Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial.

BACKGROUND: Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs. METHODS: ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages. DISCUSSION: This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

Effect of niacin supplementation on nausea-like behaviour in an isoniazid-induced mouse model of pellagra.

Niacin deficiency causes pellagra, the symptoms of which include dermatitis, diarrhoea and dementia. Investigating the mechanism underlying these phenotypes has been challenging due to the lack of an appropriate animal model. Here, we report a mouse model of pellagra-related nausea induced by feeding mice a low-niacin diet and administering isoniazid (INH), which is thought to induce pellagra. Mice fed a normal or low-niacin diet received INH (0·3 or 1·0 mg/mg per animal, twice daily, 5 d), and nausea was evaluated based on pica behaviour, which considered the rodent equivalent of the emetic reflex. Furthermore, the effect of therapeutic niacin administration on nausea was evaluated in this model. Urinary and hepatic metabolite levels were analysed by LC coupled with MS. INH-induced pica was observed in mice fed a low-niacin diet but not in those fed a normal diet. Levels of urinary metabolites, such as 1-methyl-2-pyridone-5-carboxamide, kynurenic acid and xanthurenic acid, were significantly reduced in the mice treated with INH compared with those that did not receive INH. Furthermore, niacin supplementation prevented pica and restored the levels of some metabolites in this mouse model. Our findings suggest that INH-related nausea is pellagra-like. We also believe that our newly established method for quantifying pica is a useful tool for investigating the mechanisms of pellagra-related nausea.

Isoniazid induced palmoplantar hyperhidrosis.

Secondary focal hyperhidrosis is usually due to peripheral or central neuronal defects and is a complex dysfunction of the parasympathetic and sympathetic nervous system. Palmoplantar hyperhidrosis has been described with various types of polyneuropathies such as diabetic but has not previously been described with isoniazid. We report a 15-year-old boy, being followed for neurotuberculosis, who presented with burning sensation and hyperhidrosis of both palms and soles five months after starting antitubercular therapy. With oral pyridoxine supplementation, the paraesthesia and hyperhidrosis reduced to minimal severity over the next four months. Before commencing antiperspirants, simple pyridoxine supplementation can lead to the reversal of symptoms in such cases.

Ameliorative potential of Adhatoda vasica against anti-tubercular drugs induced hepatic impairments in female Wistar rats in relation to oxidative stress and xeno-metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Adhatoda vasica Nees is widely used herb of indigenous system to treat various ailments especially upper respiratory tract infections. Not only, anti-tubercular efficacy of crude extract and phytoconstituents of A. vasica has been documented but its hepatoprotective role against various drugs mediated hepatic alterations in different animal models has also been observed. BACKGROUND AND PURPOSE: Isoniazid, rifampicin and pyrazinamide (H-R-Z) are anti-tubercular drugs normally prescribed by health professionals for the treatment of tuberculosis, however along with their medical effectiveness these drugs also exhibit hepatotoxicity among TB patients. Unexpectedly, substantial toxicological data on the metabolism of anti-TB drugs are available but the mystery behind these xenobiotics is too complex and partly implicit. In this study, we further explored the hepatotoxic effects of these xeno-metabolic products and their amelioration by Adhatoda vasica Nees by elucidating its mechanistic action. METHODS: We generated a hepatotoxic rodent model by oral administration of H, R and Z (30.85, 61.7 and 132.65 mg/kg body weight) drugs for 25 days in Wistar rats. Additionally, to achieve hepatoprotection two different doses of Adhatoda vasica Nees ethanolic leaf extract (200 and 300 mg/kg body weight) were used along with H-R-Z dosage, orally and once daily for 25 days and tried to ascertain their mechanistic action. For this, initially phytoconstituents of the extract were evaluated followed by extract standardization using RP-HPLC and FTIR methods. Furthermore, antioxidant activity of the extract was analyzed by DPPH assay. Finally, different treated groups were analyzed for hepatic oxidative stress markers, antioxidant markers, histopathological changes and gene expression study including CYP2E1, CYP7A1, NAT, NR1I2 and UGT1A1 genes involved in phase I and phase II xeno-metabolism. RESULTS: Estimated content of vasicine in RP-HPLC method and free-radical scavenging activity in DPPH assay was found to be 134.519 ± 0.00269µg/10mg of leaf extract and 47.81 µg/mL respectively. In H-R-Z treated group, a significant increase in the levels of thiobarbituric acid, significant reduction in the levels of GSH, and enzymatic markers and marked changes in hepatic histological architecture were observed. In addition, there was significance up-regulation of CYP7A and NAT genes, down-regulation of CYP2E1 gene and insignificant expression levels of NR1I2 and UGT1A1 genes were observed in H-R-Z group. Conversely, high dose of A. vasica extract effectively diminished these alterations by declining oxidative stress and boosting of antioxidant levels. In addition, it acted as bi-functional inducer of both phase I (CYP2E1) and phase II (NAT and UGT1A1) enzyme systems. CONCLUSION: Hence, we concluded that anti-TB drugs exposure has potential to generate reactive metabolites that eventually cause hepatotoxicity by altering oxidant-antioxidant levels and their own metabolism. This study not only emphasized on xeno-metabolism mediated hepatic alterations but also explore the benefit of A. vasica on these toxic insults.

Lipid peroxidation aggravates anti-tuberculosis drug-induced liver injury: Evidence of ferroptosis induction.

Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common adverse reaction of anti-tuberculosis drug treatment. Studies have shown that isoniazid (INH) and rifampicin (RFP) are mainly metabolized in the liver and a large amount of intracellular glutathione is used up during the metabolism of these drugs, resulting in lipid peroxidation and hepatocyte death. Ferroptosis is a novel form of programmed cell death caused by iron-ion-dependent lipid peroxidation. In this study, we explored lipid peroxidation and ferroptosis during ATB-DILI. Morphology of ferroptosis was discovered in ATB-DILI mouse livers by transmission electron microscopy. Flow cytometry was used to assess the molecular markers of lipid peroxidation and ferroptosis including reactive oxygen species, lipid peroxidation, and cellular iron content. Glutathione peroxidase 4 (GPX4) was depleted, while acyl-CoA synthetase long chain family member 4 (ACSL4) was overexpressed in the ATB-DILI tissues. And glutathione supplementation significantly reduced the level of lipid peroxidation and the risk of liver damage. Retrospective study of tuberculosis patients who underwent INH and RFP treatment also revealed an association between the intake of glutathione and a negative ATB-DILI rate. In addition, iron supplementation enhanced the degree of lipid peroxidation and liver injury induced by INH and RFP in vivo and clinical retrospective study. Taken together, these results indicate that lipid peroxidation and evidence suggestive of ferroptosis occurs during ATB-DILI, and glutathione replenishment prevents this process while iron supplementation augmenting this effect.

Rosa brunonii Lindely fruit as a new protective agent evaluated against Rif/INH induced toxicity in rats.

Rosa brunonii L., a less investigated plant contains flavonoid glycosides and is used to treat stomach ailments, heart problems, and diabetes in folk. The crude extract of the plant possesses antioxidant activity. The current work was aimed to investigate the presence of phytochemicals, antioxidative stress and protective potential of chloroform extract of the Rosa brunonii L. fruits (RBFCE) against liver and kidney toxicity induced by anti-tuberculosis drugs, rifampicin/isoniazid (Rif/INH) in Wistar albino rats. Animals were divided into six groups, each comprising 6 rats and fed with a standard pelleted diet. Normal control group was given only a standard pelleted diet. The vehicle control group received 0.5% carboxymethylcellulose (CMC) aqueous solution (vehicle). Negative and positive control groups were given Rif/INH (50+50 mg/kg, p.o) and silymarin (SILM) (200 mg/kg, p.o) in 0.5% vehicle for 30 days, respectively. Extract treated groups received low and high doses of RBFCE (500 mg/kg, p.o and 1000 mg/kg, p.o respectively) in 0.5% vehicle for 30 days. At a higher dose, animals showed significantly reduced Rif/INH induced toxicity in liver and kidney tissues as indicated by the normalized serum biochemical markers and histopathological investigations. The present exploration reveals the presence of strong antioxidant phytochemical constituents, antioxidative stress and protective potential of RBFCE against Rif/INH induced hepatic and renal damage.

Factors affecting uptake and completion of isoniazid preventive therapy among HIV-infected children at a national referral hospital, Kenya: a mixed quantitative and qualitative study.

BACKGROUND: Tuberculosis (TB) is the most common opportunistic infection and the leading cause of death in people living with HIV (PLHIV). HIV-infected children are at a higher risk of TB infection and disease compared to those without HIV. Isoniazid preventive therapy (IPT) is an effective intervention in preventing progression of latent TB infection to active TB. The World Health Organization (WHO) currently recommends that all children aged > 12 months and adults living with HIV in whom active TB has been excluded should receive a 6-months course of IPT as part of a comprehensive package of HIV care. Despite this recommendation, the uptake of IPT among PLHIV has been suboptimal globally. This study sought to determine the factors affecting IPT uptake and completion among HIV-infected children in a large HIV care centre in Nairobi, Kenya. METHOD: This was a cross-sectional mixed methods study comprising of quantitative and qualitative study designs. Medical records of 225 HIV-infected children aged 1 to < 10 years, in care in the Kenyatta National Hospital Comprehensive Care Centre (KNH CCC) were retrospectively reviewed, and 8 purposively selected healthcare providers and 18 consecutively selected caregivers of children were interviewed. RESULTS: IPT uptake among CLHIV in care in the KNH CCC was 68% (152/225) while the treatment completion rate was 82% (94/115). IPT-related health education and counselling were the main facilitators of IPT uptake and completion, while fear of adverse drug reaction, pill burden and lack of an integrated monitoring and evaluation system for IPT were the major barriers. CONCLUSION: The IPT uptake in this study was low and fell short of the set global target of > 90%. The completion rate was however acceptable. There is an urgent need to address the identified barriers.

[Lichenoid drug eruption with antituberculosis drugs associated with an anonychia]. / Toxidermie lichénoïde aux antituberculeux associée à une anonychie.

INTRODUCTION: Lichenoid cutaneous reactions to antituberculosis drugs are rare. Herein we report a new case. PATIENTS AND METHODS: A 41-year-old patient was seen for a profuse and pruriginous rash occurring 2 weeks after administration of rifampicin and isoniazid for pulmonary tuberculosis. Dermatological examination revealed polymorphic erythemato-squamous plaques with lichenoid, psoriatic and eczematous features, associated with cheilitis, erosions on the cheeks and diffuse onychodystrophy. The skin biopsy confirmed a lichenoid reaction. The pharmacovigilance investigation incriminated isoniazid and rifampicin. The patient was treated with topical corticosteroids and UVB phototherapy. The outcome involved complete regression of the eruption but with secondary anonychia. DISCUSSION: Antituberculosis drugs including isoniazid and rifampicin are known to induce lichenoid reactions. It is difficult to distinguish the results from lichen planus. The clinical polymorphism of the rash as well as the patient's drug intake militate in favour of a diagnosis of lichenoid reaction. Widespread ungual involvement, which is extremely rare, warranted early management in order to avert irreversible anonychia.

Nonclinical evaluation of IQG-607, an anti-tuberculosis candidate with potential use in combination drug therapy.

New effective compounds to treat tuberculosis are urgently needed. IQG-607 is an orally active anti-tuberculosis drug candidate, with promising preliminary safety profile and anti-mycobacterial activity in both in vitro and in vivo models of tuberculosis infection. Here, we evaluated the mutagenic and genotoxic effects of IQG-607, and its interactions with CYP450 isoforms. Moreover, we describe for the first time a combination study of IQG-607 in Mycobacterium tuberculosis-infected mice. Importantly, IQG-607 had additive effects when combined with the first-line anti-tuberculosis drugs rifampin and pyrazinamide in mice. IQG-607 presented weak to moderate inhibitory potential against CYP450 isoforms 3A4, 1A2, 2C9, 2C19, 2D6, and 2E1. The Salmonella mutagenicity test revealed that IQG-607 induced base pair substitution mutations in the strains TA100 and TA1535. However, in the presence of human metabolic S9 fraction, no mutagenic effect was detected in any strain. Additionally, IQG-607 did not increase micronucleus frequencies in mice, at any dose tested, 25, 100, or 250 mg/kg. The favorable activity in combination with first-line drugs and mild to moderate toxic events described in this study suggest that IQG-607 represents a candidate for clinical development.

Fluoroquinolones for the treatment of latent Mycobacterium tuberculosis infection in liver transplantation.

Solid organ transplantation (SOT) is the best treatment option for end-stage organ disease. Newer immunosuppressive agents have reduced the incidence of graft rejection but have increased the risk of infection, particularly due to the reactivation of latent infections due to opportunistic agents such as Mycobacterium tuberculosis. Active tuberculosis (TB) after SOT is a significant cause of morbidity and mortality. Most cases of posttransplant TB are secondary to reactivation of latent tuberculosis infection (LTBI) due to the effects of long-term immunosuppressive therapy. Risk minimization strategies have been developed to diagnose LTBI and initiate treatment prior to transplantation. Isoniazid with vitamin B6 supplementation is the treatment of choice. However, liver transplantation (LT) candidates and recipients have an increased risk of isoniazid-induced liver toxicity, leading to lower treatment completion rates than in other SOT populations. Fluoroquinolones (FQs) exhibit good in vitro antimycobacterial activity and a lower risk of drug-induced liver injury than isoniazid. In the present review, we highlight the disease burden posed by posttransplant TB and summarize the emerging clinical evidence supporting the use of FQs for the treatment of LTBI in LT recipients and candidates.

Telfairia occidentalis (Cucurbitaceae) pulp extract mitigates rifampicin-isoniazid-induced hepatotoxicity in an in vivo rat model of oxidative stress.

OBJECTIVE: Drug-induced liver injury complicates antituberculosis drug treatment and is a leading cause of death worldwide. The aim of this study is to establish the ethnomedicinal claim of hepatoprotective effects of fruit pulp extract of Telfairia occidentalis against rifampicin (RIF) and isoniazid (INH)-induced oxidative stress in rats. METHODS: T. occidentalis pulp extract (TOPE) (125-500 mg/kg) and silymarin (50 mg/kg) were evaluated in an induced hepatotoxicity model of oxidative stress in Wistar rats by intoxication with RIF and INH (100 mg/kg each) orally for 60 d. Markers indicating oxidative stress and hepatic damage such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. Biomarkers of antioxidant status, including catalase, glutathione reductase, glutathione peroxidase and superoxide dismutase, and marker of lipid peroxidation, malondialdehyde (MDA), were assayed using standard procedures. The hematological profile, lipid profile, serum markers for kidney function and histopathological examination were also assessed. RESULTS: Intoxication with RIF and INH markedly reduced the hematological indices and elevated the biochemical enzyme markers (AST, ALT and ALP, P < 0.001) and lipid profile (P < 0.001), while antioxidant biomarkers were significantly (P < 0.01) depressed and MDA was elevated. However, pretreatment with TOPE significantly (P < 0.001) alleviated this alteration and sustained the antioxidant potentials. The histopathological morphology supports the biochemical evidence of hepatoprotection. CONCLUSION: Current study is indicative of potential antioxidant activity, hepatoprotective effects and plausible therapeutic alleviation of RIF-INH-induced hepatotoxicity of TOPE in laboratory animals.

Isoniazid-induced neuropathy in a pre-pubertal child.

Isoniazid (INH)-induced peripheral neuritis is not uncommonly reported in adults, especially those with malnutrition and alcoholism, but it is very rare in children. INH leads to peripheral neuritis by causing a deficiency in the serum level of pyridoxine which depends on the dose of INH, duration of treatment and the patient's nutritional and acetylator status. A 12-year-old girl developed tingling and numbness of the lower limbs after commencing anti-tuberculous therapy which included INH 10 mg/kg/day. The symptoms continued despite the dose being reduced to 5 mg/kg/day. Nerve conduction velocity was normal. Her diet was poor: she consumed little or no fruit and vegetables and ate mostly dal and rice. Discontinuation of INH was advised and her therapy was changed to ofloxacin, rifampicin, ethambutol and pyrazinamide along with a high dose of pyridoxine and multi-vitamins. The tingling and numbness subsided within 15 days, after which INH was prescribed at the dose of 10 mg/kg/day. Although INH-induced neuropathy is rare in children, the World Health Organization recommends pyridoxine prophylaxis for children on INH who are malnourished or have HIV infection.

Isoniazid-induced encephalopathy in an end-stage renal disease patient - A case report and literature review.

Patients with end stage renal disease have higher risk of tuberculosis due to lower cell-mediated immunity. Standard regime of anti-tuberculosis contains isoniazid where neurological side effects such as seizure and encephalopathy have been documented. We present a case of isoniazid-induced encephalopathy in a haemodialysis patient. A literature review on isoniazid-induced encephalopathy was done. Recognition of this condition is important as it is reversible with cessation of isoniazid and institution of high dose pyridoxine.

A systematic review of clinical outcomes on the WHO Category II retreatment regimen for tuberculosis.

OBJECTIVE: To assess the clinical outcomes of patients prescribed the World Health Organization (WHO) Category II retreatment regimen for tuberculosis (TB). DESIGN: A systematic review of the literature was performed by searching Medscape, Embase and Scopus databases for cohort studies and clinical trials reporting outcomes in adult patients on the Category II retreatment regimen. RESULTS: The proportion of patients successfully completing the retreatment regimen varied from 27% to 92% in the 39 studies included in this review. In only 2/39 (5%) studies was the treatment success rate > 85%. There are very few data concerning outcomes in patients categorised as 'other', and outcomes in this subgroup are variable. Of the five studies reporting disaggregated outcomes in human immunodeficiency virus (HIV) positive people, four demonstrated worse outcomes than in HIV-negative people on the retreatment regimen. Only four studies reported disaggregated outcomes in patients with isoniazid (INH) resistance, and treatment success rates varied from 11% to 78%. CONCLUSION: Clinical outcomes on the Category II retreatment regimen are poor across various populations. Improvements in management should consider the holistic treatment of comorbidity and comprehensive approaches to drug resistance in patients with recurrent TB, including a standardised approach for the management of INH resistance in patients who develop recurrent TB in settings without reliable access to comprehensive drug susceptibility testing.

[Optochiasmatic tuberculomas as a paradoxical reaction to treatment for meningeal tuberculosis]. / Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

TITLE: Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

The Role of Tamarix gallica Leaves Extract in Liver Injury Induced by Rifampicin Plus Isoniazid in Sprague Dawley Rats.

The Tamarix gallica leaves extract (TGLE) was investigated for hepatoprotective potential against rifampicin (RIF) plus isoniazid (INH)-induced liver injury in Sprague Dawley (SD) rats. All the rats of groups III and IV received 100 and 200 mg/kg body wt, respectively, of the suspension of TGLE while group V received silymarin 100 mg/kg body wt orally. After 10 min, they, along with group II, received INH plus RIF each day (50 mg/kg body wt, by mouth (PO) each) for 28 days. Group I received 10 ml/kg body wt, PO of vehicle, i.e., 1% aqueous carboxymethyl cellulose (1% CMC) throughout the study. At the end of the experiment, blood was obtained through the retro-orbital plexus under light anesthesia and the serum was separated from the sacrificed animals. A small portion of isolated liver tissue was fixed in 10% formaldehyde for histopathological examinations. The levels of elevated serum bilirubin (p > .05-p < .05), alanine transaminase (p > .05-p < .01), aspartate transaminase (p > .05-p < .01), alkaline phosphatase (p < .05-p < .01), lactate dehydrogenase (p < .05-p < .01), and cholesterol (p > .05-p < .01) decreased while the levels of decreased total protein (p > .05-p < .05) and albumin (p < .05-p < .05) increased in TGLE-treated groups III and IV as compared to group II, and the serum marker enzyme levels were toward normal, indicating protection against liver injury. It was well supported with histopathological results. Thus, Tamarix gallica leaves extract possesses promising hepatoprotective activity against RIF plus INH-induced liver injury in experimental rats.

The Effects of Aloe Vera on TNF-a Levels, the Percentage of Nk Cells and Th 17 Cells in Rat That Received Izoniazid and Rifampycin.

BACKGROUND: The present study was undertaken to investigate the hepatoprotective effect of Aloe vera against side effect of antituberculosis drug. MATERIAL AND METHODS: Twenty-five rats will be divided into five groups, namely the control group (without any treatment), the group of rats treated with anti-tuberculosis drugs, and a group of rats were treated antituberculosis drugs and got Aloe vera extract at a dose of 40; 80; and 120 mg/kg body weight. Antituberculosis drugs are isoniazid and rifampicin a dose of 50 mg/kg body weight. RESULTS: Antituberculosis treated group showed significantly increase levels of TNF-a, the percentage of NK cells and the number of Th17 cells compared with the control group (p < 0.05). All doses of Aloe vera reduce levels of TNF-a compared with the antituberculosis group (p < 0.05), although it has not yet reached levels comparable to the control group (p > 0.05). Aloe vera at first and the third dose lower the number of NK cells compared to the antituberculosis group, although it has not yet reached a significant difference (p > 0.05). The first dose of Aloe vera was significantly decreased the percentage of Th17 cells compared to the antituberculosis drug group (p < 0.05), although it has not yet reached levels comparable to the control group (p > 0.05). CONCLUSIONS: It was concluded that administration of Aloe vera can suppress the production of TNF-a and the percentage of Th17 cells as a result of antituberculosis drug administration. Thus, Aloe vera can be a useful alternative to natural materials in the successful treatment of tuberculosis through the inhibition of side effect.

Chronic dialysis, NAT2 polymorphisms, and the risk of isoniazid-induced encephalopathy - case report and literature review.

BACKGROUND: Isoniazid is the most widely used anti-tuberculosis agent, yet it may lead to life-threatening complications. CASE PRESENTATION: Here we report the case of a chronic hemodialysis patient who developed severe encephalopathy after the start of isoniazid. Blood levels of isoniazid were elevated, and acetyl-isoniazid over isoniazid ratio was decreased 3 h after intake of the medication, suggesting that a slow acetylator phenotype may have contributed to drug toxicity, in addition to pyridoxal phosphate removal by dialysis. This hypothesis was confirmed by sequencing of NAT2, the gene responsible for isoniazid elimination, and identification of NAT2 polymorphisms compatible with a slow acetylator phenotype. Isoniazid withdrawal along with supplementation using high doses of pyridoxine successfully reversed the drug toxicity. Isoniazid toxicity occurs in populations at risk, including patients with chronic kidney failure or NAT2 polymorphisms, who have a disturbed metabolism of pyridoxine or isoniazid, respectively, and those on renal replacement therapies, in whom pyridoxal phosphate - the active metabolite of pyridoxine - is inadvertently removed by dialysis. CONCLUSIONS: Physicians should be aware of the increased risk of isoniazid toxicity in patients on dialysis and in those with a slow acetylator phenotype conferred by NAT2 polymorphisms. Adaptation of prescription - either with higher doses of pyridoxine or decreased doses of isoniazid, respectively - has been suggested to reduce the risk of potentially life-threatening toxicity of isoniazid.