TB therapeutic drug monitoring - analysis of opportunities in Romania and Ukraine.

INTRODUCTION: Therapeutic drug monitoring (TDM) could improve TB treatment outcomes by avoiding drug toxicity or underdosing. In this study, we describe the patient burden in three TB centres in Romania and Ukraine with a TDM indication, as per the current guidelines, in order to estimate the feasibility of implementing TDM.METHODS: A retrospective multi-centre study was conducted at the Iasi Lung Hospital (Iasi, Romania), Bucharest Marius Nasta Institute (Bucharest, Romania) and Chernivtsi TB Centre (Chernivtsi, Ukraine) in adult hospitalised TB patients.RESULTS: A total of 927 participants were admitted, of whom 37.8% had at least one indication for TDM, the most frequent being slow response to TB treatment (202/345, 58.6%); 55.5% had at least one cavity present on chest X-ray. Patients with a TDM indication stayed in the hospital for a median of 67 days and took on average 2 months more to reach a successful TB outcome.CONCLUSION: TDM could be a valuable tool to improve management of selected TB patients. The decision on whether to perform TDM is often delayed by 2 months due to waiting for culture results after treatment initiation. A randomised control trial should be performed in order to define TDM's precise role in TB therapy.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

eHealth in TB clinical management.

BACKGROUND: The constant expansion of internet and mobile technologies has created new opportunities in the field of eHealth, or the digital delivery of healthcare services. This TB meta-analysis aims to examine eHealth and its impact on TB clinical management in order to formulate recommendations for further development.METHODS: A systematic search was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework in PubMed and Embase of articles published up to April 2021. Screening, extraction and quality assessment were performed by two independent researchers. Studies evaluating an internet and/or mobile-based eHealth intervention with an impact on TB clinical management were included. Outcomes were organised following the five domains described in the WHO "Recommendations on Digital Interventions for Health System Strengthening" guideline.RESULTS: Search strategy yielded 3,873 studies, and 89 full texts were finally included. eHealth tended to enhance screening, diagnosis and treatment indicators, while being cost-effective and acceptable to users. The main challenges concern hardware malfunction and software misuse.CONCLUSION: This study offers a broad overview of the innovative field of eHealth applications in TB. Different studies implementing eHealth solutions consistently reported on benefits, but also on specific challenges. eHealth is a promising field of research and could enhance clinical management of TB.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Paradoxical sleep deprivation increases the content of glutamate and glutamine in rat cerebral cortex.

We investigated the influence of the sleep/waking cycle, the effects of paradoxical sleep deprivation (PSD) and of the vigilance-promoting drug modafinil on the amino acid contents of rat brain cortex. No significant nycthemeral variations in amino acid levels could be detected. PSD (12-24 hours), using the water tank method, significantly increased the levels of glutamate and glutamine. The increase was still observed after the sleep rebound period. gamma-Aminobutyric acid (GABA) levels did not change significantly during the instrumental sleep deprivation but increased during the rebound period. Control experiments indicate that the increase in glutamate and glutamine levels is due to PSD rather than to the stress associated with the experimental procedure. The increase in glutamate content cannot arise only from transamination reactions, because the levels of other amino acids (such as aspartate) did not decrease. Modafinil treatment did not significantly modify the brain cortex content of any of the amino acids tested.

An atypical anion transporter functioning at acid pH in neuroblastoma cells.

At pH 7.4, 36Cl- uptake by neuroblastoma cells was Na(+)-independent, saturable and blocked by submicromolar concentrations of DIDS. This suggests that at this pH, Cl- transport is mediated by an exchanger analogous to erythroid band 3. At pH 6.2, 36Cl- uptake was markedly activated by external carboxylate anions such as acetate. Acetate-stimulated 36Cl- uptake was blocked by DIDS (IC50 = 0.15 microM). Saturation by external 36Cl- was observed with K0.5 = 8 mM. K0.5 was not modified by acetate. As 36Cl efflux is also activated by acetate, we suggest the presence, in neuroblastoma cells, of an anion exchanger activated by carboxylic anions. This exchanger is active when the extracellular pH is 6.0-6.5.

Radioimmunoassay of IgG and IgM anti-albumin autoantibodies in human serum.

An antigen-coated plate radioimmunoassay used to detect autoantibodies of IgG and IgM classes against human serum albumin is described. It comprises 3 steps: (a) adsorption of glutaraldehyde-polymerized human serum albumin on the wells of a plastic plate, (b) incubation of the serum to be tested with the antigen in the wells, and (c) the addition of radiolabelled antibodies against human IgG or IgM. The method has been used to estimate the level of anti-albumin autoantibodies (AAA) belonging to IgG or IgM classes in the sera of normal subjects and patients with liver diseases.

A probabilistic approach to ageing and elimination of senescent plasma protein.

A probabilistic mechanism of plasma protein ageing and elimination is suggested, based on the following assumptions: (1) ageing of plasma protein molecules is the result of their interaction with some microenvironmental factors, acting as disturbing factors; (2) a protein species is characterized by a definite spectrum of conformational substates, some of which, "altered" substates, are specifically recognized by a selective catabolic system and then compulsorily eliminated; (3) the disturbing (ageing) factors act by increasing the probability of reaching an "altered" substate. Based on these assumptions a mathematical model, giving the expression of the normalized catabolic rate as a function of the frequency and the effectiveness of disturbing impacts, is set up and some possible correlations with physicochemical data are discussed.

Immunochemical characterization of anti-albumin antibodies in liver diseases.

Anti-albumin antibodies (AAA) were isolated from sera of hepatic patients and normal individuals by affinity chromatography on insolubilized glutaraldehyde-treated human albumin. Anti-albumin antibodies were found to belong to IgG and IgM classes in both normal and hepatic patients. The normal level of AAA increased in pathologic conditions, the increase recorded for IgM AAA being higher than that for IgG AAA. The dissociation rate of AAA from the radiolabeled antigen in normal and hepatic sera showed that the affinity of AAA was higher in normal sera than in sera of patients with chronic liver disease and acute viral hepatitis. Anti-albumin antibodies were fractionated into two populations (AAA1 and AAA2) by a two-step chromatographic procedure. AAA1 and AAA2 were found different as regards their affinity for the antigen; specifically, AAA1 affinity was higher than that of AAA2. The other difference between AAA1 and AAA2 might stand in their specificity for the haptenic and structural determinants present in the glutaraldehyde-treated albumin.

Anti-albumin antibodies in normal rabbit sera.

Antibodies reacting with homologous glutaraldehyde (GA)-modified albumin were demonstrated in normal rabbit sera (NRS) by passive hemagglutination and direct binding assay. The ability of rabbit anti-albumin antibodies (AAA) to react with homologous GA-modified albumin was found to increase with the degree of albumin polymerization. AAA did not react with GA-treated monomeric albumin. It was proved that rabbit AAA are not species-specific since they react also with heterologous GA-polymerized albumin. The possible role of AAA in the catabolism of in vivo aged albumin molecules, antigenically similar with GA-induced albumin polymers, is discussed.

Antibodies against glutaraldehyde-modified albumin in normal mouse sera.

An antigen-coated plate radioimmunoassay was used to detect antibodies against homologous glutaraldehyde-modified albumin (in monomeric or polymeric form) in normal mouse sera. Mouse antibodies reacted also with heterologous glutaraldehyde-treated albumin; for instance human albumin. Immunoelectrophoresis of purified anti-albumin antibodies and adsorption experiments on protein A-Sepharose 4B gel indicated that mouse antibodies belong mainly to the IgG class. The ability of mouse anti-albumin antibodies to react also with pyridinium compounds suggested that such structures are probably part of the new antigenic determinants induced in mouse albumin by glutaraldehyde treatment. It was assumed that anti-albumin antibodies have a physiologic role in the recognition and removal from the circulation of in vivo 'aged' mouse albumin.

An immunological hypothesis for plasma protein catabolism.

A selective mechanism of plasma protein catabolism is suggested, based on three main assumptions: (1) plasma proteins are submitted to molecular ageing thus achieving "modified" forms after a given time period; (2) the system recognizing the "modified" molecules consists of preformed physiological autoantibodies; (3) the elimination of the immune complexes formed between "modified" proteins and the corresponding autoantibodies takes place via binding to Fc receptor bearing cells.

Deuterium oxide effects upon three parameters characterizing the activity of glycerol-extracted muscle: phosphate release, ATP-induced shortening, and 22Na+ distribution.

ATP splitting activity is progressively reduced with increasing heavy water (D2)) concentration. In contrast, sarcomere shorteining inhibition produced by D2O does not significantly depend on its concentration. Even at low concentration, the presence of D2O does reduce the excessive accumulation of radioactive sodium within glycerinated frog muscle. These heavy water effects on muscular contraction and soidum distribution can be interpreted to indicate adsorbed water within the cells. Evaluation of these experimental results in terms of Gibbs free enthalpy of binding at the adsorption sites of D20 or H20 is in good agreement with the data in the literature.