RESUMO
BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.
Assuntos
Antituberculosos/economia , Tuberculose/tratamento farmacológico , Tuberculose/economia , Bangladesh , Brasil , Análise Custo-Benefício , Atenção à Saúde/economia , Custos de Medicamentos , Custos de Cuidados de Saúde , Gastos em Saúde , Serviços de Saúde/economia , Humanos , Modelos Teóricos , África do Sul , Tanzânia , Resultado do TratamentoRESUMO
Vasoactive intestinal peptide-like and peptide histidine isoleucine-like immunoreactivities were detected in the excretory duct of adult male and female Nippostrongylus brasiliensis, thus indicating the source of these two physiologically active peptides previously isolated from the excretory/secretory products of adult N. brasiliensis. In the nervous system immunoreactivity to both these peptides was confined to females and was found in the neurons of the ovijector associated ganglion. This is consistent with co-synthesis of vasoactive intestinal peptide-like and peptide histidine isoleucine-like peptides which has also been shown to occur in all mammalian vasoactive intestinal peptid-ergic neurons studied to date. However, in addition to this, and in common to some previous studies on helminth vasoactive intestinal peptide and peptide histidine isoleucine immunoreactivities, co-synthesis of the peptides was not indicated in a pair of branched neurons which projected posteriorly and peripherally from the ganglion associated with the ovijector of females and which terminated in two pairs of ganglia also exhibiting vasoactive intestinal peptide-like immunoreactivity only. The position of these ganglia indicated that they innervate muscles close to the body wall and may be responsible for the muscular contractions required for expulsion of eggs from female Nippostrongylus brasiliensis. This is also the first study to successfully detect these peptides in the excretory system of gastrointestinal nematodes.
Assuntos
Neurônios/química , Neuropeptídeos/análise , Nippostrongylus/química , Peptídeo PHI/análise , Peptídeo Intestinal Vasoativo/análise , Animais , Feminino , Imuno-Histoquímica , Masculino , Microscopia Confocal , RatosRESUMO
Vasoactive intestinal polypeptide (VIP)-like protein was detected by dot blot analysis in the excretions/secretions (E/S) of Nematodirus battus and Ascaridia galli and was confirmed in the E/S of Nippostrongylus brasiliensis. ELISA analysis showed that N. brasiliensis E/S contained the highest proportion of VIP-like protein (28.04 pmoles/mg of total E/S protein) and A. galli E/S contained the lowest (10.89 pmoles/mg of total E/S protein). Peptide histidine isoleucine (PHI)-like protein was detected by dot blot analysis in the E/S products of N. brasiliensis, N. battus and A. galli. ELISA analysis suggested that A. galli E/S contained the highest proportion of PHI (20.77 nmoles/mg of total E/S protein) and N. battus E/S contained the lowest (0.67 nmoles/mg of total E/S protein). The possible significance of VIP-like and PHI-like substances in the E/S of gastrointestinal nematodes is discussed.
Assuntos
Ascaridia/metabolismo , Nematoides/metabolismo , Nippostrongylus/metabolismo , Peptídeo PHI/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Galinhas , Masculino , OvinosRESUMO
The 50-30 kDa fraction isolated from the excretory/secretory products (E/S) of the nematode Nippostrongylus brasiliensis significantly decreased the amplitude of contraction of segments of uninfected rat intestine when injected into the lumen of the segments maintained in an organ bath. Dot blot analysis of the fraction suggested that it was similar in immunoreactivity to porcine vasoactive intestinal polypeptide (VIP). When antiserum to porcine VIP was mixed with N. brasiliensis E/S and the mixtures were injected into the lumen of segments of rat intestine, the inhibitory effect of the E/S on amplitude of contraction decreased. When physiological concentrations of porcine VIP (12.9 pmol/ml) were injected into the lumen of segments of uninfected rat intestine the amplitude of contraction decreased significantly. Western blot analysis of the E/S, using antiserum to porcine VIP, recognized a 30 kDa protein in the E/S and also in whole worm homogenate suggesting that synthesis of the peptide occurs inside the nematode. Peptide histidine isoleucine (PHI)-like immunoreactivity was detected in a 68 kDa fraction of the E/S and the homogenate but this fraction did not affect the amplitude of contractions of the intestine.
Assuntos
Proteínas de Helminto/fisiologia , Intestinos , Nippostrongylus/fisiologia , Peptídeo Intestinal Vasoativo/química , Animais , Proteínas de Helminto/química , Proteínas de Helminto/metabolismo , Técnicas In Vitro , Ratos , SuínosRESUMO
Whole worm homogenates and excretory/secretory (E/S) products of adult Nippostrongylus brasiliensis significantly decreased the amplitude of contractions of segments of uninfected rat intestine maintained in an organ bath, with significantly larger volumes of E/S products being required to bring about a similar decrease to that caused by the whole worm homogenate. Boiled samples of homogenate and E/S products significantly decreased the amplitude of contractions of uninfected rat intestine, but larger volumes were needed than with unboiled samples. Frequency of contraction was unaltered by homogenates or E/S products. When electric eel AChE was injected into the lumen of segments of uninfected rat intestine maintained in an organ bath there was no significant decrease in the amplitude of contractions. These results suggest that substances present in the E/S products of N. brasiliensis significantly reduce the amplitude of contractions of uninfected rat intestine in vitro and that the biochemical holdfast responsible for this phenomenon may not be AChE.
Assuntos
Acetilcolinesterase/farmacologia , Proteínas de Helminto/farmacologia , Intestinos/efeitos dos fármacos , Nippostrongylus/metabolismo , Animais , Electrophorus , Feminino , Intestinos/fisiologia , Contração Muscular/efeitos dos fármacos , Concentração Osmolar , Ratos , Ratos WistarRESUMO
The interactions of tetra-4N-methylpyridyl porphyrin and its zinc(II), copper(II) and manganese(III) complexes with brewer's yeast type V phenylalanine specific tRNA have been evaluated by high-resolution NMR. Differences in chemical shifts have been noted for three proton resonances in response to the presence of small quantities of the free base and the zinc and copper complexes. The protons giving rise to these signals are located on bases T54 and psi 55, both of which are involved in the primary intraloop and interloop hydrogen bonds that hold the D and T psi C loops together in the tertiary structure. In addition, broadening of specific resonances due to hydrogen bonding protons in the D stem at low ratios of porphyrin to tRNA indicates that the association of porphyrins increases the rate of imino proton exchange. The titration of the tRNA with the manganese(III) complex did not reveal shifts or specific broadening comparable to the other porphyrins at low ratios. The changes induced in the NMR spectrum of tRNA by porphyrins define their site of interaction with the polynucleotide. This site, at the outside of the elbow-bend in the tRNA 'L', is different from the locus of binding in tRNA for other classical DNA intercalators. Furthermore, a new mode of binding may be involved that is neither intercalative nor simply electrostatic.
Assuntos
Porfirinas , RNA de Transferência Aminoácido-Específico , RNA de Transferência de Fenilalanina , Sítios de Ligação , Cátions Bivalentes , Cobre , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Manganês , Conformação de Ácido Nucleico , ZincoRESUMO
Venezuelan equine encephalomyelitis (VEE) TC-84 vaccinal virus, from 10-1. quantities of infected duck embryo fibroblast cell culture fluids, was isolated by combined continuous-flow centrifugation with isopycnic banding in sucrose. Most of the recovered infectivity and hemagglutinating activity were in a single band at a buoyant density (rho) of 1.2. About 90% of the total input protein (450-520 mg) was removed with the effluent, whereas most of the remaining 10% also banded at a rho of 1.2. Infectivity was inactivated with formalin at a final concentration of 0.05% at 37 degrees C for 24 hr. Formalin-inactivated virus retained its immunogenicity and induced VEE virus-specific antibody in horses and guinea pigs. The horses and those guinea pigs that received equivalent doses of vaccine survived after a challenge of their immunity with virulent VEE virus.