 household contacts. Nine of the 20 positive household contacts were asymptomatic. Among the 16 infants with proven pertussis, apnoea was more frequent than in a control group for whom PCR was negative with both children and household contacts (69% vs. 28%). It was concluded that real-time PCR performed with samples from household contacts facilitates the diagnosis of infants suspected clinically of having pertussis, thereby enabling earlier treatment.
Asunto(s)
Apnea/microbiología , Infecciones por Bordetella/epidemiología , Infección Hospitalaria/epidemiología , Familia , Tos Ferina/microbiología , Bordetella pertussis/genética , Bordetella pertussis/aislamiento & purificación , Humanos , Lactante , Reacción en Cadena de la PolimerasaRESUMEN
Earlier studies have shown guanine arabinoside (ara-G) is an effective agent against growth of T-cell lines and freshly isolated human T-leukemic cells. However, poor water solubility of ara-G limits clinical use. 2-Amino-6-methoxypurine arabinoside (506U) is a water-soluble prodrug converted to ara-G by adenosine deaminase. 506U is not a substrate for deoxycytidine kinase, adenosine kinase, or purine nucleoside phosphorylase and is phosphorylated by mitochondrial deoxyguanosine kinase at a rate 4% that of ara-G phosphorylation. Mitochondrial DNA polymerase was the least sensitive to ara-GTP inhibition of the five human DNA polymerases tested. [3H]506U was anabolized to ara-G 5'-phosphates in CEM cells but not to phosphorylated metabolites of 506U. 506U was selective for transformed T over B cells and also inhibited growth in two of three monocytic lines tested. 506U given i.v. to cynomolgus monkeys was rapidly converted to ara-G; the ara-G had a half-life of approximately 2 h. 506U had in vivo dose-dependent efficacy against human T-cell tumors in immunodeficient mice. A Phase 1 trial of 506U against refractory hematological malignancies is now in progress at two study sites.
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Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Leucemia de Células T/tratamiento farmacológico , Profármacos/uso terapéutico , Animales , Antineoplásicos/metabolismo , Arabinonucleósidos/metabolismo , Arabinonucleotidos/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Guanosina Trifosfato/análogos & derivados , Guanosina Trifosfato/metabolismo , Humanos , Leucemia de Células B/tratamiento farmacológico , Leucemia de Células T/metabolismo , Macaca fascicularis/metabolismo , Ratones , Ratones Desnudos , Inhibidores de la Síntesis del Ácido Nucleico , Profármacos/metabolismo , Células Tumorales CultivadasRESUMEN
The effect of acyclovir on the deoxyribonucleoside triphosphate pools of Vero cells infected with herpes simplex virus type 1 was examined. Deoxyguanosine triphosphate and deoxyadenosine triphosphate pool levels in infected cells treated with acyclovir increased dramatically compared with pool levels in untreated infected cels. The increases were due, at least in part, to inhibition of viral DNA polymerase activity which resulted in reduced utilization of the deoxyribonucleoside triphosphates. Differences of as much as 26 times were detected in the sensitivity of herpes simplex virus type 1 to inhibition by acyclovir with different Vero cell cultures. These results were due to differences in acyclovir triphosphate levels, not to differences in deoxyguanosine triphosphate levels.
Asunto(s)
Antivirales/farmacología , Desoxirribonucleótidos/metabolismo , Guanina/análogos & derivados , Simplexvirus/crecimiento & desarrollo , Aciclovir , Animales , Línea Celular , Chlorocebus aethiops , Nucleótidos de Desoxiadenina/metabolismo , Nucleótidos de Desoxicitosina/metabolismo , Nucleótidos de Desoxiguanina/metabolismo , Guanina/metabolismo , Guanina/farmacología , Ácido Fosfonoacético/farmacología , Nucleótidos de Timina/metabolismoRESUMEN
The pharmacokinetics of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) inhibition of adenosine deaminase (ADA) was measured in vivo in CBA mice. The in vivo assay utilized injection of 10-100 nmoles [2-3H]adenosine and measurement of blood 3H2O 20 min later. A single oral dose of EHNA (50 mg/kg) totally inhibited ADA for 4 hr and caused a large increase in conversion of [2-3H]adenosine to [2-3H]ATP. EHNA (3 mg/kg) decreased deamination by 50% for 2-6 hr, depending on the dose of adenosine used. Mice dosed with EHNA (100 mg/kg) once daily for 7 days showed the same ADA recovery rate as mice dosed only once. High single oral doses of EHNA had no effect on blood ATP and GTP pools.
Asunto(s)
Adenina/análogos & derivados , Inhibidores de la Adenosina Desaminasa , Nucleósido Desaminasas/antagonistas & inhibidores , Adenina/farmacología , Adenosina Trifosfato/sangre , Animales , Relación Dosis-Respuesta a Droga , Eritrocitos/metabolismo , Guanosina Trifosfato/sangre , Cinética , Ratones , Ratones Endogámicos CBARESUMEN
Compound B103U, 4-hydroxy-6-mercaptopyrazolo[3,4-d]pyrimidine, was investigated as an inhibitor of human xanthine oxidase. Studies in vitro demonstrated that it was significantly more potent than oxypurinol, 4,6-dihydroxypyrazolo[3,4-d]pyrimidine. It formed an initial complex with electron-rich (reduced) human xanthine oxidase that was tighter than the corresponding complex formed by oxypurinol. The initial complexes with each inhibitor and reduced enzyme were internally rearranged into more stable complexes with first-order rate constants of 2.5 to 3 per min. However, the half-life of the isomerized (stable) complex with B103U was three to four times longer than the half-life of the analogous complex with oxypurinol. This stability was previously noted by Massey et al. (J. Biol Chem 254: 2837-2844, 1970) with B103U and bovine xanthine oxidase. The overall Ki values accounting for the initial and isomerized complexes were 5 nM for B103U and 100 nM for oxypurinol. B103U was also more potent as an inhibitor of bovine xanthine oxidase-catalyzed generation of superoxide radicals. Studies in mice revealed that the relative in vitro potency of B103U was not sustained in vivo. Compared to the inhibition of xanthine oxidase by oxypurinol, inhibition by B103U was neither more potent nor longer lasting. This shortcoming was not caused by weaker inhibition of mouse xanthine oxidase. Instead, it was the result of poor bioavailability. Plasma levels of available B103U rapidly decreased from samples of mouse and human blood because of reversible binding to serum proteins. B103U was also susceptible to oxidation. Two equivalents of H2O2 stoichiometrically oxidized the 6-thiol substituent to a sulfinic acid. This oxidized product was three orders of magnitude weaker as an inhibitor of xanthine oxidase than was B103U.
Asunto(s)
Oxipurinol/farmacología , Pirimidinas/farmacología , Xantina Oxidasa/antagonistas & inhibidores , Animales , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Radicales Libres , Humanos , Peróxido de Hidrógeno , Hipoxantina , Hipoxantinas , Cinética , Ratones , Oxipurinol/análogos & derivados , Oxipurinol/farmacocinética , Superóxidos/metabolismo , Ácido Úrico/metabolismoRESUMEN
6-Dimethylamino-9-(beta-D-arabinofuranosyl)-9H-purine (ara-DMAP) effectively prevented the development of rash and appreciably reduced viremia in simian varicella virus-infected monkeys. Doses of 100 and 50 mg/kg/day, administered orally, were highly effective. The lowest dose of 20 mg/kg/day was much less effective in preventing moderate viremia. However, the 20 mg/kg/day did prevent the development of rash in two of three monkeys. All three doses of ara-DMAP reduced liver infection as reflected by lower aspartate aminotransferase values in the sera of the African green monkeys. Orally administered ara-DMAP was rapidly absorbed. However, significant variation among individual monkeys in the AUC values, peak plasma levels, and plasma half-lives were observed.
Asunto(s)
Antivirales/farmacocinética , Varicela/tratamiento farmacológico , Vidarabina/análogos & derivados , Administración Oral , Animales , Animales Salvajes , Antivirales/sangre , Antivirales/uso terapéutico , Aspartato Aminotransferasas/sangre , Chlorocebus aethiops , Evaluación de Medicamentos , Semivida , Efectividad Biológica Relativa , Piel/patología , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/farmacocinética , Vidarabina/uso terapéutico , Viremia/tratamiento farmacológicoRESUMEN
Rapid and reliable methods for the determination of survival, proliferation, and metabolic activity of immobilized cells in gels are described. The first method is based on an MTT assay that measures qualitatively and quantitatively the metabolic activity of the cells. The second method determines cell number by measuring the amount of DNA available for Feulgen staining. In the third method, two fluorescent dyes are used to differentially stain viable and dead cells. The fourth method involves the use of glutaraldehyde to protect the cells when melting the gel to facilitate hemocytometric count. The presented techniques should help to test the efficiency of the immobilization procedures and to monitor the growth and survival of immobilized cells.
Asunto(s)
Biotecnología/métodos , Recuento de Células/métodos , Colorantes de Rosanilina , Animales , División Celular , Supervivencia Celular , Colorantes/metabolismo , ADN/análisis , Fijadores , Colorantes Fluorescentes , Geles , Glutaral , Hibridomas , Ratones , Sefarosa , Coloración y Etiquetado , Sales de Tetrazolio , Tiazoles , Azul de TripanoRESUMEN
Cognitive-behavioral and behavioral interventions, which have been successfully used to manage chronic pain unrelated to cancer, are an acceptable treatment for the psychobiological factors, including the expression of feelings, associated with pain in cancer patients. However, testing the effectiveness of complex multidimensional programs is difficult because of confounding factors such as progression of disease and measurement of potentially reactive outcomes. Patients were enrolled in theoretically strong individualized treatment programs for 5 weeks, with follow-up observation at 9 and 17 weeks. Weekly strategies were chosen to contribute to the achievement of patient-selected pretreatment goals. Interventions were designed to achieve psychobiological outcomes such as a decrease in inaccurate expectations, an increase in the use of positive comparisons and positive self-statements, a decrease in autonomic arousal, and promotion of self-efficacy. Two case studies provide examples of individual differences in treatment needs and the realities of clinical care.
Asunto(s)
Terapia Cognitivo-Conductual/métodos , Neoplasias/fisiopatología , Dolor/enfermería , Neoplasias de la Mama/fisiopatología , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Neoplasias Hepáticas/fisiopatología , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Evaluación en Enfermería , Dolor/etiología , Planificación de Atención al PacienteRESUMEN
The aim of this study was to evaluate how clinical students reacted to the use of Podcasts for undergraduate teaching. The most popular way of listening to them was on a computer. Students scored highly the subject matter of the Podcasts and used them for learning around the subject, especially during examination time. Podcasts are a valuable vehicle for delivering learning materials to students: offering flexibility but in tune with students' love of downloading materials to use when they wish.
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Instrucción por Computador/métodos , Educación en Odontología/métodos , Tecnología Educacional/métodos , Prostodoncia/educación , Grabación en Cinta/instrumentación , Adulto , Actitud hacia los Computadores , Recursos Audiovisuales , Tecnología Educacional/instrumentación , Humanos , Internet , Evaluación de Programas y Proyectos de Salud , Estudiantes de Odontología/psicología , Reino Unido , Grabación de Cinta de Video/instrumentación , Adulto JovenAsunto(s)
Nutrición Enteral/métodos , Enfermedades Gastrointestinales/terapia , Gastrostomía/métodos , Errores Innatos del Metabolismo/terapia , Desnutrición Proteico-Calórica/terapia , Niño , Preescolar , Diarrea/etiología , Nutrición Enteral/efectos adversos , Falla de Equipo , Alimentos Formulados , Gastrostomía/efectos adversos , Humanos , Lactante , Vómitos/etiologíaRESUMEN
The ability of LM cells, thymidine kinase-deficient LM cells (LMTK-), and LMTK- cells transformed to the LMTK+ phenotype by herpes simplex virus type 1 genetic information (LH7 cells) to anabolize the acyclovir congener ganciclovir was examined. About 50-fold more ganciclovir triphosphate was produced by LH7 cells than by either LM or LMTK- cells. Growth inhibition studies indicated that 180 and 120 microM ganciclovir were required to achieve 50% growth inhibition of LM and LMTK- cells, respectively; only 0.07 microM ganciclovir was necessary to achieve 50% inhibition of LH7 cells. DNA synthesis in the transformed cells was significantly reduced by ganciclovir treatment, whereas ganciclovir had little effect on DNA synthesis in the nontransformed cells. Alkaline sucrose gradient sedimentation analysis of transformed cellular DNA indicated that LH7 DNA synthesized in the presence of ganciclovir chased into mature DNA. Both LM and LH7 DNA synthesized in the presence of ganciclovir exhibited a concentration-dependent reduction in the rate of elongation into mature DNA. Finally, [14C]ganciclovir was incorporated internally into the growing chains of LH7 cells.
Asunto(s)
Aciclovir/análogos & derivados , Antivirales/farmacología , Transformación Celular Viral/efectos de los fármacos , ADN Viral/biosíntesis , Simplexvirus/genética , Aciclovir/farmacología , Animales , División Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , ADN Viral/análisis , Ganciclovir , Células L , Ratones , Extensión de la Cadena Peptídica de Translación/efectos de los fármacos , Transfección , Transformación GenéticaRESUMEN
9-([2-Hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine (BW B759U) is more potent and has a more prolonged inhibitory effect against Epstein-Barr virus (EBV) in vitro than does acyclovir (ACV). To assess the mechanism of this difference, we first compared the extent of phosphorylation of the two drugs in superinfected Raji cells. BW B759U is phosphorylated to levels 100-fold higher than is ACV. In addition, lower levels of phosphorylation of BW B759U and ACV were observed in uninfected Raji cells. Studies on the kinetics of formation of BW B759U triphosphate in superinfected Raji cells indicated that drug-phosphorylating activity was detected as early as 3 h after superinfection; this activity was steadily maintained for the first 7 h, followed by a burst of activity between 7 and 10 h and a doubling of phosphorylation between 10 and 25 h. During the superinfection cycle, the pool sizes of deoxyribonucleoside and ribonucleoside triphosphates were increased and reached their maxima at 10 h after infection. The maximal amount of triphosphorylated drug in a virus producer cell, P3HR-1 (LS), was obtained at 21 h after drug treatment. During long-term drug treatment, approximately 44 and 77% reduction in EBV genome copies per cell was observed on days 3 and 7, respectively. In a separate experiment, after treatment of P3HR-1 (LS) cells with BW B759U for 36 h, 4.2 pmol of BW B759U triphosphate per 10(6) cells was achieved. After the cells were released into drug-free medium, drug triphosphate was rapidly decreased to 11% of the original level in 1 day. Thereafter, the decrease was slow but steady, down to 0.22 pmol/10(6) P3HR-1 cells by 5 days. We calculated that 0.22 pmol of BW B759U triphosphate per 10(6) cells represents a cellular concentration of 0.22 microM, which is theoretically enough to inhibit EBV replication. This is based upon a comparison with the 50% effective dose of BW B759U (0.05 microM) for inhibition of genome replication and a Ki of 0.08 microM for BW B759U triphosphate inhibition of EBV DNA polymerase.
Asunto(s)
Aciclovir/análogos & derivados , Antivirales/metabolismo , Herpesvirus Humano 4/efectos de los fármacos , Linfocitos/microbiología , Aciclovir/metabolismo , Aciclovir/farmacología , Antivirales/farmacología , Biotransformación , Línea Celular , Desoxirribonucleótidos/metabolismo , Ganciclovir , Herpesvirus Humano 4/fisiología , Humanos , Cinética , Fosforilación , Ribonucleótidos/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
The metabolism of 6-dimethylaminopurine arabinoside (ara-DMAP), a potent inhibitor of varicella-zoster virus replication in vitro, was studied in rats and cynomolgus monkeys. Rats dosed intraperitoneally or orally with ara-DMAP excreted unchanged ara-DMAP and one major metabolite, 6-methylaminopurine arabinoside (ara-MAP), in the urine. They also excreted allantoin and small amounts (less than 4% of the dose each) of hypoxanthine arabinoside (ara-H) and adenine arabinoside (ara-A). The relative amount of each urinary metabolite excreted remained fairly constant for intraperitoneal ara-DMAP doses of 0.3 to 50 mg/kg of body weight. Rats pretreated with an inhibitor of microsomal N-demethylation, SKF-525-A, excreted more unchanged ara-DMAP and much less ara-MAP than did rats given ara-DMAP alone. Rats pretreated with the adenosine deaminase inhibitor deoxycoformycin excreted more ara-MAP and much less ara-H and allantoin. ara-MAP was shown to be a competitive alternative substrate inhibitor of adenosine deaminase (Ki = 16 microM). Rats given ara-DMAP intravenously rapidly converted it to ara-MAP and purine metabolism end products; however, ara-A generated from ara-DMAP had a half-life that was four times longer than that of ara-A given intravenously. In contrast to rats, cynomolgus monkeys dosed intravenously with ara-DMAP formed ara-H as the major plasma and urinary end metabolite. Rat liver microsomes demethylated ara-DMAP much more rapidly than human liver microsomes did. ara-DMAP is initially N-demethylated by microsomal enzymes to form ara-MAP. This metabolite is further metabolized by either adenosine deaminase, which removes methylamine to form ara-H, or by microsomal enzymes, which remove the second methyl group to form ara-A.
Asunto(s)
Antivirales/metabolismo , Herpesvirus Humano 3/efectos de los fármacos , Vidarabina/análogos & derivados , Inhibidores de la Adenosina Desaminasa , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Arabinonucleósidos/metabolismo , Arabinonucleósidos/orina , Cromatografía Líquida de Alta Presión , Semivida , Herpesvirus Humano 3/fisiología , Humanos , Técnicas In Vitro , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Proadifeno/farmacología , Ratas , Ratas Endogámicas , Especificidad de la Especie , Vidarabina/metabolismo , Vidarabina/farmacocinética , Vidarabina/farmacología , Vidarabina/orina , Replicación Viral/efectos de los fármacosRESUMEN
Synchronous cultures of Chlorella, that were obtained with minimum metabolic perturbation by centrifugal selection, reveal that progress through the cell cycle requires no change in the poly(A)+ mRNA population, although changes do occur during nutritional adaptation. Of the abundant soluble proteins, 93% are synthesized continuously through the cell cycle and those that are discontinuous show similar patterns in control cells. The synthesis of proteins is compared with parallel studies of accumulation of enzyme activity and it is shown that there is no discrepancy in their pattern of accumulation when both are studied under the same culture conditions. The eukaryote cell cycle can allow stable relative rates of synthesis of most proteins and balanced rates of accumulation of most enzyme activities. Macromolecule classes differ in their rates of accumulation throughout the cell cycle: total RNA increases linearly, poly(A)+ RNA accumulation is restricted to G1 phase, but total protein accumulation accelerates smoothly through G1, S and mitosis phases, pausing at cytokinesis. There is no evidence that the cell cycle requires an extensive programme of differential enzyme synthesis. The cycle can therefore proceed with minimum disturbance of metabolism required for growth.