RESUMO
A pilot study was undertaken to investigate the effects of the intake of capsules containing the plant sterols and sterolins (BSS:BSSG mixture) on selected immune parameters of volunteers participating in an ultra-marathon in Cape Town, South Africa. Those runners having received active capsules (n=9) showed less neutrophilia, lymphopenia and leukocytosis when compared to their counterparts having received placebo capsules (n=8): the placebo treated individuals showed significant increases in their total white blood cell numbers as well as in their neutrophils (p=0.03 and 0.03 respectively). Furthermore, statistically significant increases within lymphocyte subsets were observed in the runners having received the active capsules: CD3+ cells increased (p=0.02) as did CD4+ cells (p=0.03). In parallel, the BSS:BSSG capsules decreased the plasma level of IL6 in the runners using the active capsules (p=0.08) and significantly decreased the cortisol: DHEAs ratio (p=0.03), suggesting that these volunteers had less of an inflammatory response and were less immune suppressed during the post-marathon recovery period. These findings justify further investigations into the use of the phytosterols to prevent the subtle immunosuppression associated with excessive physical stress.
Assuntos
Exercício Físico/fisiologia , Terapia de Imunossupressão , Inflamação , Fitosteróis/farmacologia , Sitosteroides/farmacologia , Adulto , Contagem de Células Sanguíneas , Suplementos Nutricionais , Feminino , Humanos , Leucocitose , Subpopulações de Linfócitos , Linfopenia , Masculino , Pessoa de Meia-Idade , Neutrófilos , Fitosteróis/administração & dosagem , Sitosteroides/administração & dosagemRESUMO
The study was undertaken to show that polymorphic isoniazid elimination in humans is trimodal; that the acetylator genotype and eliminator phenotype of the individual patient are concordant; and that the differences in the pharmacokinetic parameters of fast, intermediate, and slow eliminator subgroups are statistically significant. Sixty adult patients of both sexes and of mixed race with tuberculosis participated in the trial. The apparent elimination rate constant (k, h(-1)) and the area under the isoniazid concentration-time curve (AUC, mg/L/h), over the interval 2 to 6 h after oral isoniazid were determined in all patients; NAT2 allele composition was determined in 47 patients. Serum INH concentrations were determined by HPLC and genotypes by PCR/restriction enzyme analysis. Three eliminator phenotypes could be distinguished, and concordance between the phenotype and the genotype of the individual could be demonstrated. The isoniazid concentration-time profiles of the three eliminator subgroups were significantly different (p < 0.05). The NAT2*12A allele, which codes for fast acetylation, has a high frequency in the population studied, the intermediate acetylator genotype is constituted of codominant fast and slow alleles, and the distribution of phenotypes/genotypes in the population is consistent with Hardy-Weinberg predictions. The therapeutic implications of polymorphic isoniazid metabolism are discussed.
Assuntos
Antituberculosos/farmacocinética , Arilamina N-Acetiltransferase/genética , Isoniazida/farmacocinética , Tuberculose Pulmonar/metabolismo , Acetilação , Adulto , Alelos , Antituberculosos/uso terapêutico , Feminino , Genótipo , Humanos , Isoniazida/uso terapêutico , Masculino , Fenótipo , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Following ligand binding a number of cell-surface receptors become phosphorylated at tyrosine residues of their cytosolic domains. These phosphorylations are associated with initiation of a signalling programme involving a sequence of tyrosine-phosphorylated protein-protein interactions. In the recognition process between phosphorylated proteins, electrostatic interactions between negatively charged phosphorylated tyrosines, serine and threonine residues and positively charged lysines play an important role as well as hydrophobic and H-bonding reactions. We suggest in this paper that the fairly high-energy phosphate bond of certain protein phosphorylated tyrosines are possibly involved in inducing transitory protein cross-linking reactions. Through a process involving transfer of an activated phosphate of phosphorylated tyrosine to a side-chain carboxyl group of the receptor or next protein of the signalling sequence, an acyl phosphate is formed. This then acylates a hydroxyl group on a serine, threonine or tyrosine residue of the protein not carrying the carboxyl phosphate to give an ester linkage, thus cross-linking the two proteins of the signalling pathway. The covalent ester linkage is labile to hydrolysis and depending on the protein-protein molecular environment it might have a finite half-life. On hydrolysis, the transitory covalent linkage is broken with separation of the proteins. It is suggested therefore that formation of a protein-protein ester linkage introduces a type of timing device into the system. Breakdown of the original protein-phosphorylated tyrosine in this case therefore does not involve a phosphatase enzyme.
Assuntos
Fosfoproteínas/metabolismo , Fosfotirosina , Receptores de Superfície Celular/metabolismo , Animais , Modelos Químicos , Modelos Estruturais , Fosfosserina , Fosfotreonina , Ligação Proteica , Receptores Fc/química , Receptores Fc/metabolismo , Transdução de Sinais , Eletricidade EstáticaRESUMO
OBJECTIVE: To evaluate the adjuvant effect of beta-sitosterol and its glucoside in the treatment of culture proven pulmonary tuberculosis (PTB). DESIGN: A blinded randomised placebo-controlled trial in culture proven drug sensitive PTB. Patients were hospitalised for the duration of treatment and evaluated at monthly intervals with regard to sputum culture positivity, chest radiography, weight gain, Mantoux test response, routine haematology and liver functions. STATISTICAL EVALUATION: General linear models for repeated measures (SAS GLM package) compared the interaction effects, group effects and time effects of findings in 19 patients receiving sitosterols with those in 18 patients receiving a placebo (talcum powder). Absolute values and change from baseline values were evaluated, although only the latter are reported. RESULTS: Weight gain was significantly greater in the sitosterol group (mean weight gain 8.9 kg) than the placebo group (mean gain 6.1 kg) (P = 0.0023 group effects; P = 0.0001 for time effects). Speed of achieving culture negativity, radiological improvement and induration on Mantoux testing was similar in the two groups. Change in lymphocyte counts from baseline was significantly higher in the sitosterol group (P = 0.0001 and P = 0.0001 for group and time effects) as was the increase in eosinophil counts (P = 0.0001 and P = 0.0137 for group and time effects). CONCLUSION: The study has shown significantly improved weight gain and higher lymphocyte and eosinophil counts in PTB patients receiving sitosterols in addition to an efficacious antituberculosis regimen. Sitosterols and their possible mode of action should now be evaluated in larger numbers of tuberculosis patients and in diseases with a similar immunopathogenesis.
Assuntos
Sitosteroides/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adulto , Antituberculosos/uso terapêutico , Humanos , Contagem de Leucócitos , Masculino , Tuberculose Pulmonar/sangue , Aumento de PesoRESUMO
The phytosterols, beta-sitosterol (BSS), and its glucoside (BSSG) enhance the in vitro proliferative response of T-cells stimulated by sub-optimal concentrations of phytohaemagglutinin (PHA) several fold at extremely low concentrations (femtogram level). A 100:1 (mass:mass) ratio of BSS:BSSG (termed essential sterolin formulation, ESF) showed higher stimulation than the individual sterols at the same concentration. In vivo activity of ESF was also demonstrated when volunteers ingested ESF for 4 weeks. Proliferation of their T-cells, stimulated maximally with PHA, was significantly enhanced (20-920%) when compared to baseline values. In vitro, ESF (1 microgram.ml) was able to significantly enhance the expression of CD25 and HLA-Dr activation antigens on T-cells and increased the secretion, into the medium, of IL-2 and gamma interferon. NK-cell activity was also increased by BSS and BSSG alone, but with EST a higher activity was always found at different effector:target ratios (100:1 12:1).
Assuntos
Sitosteroides/farmacologia , Linfócitos T/imunologia , Adjuvantes Imunológicos/farmacologia , Adulto , Antineoplásicos/farmacologia , Relação Dose-Resposta Imunológica , Combinação de Medicamentos , Feminino , Antígenos HLA-DR/fisiologia , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismoRESUMO
This study concerns the pharmacokinetic behaviour and cardiovascular effects of rapid infusions of hypoxoside (CAS 83643-94-1) and rooperol (CAS 83644-00-2) in anaesthetised Chacma baboons. Institutional approval was obtained and animal care conformed to international guidelines. Hypoxoside (500 mg) and rooperol (240 mg) dissolved in isotonic saline were infused during 15 min. Concentration-time data from high performance liquid chromatography of arterial blood samples were subjected to non-linear curve-fitting to obtain two-compartment mammillary pharmacokinetic models. Mean values were: [Table: see text] Hypoxoside was eliminated without significant metabolite formation and it revealed no cardiovascular effects. Rooperol was metabolized rapidly with formation of nine metabolites of which the major three were the diglucuronide, disulphate and mixed glucuronide sulphate. Rooperol caused moderate, transient increased cardiac output, stroke volume and vascular pressures without increased heart rate or filling pressures, suggestive of increased myocardial contractility probably allied to its catechol structure.
Assuntos
Alcinos/farmacologia , Alcinos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Catecóis/farmacologia , Catecóis/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/farmacocinética , Glucosídeos/farmacologia , Glucosídeos/farmacocinética , Hemodinâmica/efeitos dos fármacos , Alcinos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Catecóis/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Glucosídeos/administração & dosagem , Meia-Vida , Infusões Intravenosas , Papio , Volume Sistólico/efeitos dos fármacosRESUMO
The basic principle of derivatization of a hydrazide moiety with an aldehyde as applied in the method developed by Lacroix et al. [J. Chromatogr., 307 (1984) 137-144] for the quantitation of isoniazid and acetylisoniazid was improved by modification, standardization and extension to allow quantitation of hydrazine in patient samples. It could be shown that 40 microliters of 1% methanolic cinnamaldehyde per 200 microliters of deproteinized analysate gave maximal chromophoric isoniazid-cinnamaldehyde conjugate, read at 340 nm. The hydrolytic loss of isoniazid, crucial to the quantitation of acetylisoniazid, could be compensated for by introduction of an appropriate set of calibration curves. Although the method described here allows quantitation of monoacetylhydrazine and diacetylhydrazine, in addition to hydrazine, in mono-spiked samples, the method cannot be used for the quantitation of the acetylated metabolites of hydrazine in patient samples because of a lack of specificity. Linear calibration curves in the range 1-25 micrograms/ml for isoniazid and acetylisoniazid, 10-400 ng/ml for hydrazine and 50-1000 ng/ml for monoacetylhydrazine and diacetylhydrazine, could be constructed; analyte recoveries approaching 100% could be achieved in all instances.
Assuntos
Antituberculosos/análise , Cromatografia Líquida de Alta Pressão/métodos , Hidrazinas/análise , Isoniazida/análise , Cromatografia Líquida de Alta Pressão/estatística & dados numéricos , Estabilidade de Medicamentos , Humanos , Hidrazinas/sangue , Hidrazinas/urina , Hidrólise , Isoniazida/análogos & derivados , Isoniazida/sangue , Isoniazida/urina , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To study the pharmacokinetic behaviour of hypoxoside taken orally by 24 patients with lung cancer. DESIGN: Randomised open study with three single doses of 1,600, 2,400 and 3,200 mg standardised Hypoxis plant extract (200 mg capsules) and a multiple-dose study on the first 6 patients taking 4 capsules 3 times daily for 11 days. PARTICIPANTS AND SETTING: Patients with histologically proven squamous, large-cell or adenocarcinoma were hospitalised at the Radiation Oncology Ward, Karl Bremer Hospital, Bellville, W. Cape. METHODS: Blood was drawn at regular intervals up to 75 hours after single doses and the concentrations of metabolites of the aglucone of hypoxoside, rooperol, were measured with a high-performance liquid chromatography method. For the multiple-dose study blood was drawn before the first dose each day. Concentration-time relationships were analysed according to a conventional single open-compartment model and also by using the NONMEM digital computer programme. RESULTS: Neither hypoxoside nor rooperol appear in circulation. This is due to complete phase II biotransformation to diglucuronide, disulphate and mixed glucuronide-sulphate metabolites, of which the latter is the major component. Considerable interpatient variation in concentration-time relationships was found in the single-dose studies. It was due to an active enterohepatic recirculation in some patients and a distinct lag phase in others together with zero-order rate of formation of rooperol in the colon. Computer modelling indicated a single open-compartment model in which the mass of the patient did not influence volume of distribution and clearance because formation of the metabolites is dependent on the metabolising capacity of the patient. However, the elimination of the metabolites follows first-order kinetics with half-lives ranging from 50 hours for the major metabolite to 20 hours for the two minor metabolites. Multiple-dose studies also showed large interpatient variation. CONCLUSION: In order to reach metabolite levels near 100 micrograms/ml, which have been shown to be tumouricidal after enzymatic deconjugation to rooperol, maintenance doses need to be individualised for each patient. For most patients, however, a daily dose of 2,400 mg was sufficient.
Assuntos
Alcinos/farmacocinética , Antineoplásicos/farmacocinética , Glucosídeos/farmacocinética , Adulto , Idoso , Alcinos/administração & dosagem , Alcinos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Glucosídeos/administração & dosagem , Glucosídeos/uso terapêutico , Humanos , Pneumopatias/tratamento farmacológico , Pneumopatias/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess the toxicity of hypoxoside taken orally by 24 patients with lung cancer. DESIGN: Open study with patients taking 1,200-3,200 mg standardised Hypoxis plant extract (200 mg capsules) per day divided in 3 doses in order to maintain metabolite blood levels near 100 micrograms/ml. PARTICIPANTS AND SETTING: Patients with histologically proven squamous, large-cell or adenocarcinoma were hospitalised initially at the radiation oncology ward, Karl Bremer Hospital, Bellville, W. Cape. Thereafter they returned every 2 weeks for full clinical examinations. METHODS: Routine biochemical and haematological measurements were done. Patients underwent regular full clinical examinations including radiographs and computed tomography scanning according to the discretion of the principal investigator. RESULTS: Nineteen patients on hypoxoside therapy survived for an average of 4 months with progression of their primary tumours and metastases, while 5 survived for more than a year. One of them survived for 5 years and histological examination of the primary lesion showed absence of cancer. No toxic effects, in clinical examinations or biochemical or haematological measurements, were found that could be ascribed to the ingestion of hypoxoside. Only one occasion of possible drug intolerance, with anxiety, nausea, vomiting and diarrhoea, was noted. CONCLUSION: The absence of toxicity warrants further investigation of hypoxoside as an oral prodrug, especially in patients with slow-growing necrotising tumours that are inoperable and have high concentrations of beta-glucuronidase and sulphatase as well as a high sensitivity for rooperol.
Assuntos
Alcinos/efeitos adversos , Antineoplásicos/efeitos adversos , Glucosídeos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Pró-Fármacos/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Alcinos/administração & dosagem , Alcinos/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Estudos de Avaliação como Assunto , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinéticaRESUMO
Methanol extracts of the corms of Hypoxis rooperi and H. latifolia were studied for their hypoxoside content by an in-line sorption enrichment HPLC technique [Kruger et al., J. Chromatogr., 612 (1993) 191]. Hypoxoside is the trivial name for (E)-1,5-bis(3'-hydroxy-4'-O-beta-D-glucopyranosyl-phenyl) pent-1-en-4-yne and rooperol the aglucone obtained from beta-glucosidase treatment. Hypoxoside and rooperol analogues containing 4, 3 and 2 hydroxyl groups resolved as separate peaks with the proportion of the latter two markedly higher in H. latifolia than in H. rooperi. After oral ingestion of hypoxoside by humans, no hypoxoside or rooperol appeared in the serum. Only rooperol was present in the faeces. The serum and urine contained at least three phase II metabolite peaks. Selective enzyme hydrolysis showed that they represent the diglucuronide, disulfate and glucuronide-sulfate conjugates of all three rooperol analogues.
Assuntos
Alcinos/análise , Antineoplásicos/análise , Catecóis/análise , Glucosídeos/análise , Inibidores de Lipoxigenase/análise , Plantas Medicinais/química , Alcinos/sangue , Alcinos/urina , Antineoplásicos/sangue , Antineoplásicos/urina , Biotransformação , Catecóis/sangue , Catecóis/urina , Cromatografia Líquida de Alta Pressão , Glucosídeos/sangue , Glucosídeos/urina , Humanos , Hidrólise , Inibidores de Lipoxigenase/sangue , Inibidores de Lipoxigenase/urina , Raízes de Plantas/químicaRESUMO
OBJECTIVE: To study the generation of the hepatotoxin hydrazine in 32 malnourished children receiving isoniazid for the treatment of tuberculous meningitis. DESIGN AND SETTING: This observational study was undertaken in the pediatric ward of a teaching hospital admitting children with advanced forms of tuberculous meningitis for treatment and management of complications. METHODS: Thirty-two children (mean age 2.28 years) receiving isoniazid 20 mg/kg/d were studied. Plasma isoniazid, acetylisoniazid, and hydrazine concentrations were determined by an HPLC method. Fourteen children were studied at weekly intervals for the first month of treatment and again after six months of therapy; 18 additional children were studied on one or more occasions during the first month of treatment only. RESULTS: The area under the curve for hydrazine two to five hours after the isoniazid dose correlated with the isoniazid elimination rate and with acetylisoniazid generation. Hydrazine production increased significantly during the first month of treatment, but decreased to approximate initial values at six months. No correlation was found between any clinical or biochemical indicator of liver dysfunction and hydrazine production. CONCLUSIONS: Hydrazine is formed in significant concentrations during the metabolism of isoniazid in young children. However, additional factors such as preexisting liver damage (e.g., from viral hepatitis) may be necessary for it to reach its toxic potential.
Assuntos
Hidrazinas/metabolismo , Isoniazida/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Criança , Transtornos da Nutrição Infantil/complicações , Pré-Escolar , Feminino , Meia-Vida , Hospitais de Ensino , Humanos , Hidrazinas/sangue , Hidrazinas/intoxicação , Lactente , Isoniazida/sangue , Isoniazida/farmacocinética , Testes de Função Hepática , Masculino , África do Sul , Tuberculose Meníngea/sangueRESUMO
A direct in-line pre-column extraction technique in which guanidinium and ammonium sulfate are used, followed by column switching, was employed to analyze serum, plasma and cerebrospinal fluid samples of patients treated for tuberculous meningitis. Resolution of a wide range of polar to non-polar xenobiotics was obtained on a C8 silica column by using a linear gradient from a binary system consisting of solvent A (0.05 M KH2PO4) and solvent B (acetonitrile-isopropanol, 4:1, v/v). Apart from the antituberculosis drugs (isoniazid, pyrazinamide, ethionamide and rifampicin) the patients received up to sixteen different medicines for prevention of complications and the treatment of symptoms. Qualitative resolution of all the drugs was obtained by the chromatographic system. Quantitation of pyrazinamide and ethionamide was achieved with high precision and low inter-sample variation.
Assuntos
Antituberculosos/análise , Antituberculosos/sangue , Antituberculosos/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos , Etionamida/análise , Etionamida/sangue , Etionamida/líquido cefalorraquidiano , Humanos , Isoniazida/análise , Isoniazida/sangue , Isoniazida/líquido cefalorraquidiano , Pirazinamida/análise , Pirazinamida/sangue , Pirazinamida/líquido cefalorraquidiano , Espectrofotometria Ultravioleta , Tuberculose Meníngea/sangue , Tuberculose Meníngea/líquido cefalorraquidiano , Tuberculose Meníngea/tratamento farmacológico , Xenobióticos/sangue , Xenobióticos/líquido cefalorraquidianoRESUMO
A novel approach has been developed for direct injection of physiological fluids on an in-line extraction pre-column followed by column switching in order to introduce the adsorbed xenobiotic onto the analytical column. The physiological fluid is pre-treated with guanidinium solution in water (200 microliters of fluid plus 300 microliters of a reagent containing 8.05 M guanidinium and 1.02 M ammonium sulfate) in order to denature protein binding sites and to serve as a universal solvent for a divergent range of polar to non-polar xenobiotics in a hydrophilic medium. A 0.5 M ammonium sulfate solution (500 microliters) is used as a pre- and post-flush reagent for the extraction pre-column (30 mm x 2.1 mm I.D.). The pre-flush reagent prepares the sorbent environment of the C18 pre-column for the hydrophobic retention of analytes. The post-flush reagent flushes non-retained sample proteins and salts to waste prior to switching the pre-column in-line with the analytical column. Universal chromatographic conditions for the analytical phase allows elution of a range of polar to non-polar xenobiotics within 20 min from an end-capped C8 silica analytical column (250 mm x 4.6 mm I.D.). This is effected by a linear gradient from a binary system consisting of solvent A (0.05 M KH2PO4) and solvent B (acetonitrile-isopropanol, 80:20, v/v).
Assuntos
Sulfato de Amônio/química , Guanidinas/química , Xenobióticos/análise , Cromatografia Líquida de Alta Pressão , Guanidina , Humanos , Indicadores e Reagentes , Intoxicação por Organofosfatos , Solventes , Espectrofotometria UltravioletaRESUMO
Salbutamol concentrations were determined by high-performance thin-layer chromatography in the sera of two sets of ten volunteers at hourly intervals for 6 h after taking one 8-mg slow-release tablet. The influence of time lapse in processing of serum samples, i.e. centrifugation, extraction and chromatography, was studied. A statistical significant instability of salbutamol in the sera of patients was found which was not present in standard drug-free serum samples spiked with salbutamol and used for construction of standard curves.
Assuntos
Albuterol/sangue , Cromatografia em Camada Fina/métodos , Ensaios Clínicos como Assunto , Humanos , Valores de Referência , Reprodutibilidade dos TestesRESUMO
Eighty-nine patients scheduled for cataract removal or lens implantation were divided randomly into three groups. Each received 5, 10 or 20 mg gentamicin subconjunctivally at times varying between 0.2 and 19 hours pre-operatively. At surgery a sample of aqueous humour was obtained and analysed for gentamicin concentration. The data for each group were subjected to non-linear regression analysis to fit an open one-compartment pharmacokinetic model with first-order kinetics. A statistically acceptable fit was obtained. The average values of the pharmacokinetic parameters obtained from the single doses were used to simulate multiple-dose kinetics. The average target intra-ocular gentamicin concentrations and dosage interval were specified in the computer program, which subsequently allowed calculation of the dose required. This allowed the construction of a simple linear nomogram that can be used to read off the dose needed for handling specific clinical situations.
Assuntos
Humor Aquoso/química , Gentamicinas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Disponibilidade Biológica , Extração de Catarata , Túnica Conjuntiva , Gentamicinas/administração & dosagem , Gentamicinas/análise , Humanos , Injeções , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Inhaled and oral salbutamol were compared in 12 asthmatic patients for prophylaxis in antigen-induced asthma. The patients were pretreated with 0.2- and 1.0-mg doses of inhaled salbutamol and with the standard oral 4- and 8-mg slow-release (SR) salbutamol preparations. Bronchodilatation was monitored over the ensuing 3 h and protection against antigen challenge at the end of the period. On each study day the degree of baseline airway hyperreactivity was determined by histamine challenge. Precautions were taken during the antigen challenge to ensure a reproducible response. Blood levels of salbutamol were monitored at hourly intervals for the 3 h after treatment and during the asthmatic reaction subsequent to challenge. Both the 0.2- and 1.0-mg inhalations caused immediate bronchodilation as compared to a placebo (p less than 0.05), but only the 1.0-mg dose protected subjects against antigen challenge (p less than 0.05). In comparison to the placebo, no bronchodilatation was achieved with the standard 4-mg oral preparation in spite of measurable blood levels, nor were the patients protected against antigen challenge at 3 h after pretreatment. However, the 8-mg SR salbutamol caused significant bronchodilatation within 2 h and suppressed antigen challenge responses as compared to placebo (p less than 0.05). It can be concluded that doses of inhaled salbutamol higher than the conventional 0.2- or the standard 4-mg oral preparations are required to protect asthmatics against inadvertent antigen exposure. In patients who are unable to use inhalers effectively, the SR preparation can be considered as an alternative.
Assuntos
Albuterol/administração & dosagem , Asma/prevenção & controle , Administração por Inalação , Administração Oral , Adolescente , Adulto , Albuterol/efeitos adversos , Albuterol/farmacocinética , Animais , Antígenos/administração & dosagem , Asma/fisiopatologia , Testes de Provocação Brônquica , Feminino , Histamina , Humanos , Masculino , Ácaros , PólenRESUMO
A study confirmed the existence of an immune reactive digitalis-like substance in normotensive and hypertensive people between the ages of 15 years and 64 years. In 13.6% of the population examined, values higher than 0.15 ng/ml of digitalis-like substances were obtained. The possible presence of this substance in a large proportion of patients should be borne in mind when interpreting digitalis measurements.
Assuntos
Glicosídeos Digitálicos/sangue , Hipertensão/sangue , Adolescente , Adulto , Idoso , Pressão Sanguínea , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
An endogenous digitalis-like substance (DLS) may be involved in the pathogenesis of essential hypertension and pre-eclampsia. The digoxin levels in maternal and cord blood of 504 randomly selected patients were determined. Since none of the patients received digoxin, these levels indicated a cross-reacting substance (immunoreactive DLS). DLS levels were significantly higher in the cord blood of pre-eclamptic patients than in the cord blood of controls. DLS levels in cord blood increased with the severity of pre-eclampsia, and levels were higher in primigravidas than in multigravidas. The structure and biological activity of DLS must be determined before definite conclusions about its role in the pathogenesis of pre-eclampsia can be made.
Assuntos
Glicosídeos Digitálicos/sangue , Digoxina/sangue , Pré-Eclâmpsia/sangue , Feminino , Sangue Fetal/análise , Humanos , GravidezRESUMO
The structure of thyroglobulin mRNA was analyzed in an inbred herd of Afrikander cattle with hereditary goitre. Northern transfer of RNA from affected animals revealed both a shorter (approximately 7100 bases) and a normal-sized (approximately 8200 bases) thyroglobulin mRNA when hybridized to bovine thyroglobulin cDNA clones. S1 nuclease mapping experiments established that 1100 bases are deleted in the 5' region of the smaller mRNA. Electron microscopy of RNA from animals with goitre hybridized to a bovine genomic DNA clone showed that the region deleted corresponds to exon 9 of the thyroglobulin gene. Southern blot analysis of the exon 9 region revealed differences between affected and control animals with the enzymes PstI and TaqI. Although they could reflect a linkage disequilibrium between the mutation and restriction fragment length polymorphism, it is noteworthy that these differences map in the region of the exon 9/intron 9 junction. Our results show that a genetic lesion in the thyroglobulin gene causes aberrant splicing of the pre-mRNA, and suggest that the responsible mutation is at the exon 9/intron 9 junction.
Assuntos
Doenças dos Bovinos/genética , Bócio/veterinária , Splicing de RNA , Tireoglobulina/genética , Animais , Sequência de Bases , Bovinos , Deleção Cromossômica , Endonucleases , Bócio/genética , Microscopia Eletrônica , Hibridização de Ácido Nucleico , RNA Mensageiro/genética , Endonucleases Específicas para DNA e RNA de Cadeia SimplesRESUMO
Congenital goiter was reported in a number of herds of Afrikander cattle in the 1950's. Some affected animals were assembled and maintained as a closed herd. Although considerable biochemical research into the nature of the disease has been conducted, no definitive report has described the mode of inheritance of the defect. This paper presents the results of breeding studies that indicate the defect is inherited as an autosomal recessive. Southern blot analysis of the thyroglobulin gene confirms this finding. In addition, serum levels of TSH (thyroid stimulating hormone, thyrotropin), T3 (3,4,3'-tri-iodothyronine), T4 (thyroxine), rT3 (3,3',5'-tri-iodothyronine), and DIT (diiodotyrosine) of goitrous animals are compared with normal animals.