ABSTRACT
BACKGROUND: Children represent a particularly vulnerable demographic in the context of drug-resistant (DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease. Approximately 25 000-30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis and treatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB). AIM: To identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage forms are not available in South Africa. METHOD: An observational study was carried out at the study site to determine how medication prescribed was manipulated and administered by nursing staff to paediatric patients in the wards. RESULTS: The observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to the formulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acid are the only drugs available and registered in the South Africa in a formulation that is suitable for administration to paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required suitable dose. DISCUSSION: Lack of availability of suitable dosage forms for paediatrics patients results in several challenges, such as additional time required for drug preparation, increased time duration of medication administration, and unpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of the treatment of paediatric patients, especially as outpatients. CONCLUSION: Research needs to focus on the development of appropriate dosage forms for the paediatric population and focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration of child-friendly dosage forms thereby ensuring a sustainable supply of medication.
Subject(s)
Antitubercular Agents , Tuberculosis, Multidrug-Resistant , Humans , South Africa , Child , Administration, Oral , Antitubercular Agents/administration & dosage , Antitubercular Agents/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Adolescent , Dosage Forms , Linezolid/administration & dosage , Linezolid/therapeutic use , Child, Preschool , Male , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/therapeutic use , FemaleABSTRACT
PURPOSE: Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens. METHODS: To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. RESULTS: The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens. CONCLUSION: The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.
Subject(s)
Aminosalicylic Acid/administration & dosage , Antitubercular Agents/administration & dosage , Tuberculosis, Multidrug-Resistant/drug therapy , Aminosalicylic Acid/pharmacokinetics , Drug Administration Schedule , Humans , Microbial Sensitivity Tests , Models, Biological , ProbabilityABSTRACT
Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.
Subject(s)
Aminosalicylic Acid/adverse effects , Aminosalicylic Acid/pharmacokinetics , Antitubercular Agents/adverse effects , Antitubercular Agents/pharmacokinetics , Adult , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/blood , Aminosalicylic Acids/adverse effects , Aminosalicylic Acids/blood , Aminosalicylic Acids/pharmacokinetics , Antitubercular Agents/administration & dosage , Antitubercular Agents/blood , Area Under Curve , Cross-Over Studies , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/adverse effects , Delayed-Action Preparations/pharmacokinetics , Drug Administration Schedule , Drug Resistance, Microbial , Drug Tolerance , Female , Gastrointestinal Diseases/blood , Gastrointestinal Diseases/chemically induced , Humans , Male , South Africa , Tuberculosis, Multidrug-Resistant/drug therapyABSTRACT
Eicosanoids like leukotrienes and prostaglandins that produced within the arachidonic acid cascade are involved in the pathogenesis of pain, acute and chronic inflammatory diseases. A promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Aiming to develop balanced COX/LOX inhibitors; 4-aminosalicylate based thiazolinones having different substituents at the 5th position of the 4-thiazolinone ring (2-22) were designed, synthesized, characterized and evaluated in vitro and in vivo for their anti-inflammatory activity. Most of the investigated compounds showed high COX-2 inhibitory potencies (IC50 39-200â¯nM) with selectivity indexes (30-84). Two compounds, 19 and 21, (IC50â¯=â¯41 and 44â¯nM), are equipotent to celecoxib (IC50â¯=â¯49â¯nM), while compound 22 (IC50â¯=â¯39â¯nM) was the most potent. For 15-LOX, compounds 5, 11, 19, 21 and 22 revealed higher potency (IC50 1.5-2.2⯵M) than zileuton (IC50 15⯵M). Thus, compounds 5, 11, 19, 21 and 22 are potent dual inhibitors of COX-2 and 15-LOX. In vivo anti-inflammatory testing of these compounds revealed that, compounds 5 and 21 had an anti-inflammatory activity similar to indomethacin and celecoxib (% inhibition of oedemaâ¯=â¯60⯱â¯9) and higher than diclofenac potassium (% inhibitionâ¯=â¯52⯱â¯29), while compound 22 (% inhibitionâ¯=â¯63⯱â¯5) was more active than the reference drugs. The results showed that the activity is controlled by the bulkiness and lipophilicity of the substituent at the 5th position. The cytotoxicity results revealed that all compounds are not cytotoxic, additionally, in an experimental model of ulcerogenic effect, the most active compounds 21 and 22 showed better safety profile than indomethacin. Further, at the active sites of the COX-1, COX-2 and 15-LOX co-crystal, 19, 21, and 22 showed high binding forces in free binding energy study, which is consistent with in vitro and in vivo results. In conclusion, these compounds are good candidates for further biological investigation as potential anti-inflammatory drugs with dual balanced inhibition of COX and 15-LOX and good safety profile.
Subject(s)
Aminosalicylic Acid/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arachidonate 15-Lipoxygenase/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Lipoxygenase Inhibitors/pharmacology , Thiazoles/pharmacology , Administration, Oral , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Carrageenan , Cell Line, Tumor , Cyclooxygenase 2 Inhibitors/administration & dosage , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Edema/chemically induced , Edema/drug therapy , Humans , Indomethacin , Lipoxygenase Inhibitors/administration & dosage , Lipoxygenase Inhibitors/chemistry , Male , Molecular Docking Simulation , Molecular Structure , Rats , Rats, Wistar , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Structure-Activity Relationship , Thiazoles/administration & dosage , Thiazoles/chemistrySubject(s)
Aminosalicylic Acid/therapeutic use , Antitubercular Agents/therapeutic use , Colitis, Ulcerative/drug therapy , Adult , Aminosalicylic Acid/administration & dosage , Antitubercular Agents/administration & dosage , Case-Control Studies , Clinical Decision Rules , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Humans , Remission Induction , Retrospective Studies , Risk Factors , Treatment Failure , Young AdultABSTRACT
Multidrug-resistant tuberculosis (MDR TB) has become a major global health concern and is also an issue in children. Children with MDR TB need longer duration of treatment with multiple drugs. The MDR TB treatment regimen usually comprises of a fluoroquinolone, an aminoglycoside, ethionamide, cycloserine, pyrazinamide and ethambutol. In the absence of pediatric friendly tablets/formulations, in most cases the adult tablets are either crushed or broken. This is likely to lead to inaccurate dosing. Very limited information is available on the pharmacokinetics of second-line anti-TB drugs in children with MDR TB, except for few studies from South Africa and one from India. Drugs such as linezolid, clofazimine are also being considered for the treatment of MDR TB in children. However, their pharmacokinetics is not known in the pediatric population. It is important to generate pharmacokinetic studies of drugs used to treat MDR TB in children in different settings, which would provide useful information on the adequacy of drug doses.
Subject(s)
Antitubercular Agents/pharmacokinetics , Tuberculosis, Multidrug-Resistant/drug therapy , Aminoglycosides/administration & dosage , Aminoglycosides/pharmacokinetics , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/pharmacokinetics , Antitubercular Agents/administration & dosage , Child , Cycloserine/administration & dosage , Cycloserine/pharmacokinetics , Ethionamide/administration & dosage , Ethionamide/pharmacokinetics , Fluoroquinolones/administration & dosage , Fluoroquinolones/pharmacokinetics , HumansABSTRACT
A symposium organized by the Cochrane IBD Group and presented at the 2017 Digestive Disease Week annual meeting reviewed the recent literature on several controversial topics in inflammatory bowel disease (IBD) management including the efficacy of oral aminosalicylates for induction and maintenance of Crohn's disease (CD), the feasibility of drug withdrawal in patients with quiescent CD, and strategies for detecting colon cancer in patients with IBD. This article summarizes the data presented at that session.
Subject(s)
Aminosalicylic Acid/adverse effects , Colitis, Ulcerative/drug therapy , Colonic Neoplasms/diagnosis , Crohn Disease/drug therapy , Administration, Oral , Aminosalicylic Acid/administration & dosage , Colonic Neoplasms/chemically induced , Humans , Prognosis , Withholding TreatmentABSTRACT
OBJECTIVES: 5-aminosalicylates (5-ASA) are frequently continued in patients with moderate-severe ulcerative colitis (UC), even after escalation to biologic agents, without evaluation of the benefit of this approach. We conducted an individual participant data (IPD) pooled analysis of trials of infliximab and golimumab in UC, to evaluate whether concomitant use of 5-ASA modifies clinical outcomes among anti-tumor necrosis factor (TNF)-α-treated patients. METHODS: We included IPD from five trials of infliximab and golimumab in patients with moderate-severe UC (ACT-1 and -2, PURSUIT-SC, PURSUIT-M, NCT00336492). Patients treated with infliximab or golimumab were categorized as receiving concomitant 5-ASA or not at time of trial entry. Primary outcome was clinical remission (Mayo Clinic Score < 3) at last follow-up for each trial; secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, we evaluated association between concomitant 5-ASA and clinical remission, after adjusting for sex, smoking, baseline disease activity, disease extent, biochemical variables (C-reactive protein, albumin, hemoglobin), and concomitant prednisone and immunomodulators. RESULTS: We included 2183 infliximab-treated or golimumab-treated patients (1715 [78.6%] on 5-ASA). Concomitant use of 5-ASA was not associated with odds of achieving clinical remission (adjusted OR, 0.67 [95% CI, 0.45-1.01], p = 0.06), clinical response (aOR, 0.89 [0.60-1.33], p = 0.58) or mucosal healing (aOR, 1.12 [0.82-1.51], p = 0.48). These results were consistent in trials of induction and maintenance therapy, and in trials of infliximab and golimumab. CONCLUSIONS: Based on IPD pooled analysis, in patients with moderate-severe UC who are escalated to anti-TNF therapy, continuing 5-ASA does not improve clinical outcomes.
Subject(s)
Aminosalicylic Acid/therapeutic use , Colitis, Ulcerative/drug therapy , Aminosalicylic Acid/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Biological Therapy , Drug Therapy, Combination , Humans , Infliximab/administration & dosage , Infliximab/therapeutic use , Randomized Controlled Trials as Topic , Treatment Outcome , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/therapeutic useABSTRACT
Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher Cmax), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.
Subject(s)
Aminosalicylic Acid/chemistry , Anti-Bacterial Agents/chemistry , Sulfamethazine/chemistry , Administration, Oral , Aerosols , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/pharmacokinetics , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Biological Availability , Crystallization , Delayed-Action Preparations , Drug Combinations , Drug Compounding , Drug Liberation , Drug Stability , Feasibility Studies , Ibuprofen/administration & dosage , Ibuprofen/chemistry , Mice , Niacin/administration & dosage , Niacin/chemistry , Niacinamide/administration & dosage , Niacinamide/chemistry , Solubility , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Sulfamethazine/administration & dosage , Sulfamethazine/pharmacokinetics , Technology, Pharmaceutical/methodsABSTRACT
Excessive manganese (Mn) accumulation in the brain may induce an extrapyramidal disorder known as manganism. Inflammatory processes play a critical role in neurodegenerative diseases. Therapeutically, non-steroidal anti-inflammatory drugs or analogous anti-inflammatory therapies have neuroprotective effects. As a non-steroidal anti-inflammatory drug, p-aminosalicylic acid (PAS) has anti-inflammatory effects, which are mediated by decreased prostaglandins E2 (PGE2) levels. The aim of the current study was to investigate whether PAS-Na treatment prevents Mn-induced behavioral changes and neuroinflammation in vivo. Male Sprague-Dawley rats were intraperitoneally (i.p.) injected with MnCl2·4H2O (15mg/kg) for 12 weeks, followed by 6 weeks PAS-Na treatment. Sub-chronic Mn exposure increased Mn levels in the whole blood, cortex, hippocampus and thalamus, and induced learning and memory deficits, concomitant with astrocytes activation in the cortex, hippocampus and thalamus. Moreover inflammatory cytokine levels in serum and brain of Mn-treated group were increased, including IL-1ß, IL-6, TNF-αand PGE2, especially in the hippocampus and thalamus. Furthermore, sub-chronic Mn exposure also increased inflammatory cytokines and COX-2 in transcription levels concomitant with increased MAPK signaling and COX-2 in the same selected brain regions. PAS-Na treatment at the highest doses also decreased Mn levels in the whole blood and selected brain tissues, and reversed the Mn-induced learning and memory deficits. PAS-Na inhibited astrocyte activation as well as the Mn-induced increase in inflammatory cytokine levels, reducing p38, ERK MAPK pathway and COX-2 activity. In contrast PAS-Na had no effects on the JNK MAPK pathway. These data establish the efficacy of PAS-Na not only as a chelating agent to mobilize whole blood Mn, but also as an anti-inflammatory agent.
Subject(s)
Aminosalicylic Acid/administration & dosage , Cyclooxygenase 2/metabolism , Encephalitis/metabolism , Encephalitis/prevention & control , MAP Kinase Signaling System/drug effects , Manganese/toxicity , Neuroprotective Agents/administration & dosage , Animals , Brain/drug effects , Brain/metabolism , Encephalitis/chemically induced , Inflammation Mediators/metabolism , Male , Manganese/metabolism , Maze Learning/drug effects , Rats, Sprague-DawleySubject(s)
Antitubercular Agents/therapeutic use , Communicable Disease Control/standards , Extensively Drug-Resistant Tuberculosis/drug therapy , Infectious Disease Medicine/standards , Tuberculosis, Multidrug-Resistant/drug therapy , Aminosalicylic Acid/administration & dosage , Carbapenems/administration & dosage , Clofazimine/administration & dosage , Diarylquinolines/administration & dosage , Humans , Isoniazid/administration & dosage , Linezolid/administration & dosage , Mycobacterium tuberculosis , Treatment Outcome , World Health OrganizationABSTRACT
ABSTRACT The main objectives of clinical therapy in Crohn's disease are clinical and endoscopic remission without the use of corticosteroids for long periods of time, prevention of hospitalization and surgery, and improvement of quality of life. The main limitation of drug therapy is the loss of response over the long term, which makes incorporation of new drugs to the therapeutic arsenal necessary. This review analyses the main drugs currently used in clinical treatment of Crohn's disease.
RESUMO Os principais objetivos da terapia clínica na doença de Crohn são a remissão clínica e endoscópica por tempo prolongado, sem o uso de corticosteroides, além de evitar hospitalizações e cirurgias, e melhorar a qualidade de vida. A principal limitação da terapêutica medicamentosa é a perda de reposta a longo prazo, o que faz com que a incorporação de novas drogas ao arsenal terapêutico seja necessária. Esta revisão aborda os principais medicamentos utilizados atualmente no tratamento clínico da doença de Crohn.
Subject(s)
Humans , Biological Therapy/standards , Crohn Disease/therapy , Immunosuppressive Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/therapeutic use , Prednisolone/adverse effects , Prednisolone/therapeutic use , Crohn Disease/drug therapy , Dose-Response Relationship, Drug , Immunosuppressive Agents/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic useABSTRACT
The main objectives of clinical therapy in Crohn's disease are clinical and endoscopic remission without the use of corticosteroids for long periods of time, prevention of hospitalization and surgery, and improvement of quality of life. The main limitation of drug therapy is the loss of response over the long term, which makes incorporation of new drugs to the therapeutic arsenal necessary. This review analyses the main drugs currently used in clinical treatment of Crohn's disease.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Biological Therapy/standards , Crohn Disease/therapy , Immunosuppressive Agents/therapeutic use , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/administration & dosage , Crohn Disease/drug therapy , Dose-Response Relationship, Drug , Humans , Immunosuppressive Agents/administration & dosage , Prednisolone/adverse effects , Prednisolone/therapeutic useABSTRACT
Manganese (Mn) overexposure induced neurological damages, which could be potentially protected by sodium para-aminosalicylic acid (PAS-Na). In this study, we systematically detected the changes of divalent metal elements in most of the organs and analyzed the distribution of the metals in Mn-exposed rats and the protection by PAS-Na. Sprague Dawley (SD) rats received intraperitoneal injections of 15mg/kg MnCl2·4H2O (5d/week for 3 weeks), followed by subcutaneous (back) injections of PAS-Na (100 and 200mg/kg, everyday for 5 weeks). The concentrations of Mn and other metal elements [Iron (Fe), Copper (Cu), Zinc (Zn), Magnesium (Mg), Calcium (Ca)] in major organs (liver, spleen, kidney, thighbone and iliac bone, cerebral cortex, hippocampus and testes) and blood by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). The results showed that Mn overexposure significantly increased Mn in most organs, Fe and Zn in liver, Fe and Mg in blood; however decreased Fe, Cu, Zn, Mg and Ca in cortex, Cu and Zn in kidney, Cu and Mg in iliac bone, and Zn in blood. In contrast, PAS-Na treatment restored most changes particularly in cortex. In conclusion, excessive Mn exposure disturbed the balance of other metal elements but PAS-Na post-treatments could restore these alterations.
Subject(s)
Aminosalicylic Acid/pharmacology , Manganese/metabolism , Manganese/pharmacology , Metals/metabolism , Aminosalicylic Acid/administration & dosage , Animals , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Manganese/administration & dosage , Manganese/blood , Metals/blood , Rats , Rats, Sprague-DawleyABSTRACT
Treatment of tuberculosis (TB) has been a therapeutic challenge because of not only the naturally high resistance level of Mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. Currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6-9 months. Although they are quite effective in treating drug susceptible TB, these lengthy treatments often lead to patient non-adherence, which catalyzes for the emergence of M. tuberculosis strains that are increasingly resistant to the few available anti-TB drugs. The rapid evolution of M. tuberculosis, from mono-drug-resistant to multiple drug-resistant, extensively drug-resistant and most recently totally drug-resistant strains, is threatening to make TB once again an untreatable disease if new therapeutic options do not soon become available. Here, I discuss the molecular mechanisms by which M. tuberculosis confers its profound resistance to antibiotics. This knowledge may help in developing novel strategies for weakening drug resistance, thus enhancing the potency of available antibiotics against both drug susceptible and resistant M. tuberculosis strains.
Subject(s)
Antitubercular Agents/therapeutic use , Drug Resistance, Multiple, Bacterial/drug effects , Mycobacterium tuberculosis/drug effects , Tuberculosis, Multidrug-Resistant/drug therapy , Aminosalicylic Acid/administration & dosage , Aminosalicylic Acid/chemistry , Aminosalicylic Acid/therapeutic use , Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/chemistry , Antibiotics, Antitubercular/therapeutic use , Antitubercular Agents/administration & dosage , Antitubercular Agents/chemistry , Drug Resistance, Multiple, Bacterial/genetics , Drug Therapy, Combination , Folic Acid/metabolism , Humans , Molecular Structure , Mycobacterium tuberculosis/genetics , Oxazoles/administration & dosage , Oxazoles/chemistry , Oxazoles/therapeutic use , Pyrazinamide/administration & dosage , Pyrazinamide/chemistry , Pyrazinamide/therapeutic useABSTRACT
OBJECTIVE: Although aminosalicylic acid (ASA) preparations have been used as first-line drugs for the treatment of ulcerative colitis (UC), no consistent view has been established regarding the ASA dose during the remission-maintenance phase of the disease. In this study, we examined whether the ASA dose should be reduced during the remission-maintenance phase. MATERIALS AND METHODS: This study included 203 patients in the remission-maintenance phase of UC. The Mayo endoscopic subscore (MES) was used to evaluate mucosa. Comparison and analysis were performed between patients whose ASA dose had been unchanged and whose dose had been reduced, between patients with endoscopic healing (EH) group and those without endoscopic healing (WEH) group, and between patients with an MES of 0 and 1. RESULTS: Comparison between the unchanged-ASA and reduced-ASA groups revealed that the remission-maintenance rate was higher in the unchanged-ASA group (p < 0.001). Next, the remission-maintenance rate was higher in the EH/unchanged-ASA group than in the EH/reduced-ASA group (p = 0.042). Comparison between the MES 0 and 1 groups revealed that the remission-maintenance rate was higher in the MES 0 group (p = 0.007). In addition, no significant difference in remission-maintenance rates was observed between the MES 0/unchanged-ASA group and the MES 0/reduced-ASA group (p = 0.108). CONCLUSION: When the same ASA dose is maintained regardless of the presence or absence of EH, remission is more likely to be maintained. If the ASA dose must be reduced, dose reduction is more advantageous after an MES of 0 is achieved.
Subject(s)
Aminosalicylic Acid/administration & dosage , Colitis, Ulcerative/drug therapy , Intestinal Mucosa/pathology , Colitis, Ulcerative/pathology , Endoscopy, Gastrointestinal , Female , Humans , Male , Middle Aged , Remission InductionABSTRACT
BACKGROUND AND AIMS: Extensive evidence has underlined the importance of mucosal healing as a treatment aim for ulcerative colitis (UC). We aimed to assess differences in the incidence of clinical relapse at 12 months between UC patients with Mayo endoscopic scores (MES) 0 and 1. METHODS: This retrospective study included consecutive patients in corticosteroid-free remission between 2008 and 2013 and with follow-up of at least 1 year, with MES 0 or 1 in complete colonoscopy. Clinical relapse was defined as need for induction treatment, treatment escalation, hospitalization or surgery. A p value <0.05 was considered statistically significant. RESULTS: The study included 138 patients, 72 (52.2%) female, with mean age of 49 (±14) years. Inflammatory activity was classified as MES 0 in 61 (44.2%) patients and MES 1 in 77 (55.8%) patients. Clinical relapse during follow-up was significantly more frequent in patients with MES 1 than MES 0 (27.3 vs 11.5%, p = 0.022), and in the multivariate analysis MES 1 was the only factor significantly associated with an increased risk of relapse (odds ratio 2.89, 95% confidence interval 1.14-7.36, p = 0.026). This association was encountered in the subgroup of patients with left-sided/extensive colitis (29.7 vs 11.1%, p = 0.049), but not proctitis (25.0 vs 12.0%, p = 0.202). CONCLUSIONS: In patients with UC in corticosteroid-free remission, particularly those with left-sided colitis or extensive colitis, MES 1 was significantly associated with a 3-fold increased risk of relapse compared with endoscopic MES 0. Our results support the use of endoscopic MES 0 as the most suitable treatment endpoint to define mucosal healing in patients with UC.
Subject(s)
Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/drug therapy , Intestinal Mucosa/pathology , Wound Healing/drug effects , Adult , Age Factors , Aged , Aminosalicylic Acid/administration & dosage , Analysis of Variance , Biological Products/administration & dosage , Cohort Studies , Colonoscopy/methods , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Intestinal Mucosa/drug effects , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Prognosis , Recurrence , Retrospective Studies , Risk Assessment , Severity of Illness Index , Sex Factors , Treatment Outcome , Wound Healing/physiologyABSTRACT
Despite the relevance of extensively drug-resistant tuberculosis (XDR-TB) to global TB control efforts, case reports on patients achieving cure are scarce. The case of a patient who was treated for more than 3 years as a multidrug-resistant TB (MDR-TB) case, and who was diagnosed retrospectively with XDR-TB, is presented herein. Soon after the initiation of a capreomycin and para-aminosalicylic acid-based regimen, the patient converted and treatment was completed successfully.
Subject(s)
Aminosalicylic Acid/therapeutic use , Antitubercular Agents/therapeutic use , Capreomycin/therapeutic use , Extensively Drug-Resistant Tuberculosis/drug therapy , Adult , Aminosalicylic Acid/administration & dosage , Capreomycin/administration & dosage , Drug Therapy, Combination , Extensively Drug-Resistant Tuberculosis/epidemiology , Female , Humans , Middle Aged , South Africa/epidemiologyABSTRACT
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with involvement of the immune system. Chronic inflammatory diseases have been associated with increased risk of cardiovascular disease (CVD) but few studies have assessed this risk in patients with UC and the influence of drug treatment. Thus, we evaluated the risk of development of CVD in women with UC in clinical remission, considering the drug treatment. MATERIAL AND METHODS: Twenty-one women with UC participated in this study: 12 used aminosalicylates (ASA group) and 9 used azathioprine added to aminosalicylates (AZA+ASA group). The healthy control group was matched for age. We evaluated blood pressure, body composition, and biochemical and immunological parameters. RESULTS: Compared to the respective control group, the UC groups showed expansion of body fat and less lean body mass. Blood pressure, pro-inflammatory cytokines, nitric oxide, C reactive protein, erythrocyte sedimentation rate (ESR), and anti-oxidized LDL antibodies were higher in UC groups. Only AZA+ASA group showed increased anti-inflammatory cytokines (IL-10 and TGF-ß). Framingham scores showed higher risk of CVD in UC groups. UC groups were compared and women treated with azathioprine showed reduction of total protein, globulin, ESR, and lymphocytes, with increased IL-6, TNF, IL-10, and TGF-ß. CONCLUSIONS: Our data suggest that women with UC in clinical remission have a higher risk for development of atherosclerosis and CVD when compared to the control group, while women treated with azathioprine seem more protected than those treated only with aminosalicylates, due to better regulation of the inflammatory process.
Subject(s)
Aminosalicylic Acid/administration & dosage , Azathioprine/administration & dosage , Cardiovascular Diseases/prevention & control , Colitis, Ulcerative/drug therapy , Inflammation/prevention & control , Adult , Biomarkers/blood , Cardiovascular Diseases/etiology , Case-Control Studies , Colitis, Ulcerative/blood , Colitis, Ulcerative/complications , Cytokines/blood , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Inflammation/etiology , Inflammation Mediators/blood , Lipids/blood , Male , Middle Aged , Remission Induction , Risk Factors , Young AdultABSTRACT
Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.).