Drug-resistant tuberculosis: what are the treatment options?

Drug-resistant tuberculosis (DR-TB) is an emerging global health threat as treatment involves complex multiple drug regimens, which are longer and more toxic than standard therapy and yet have worse outcomes. In the presence of resistance to one or more first-line drugs, an alternative regimen should be designed. A major problem is the almost complete lack of published evidence regarding the optimal drug combinations and duration of treatment for the different types of DR-TB. Current principles, some of which are based on expert opinion, are that at least three new anti-TB agents should be added to a failing regimen and four agents when multidrug resistance is suspected. All first-line oral anti-TB agents to which the Mycobacterium tuberculosis strains are susceptible should be used, plus one fluoroquinolone. In addition, one injectable anti-TB agent and one or more second-line oral anti-TB agents should be added to the regimen until the target number of drugs is reached. The duration of treatment depends on the type of drug resistance, the type and number of drugs used in the regimen, and the extent of the disease. All forms of DR-TB should receive daily, not intermittent, therapy and all doses should be directly observed. Because of the high rate of adverse drug effects, careful monitoring and appropriate management of these adverse reactions are important to achieve successful treatment. Supportive measures, such as adequate nutrition along with emotional and social supports, are an important part of the treatment. Careful consideration is required when dealing with pregnant or lactating women and HIV co-infected patients, as well as in treatment of extrapulmonary DR-TB.     

Drug-resistant tuberculosis: what do we do now?

Drug-resistant tuberculosis (TB) represents a threat to TB control programmes. Erratic and inappropriate use of currently available medications, HIV-TB co-infection, and concern about transmission of drug-resistant strains in the general population all contribute to a worrying picture. What do we do now? In the last few years, there has been considerable progress in the understanding of mechanisms of action and resistance to antituberculosis agents, and in establishing the value of directly observed therapy in preventing treatment failure. However, a limited effort has been devoted to the development of new active compounds or of rapid diagnostic tests, and their relevance to global tuberculosis control has been questioned.     

A marked increase in cocaine-related deaths in the State of Florida: precursor to an epidemic?

The history of cocaine misuse includes a destructive epidemic during the 1980s. While recent surveys suggest cocaine use is stable or decreasing, we have observed increasing trends of cocaine-related death through analysis of medical examiner data collected by the Florida Department of Law Enforcement (FDLE). Florida's per capita cocaine-related death rates nearly doubled from 2001 to 2005. Electronic collection of data such as that collected by the FDLE nationally and in real-time would greatly advance understanding of drug-use patterns and consequences. For example, results from Florida suggest that high school and college students, and members of higher socioeconomic status, appear to be at increased risk of cocaine abuse. Public health interventions are necessary to prevent another full-fledged epidemic.     

Harmonising alcohol consumption,sales and related outcomes data across the UK and Ireland: an insurmountable barrier to policy evaluation?

Abstract

There is a need to ensure public health policies are robustly evaluated to establish their benefits and harms on the population and subgroups. We aimed to assess the comparability of Northern Ireland (NI) and Republic of Ireland (RoI) alcohol-related data to determine their suitability for evaluating the effectiveness of alcohol policies on alcohol consumption, sales, and related outcomes. A comparability analysis of NI and RoI alcohol-related hospital admissions, deaths, consumption, sales, and crime administrative and survey data was undertaken. Data sources were compared, where applicable, in terms of coding systems, population coverage, definitions, quality, response/completion rates, and question similarity. The NI and RoI consumption and sales data were found not to be comparable enough for use in a natural experiment study; comparability for hospital admission data was acceptable. Key barriers to comparability included variations in population coverage and lack of overlap in questionnaire topics. Data access issues made it difficult to fully determine data comparability for alcohol-related crime and deaths. By contrast, NI alcohol-related data were more comparable with other UK countries, making comparisons for the purpose of policy evaluation possible. RoI would benefit from identifying another economically and culturally similar country with comparable alcohol-related data.     

Rimonabant as a potential new treatment for an emerging epidemic of obesity-related glomerulopathy?

Obesity and being overweight are risk factors for kidney diseases. The spectrum ranges from glomerulomegaly with or without focal or segmental glomerulosclerosis, to diabetic nephropathy, to carcinoma of the kidney and nephrolithiasis. The first sign of renal injury is microalbuminuria or frank proteinuria, in particular in the presence of hypertension. The occurrence of microalbuminuria and/or chronic kidney insufficiency (glomerular filtration rate < 60 ml/min/1.73 m(2)) is related to the increasing number of components of the metabolic syndrome; that is, central obesity, elevated fasting blood glucose level, hypertriglycerides, low high-density lipoprotein cholesterol level and hypertension. Obesity-associated renal disease should be prevented or retarded by weight reduction following lifestyle modification (salt restriction, hypocaloric diet, aerobic exercise) or eventually by antiobesity medication or bariatric surgery. Rimonabant, a new antiobesity medication, showed beneficial potential effect in treating clusters of metabolic syndrome, which may ultimately suggest potential benefit in treating obesity-related glomerulopathy.     

Is the U.S. experiencing an incipient epidemic of hallucinogen use?

NHSDA and MTF survey data indicate "epidemic"-like growth in hallucinogen use from 1992-1996 and associated increases in cocaine, crack, heroin and amphetamine use. These trends might have resulted from a proliferation of raves and dance clubs in the U.S. as occurred in Europe and elsewhere, although in contrast to evidence regarding European experiences the American epidemic involves primarily teens as opposed to persons in their twenties and involves primarily use of LSD as opposed to MDMA. This analysis highlights the need for further research into the context, significance, and consequences of these recently popular American drug use practices.     

Crohn's disease or tuberculosis?

A Nepali-born migrant was diagnosed with intestinal tuberculosis (TB) after being initially considered for Crohn's disease. Differentiating the two diseases is challenging but important owing to variation in treatment, the potential for dissemination of TB under immunosuppression for Crohn's disease, and emergent Australian migration from TB endemic countries.     

Latent tuberculosis: is there a role for thioridazine?

Approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis. In the vast majority of cases this results in latent not active disease. Latent disease is defined as a positive reaction to tuberculin antigens but without any further clinical symptoms. Models have been developed to study latent tuberculosis with the two most prominent being the in vivo murine model and the in vitro Wayne model. In both cases M. tuberculosis undergoes a change in its respiratory profile as it shifts down to a nonreplicating state. However in both the mouse and the Wayne model, dormant M. tuberculosis is sensitive to the phenothiazine thioridazine. This antibiotic has several targets, and the main one is respiration. There is a growing burden of multidrug resistant and extensively drug resistant tuberculosis. Treatment of these cases is expensive with high mortality. We propose that thioridazine alone, or with other antibiotics, be used to treat drug resistant latent tuberculosis. The advantages are that thioridazine is inexpensive, effective against drug resistant tuberculosis, well characterized and unlikely to induce drug resistance. The disadvantages include possible side effects, although these should be rare at the doses and length of time of treatment. Recent patents involving analogs of thioridazine suggest this class of drugs may hold great promise for the future treatment of the most drug resistant strains.     

Pravastatin: an evidence-based statin?

BACKGROUND: It is well known that statins lead to a markable reduction in cardiovascular morbidity and mortality. One of the first and best studied statins is pravastatin, which has been studied in both primary and secondary prevention trials. With 40 mg pravastatin daily, total cholesterol can be reduced by 25-34% with a very consistent risk reduction of 24% of death from cardiovascular diseases. Side effects are rare and usually consist of myopathy. Following the Adult Treatment Panel III (ATPIII) guidelines on cholesterol management, apart from therapeutic lifestyle changes, in high-risk patients (including patients with diabetes mellitus), cholesterol-lowering therapy should be targeted at a treatment goal of LDL cholesterol<2.5 mmol/l. Statin-lowering therapy should be commenced to adequately lower cardiovascular risk. Therefore, when the expected 25-34% LDL cholesterol lowering would be enough to reach an LDL<2.5 mmol/l, treatment should be started with pravastatin. METHOD: Trials have shown that treatment with pravastatin is safe in older patients as well as in children with familial hypercholesterolemia. RESULTS/CONCLUSION: Since obesity seems to become a worldwide problem and given the low costs of generic pravastatin, it may even be cost-effectively used in developing countries.     

Phenytoin: an anti-bipolar anticonvulsant?

Phenytoin, a classical anticonvulsant has been little studied in bipolar disorder. We completed a trial of phenytoin in mania and schizoaffective disorder, manic type. Thirty-nine patients entered a 5-wk double-blind controlled trial of haloperidol+phenytoin vs. haloperidol+placebo; 30 patients completed at least 3 wk; 25 completed 5 wk. Significantly more improvement was observed in those patients receiving phenytoin. Phenytoin has not previously been studied prophylactically in bipolar patients. Bipolar patients were studied who had at least one episode per year in the previous 2 yr despite ongoing prophylaxis. Patients were stable for a mean of 4 months (range 1-13) before entering the study. Phenytoin or placebo was added to their current therapy in a double-blind cross-over design for 6 months in each phase. Thirty observation periods of 6 months each were studied for 23 patients. Three patients had relapse on phenytoin and nine had relapse on placebo. There was a significant prophylactic effect of phenytoin in bipolar disorder [Cox's F test for comparing survival in two groups: F(6, 18)=3.44, p=0.02]. This study suggests prophylactic effects of add-on phenytoin in bipolar illness. However, the number of patients was small and confirmation is necessary. Lamotrigine has recently been reported to have antidepressant effects. In the past, small studies showed antidepressant effects for carbamazepine and valproate. To determine if such effects could be a class property of other voltage-activated sodium channel blockers such as phenytoin, we performed a double-blind controlled trial of phenytoin vs. fluoxetine in unipolar depression. Thirty-three depressed patients entered the study, and 28 completed at least 3 weeks and were included in data analyses. Weekly Hamilton Depression Scales for 6 wk showed no difference between fluoxetine and phenytoin. Clearly pharmaceutical company funding for clinical trials or advertising for phenytoin is minimal and this must be taken into account in evaluating literature on phenytoin vs. other drugs. The present data suggests that effects on affective disorder may be common to many anticonvulsants.     

Treating leprosy: an Erb-al remedy?

The leprosy pathogen Mycobacterium leprae attacks Schwann cells in the peripheral nervous system, causing them to demyelinate. Recent work by Tapinos et al. shows that a direct mechanism of demyelination induced by M. leprae depends on the binding of the bacterium to the receptor tyrosine kinase ErbB2 on Schwann cells and the resulting activation of the Ras-Raf-MEK-ERK pathway. These findings have relevance for the potential treatment of leprosy and they highlight parallels between the dedifferentiation signal in leprosy and that in nerve injury and cancer.     

Statin discontinuation: an underestimated risk?

Statin treatment is essential for the prevention of vascular disease. Despite the established benefits of statins, discontinuation of these agents is frequent. Whether statin discontinuation leads to adverse outcomes is still debated and the most convincing evidence is mainly restricted to patients who experienced an acute vascular event. It is important to establish if this phenomenon extends to other populations, like those without vascular disease but with a high calculated risk. Overall, it appears that even a brief discontinuation of statins might be harmful. Therefore, statin treatment should not be interrupted except if there is a very good reason. Moreover, patients should be instructed as to why they must adhere to their medication. Adherence should be monitored regularly.     

Thioridazine: resurrection as an antimicrobial agent?

The emergence of multiresistant bacterial strains and the continuing burden of infectious disease globally point to the urgent need for novel affordable antimicrobial drugs. Thioridazine is a phenothiazine antipsychotic drug with well-recognized antimicrobial activity, but this property has not been harnessed for clinical use as a result of its central nervous system and cardiac side-effects. The cardiotoxicity of thioridazine has recently been shown to be structurally specific at a molecular level, whereas its antimicrobial properties are shared by a number of phenothiazine analogues. This raises the possibility that its enantiomers or its inactive metabolite, the ring sulphoxide, may act as a lead compound in the future development of antimicrobial drugs to face the new challenges in infectious disease.     

Pharmacoepigenetics: an element of personalized therapy?

Introduction: Epigenetics is a rapidly growing field describing heritable alterations in gene expression that do not involve DNA sequence variations. Advances in epigenetics and epigenomics have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for the individual variation in drug response.

Areas covered: We present an overview of the major epigenetic mechanisms and their effects on the expression of drug metabolizing enzymes and drug transporters, as well as the epigenetic status of drug protein targets affecting therapy response. Recent advances in the development of pharmacoepigenetic biomarkers and epidrugs are also discussed.

Expert opinion: There is growing evidence that pharmacoepigenetics has the potential to become an important element of personalized medicine. Epigenetic modifications influence drug response, but they can also be modulated by drugs. Moreover, they can be monitored not only in the affected tissue, but also in body fluids. Nevertheless, there are very few examples of epigenetic biomarkers implemented in the clinical setting. Explanation of the interplay between genomic and epigenomic changes will contribute to the personalized medicine approach. Ultimately, both genetic biomarkers and epigenetic mechanisms should be taken into consideration in predicting drug response in the course of successful personalized therapy.     

Rimonabant: more than an anti-obesity drug?

The endocannabinoid system modulates many pathophysiological functions, including the brain pathways involved in the regulation of body weight and adipose tissue function. The selective cannabinoid CB(1) receptor antagonist, rimonabant, has undergone phase III clinical testing as anti-obesity drug. Obesity is considered a mild inflammatory condition and predisposes individuals to an increased risk of developing many diseases. It has been recently suggested that a successful intervention to treat obesity is a therapy combining weight-reducing drugs with anti-inflammatory ones. In this scenario, rimonabant's anti-obesity action is accompanied by favorable changes in markers for insulin resistance, C-reactive protein, adiponectin, tumor necrosis factor alpha (TNFalpha). The results reported by Croci and Zarini in this issue highlight the anti-inflammatory and anti-hyperalgesic effect of rimonabant in obese animals, so suggesting that it could provide a more general and aggressive strategy to protect obese patients from many pathological risks.