Nonclinical cardiovascular safety assessment of thioridazine: Impact of autonomic tone, body temperature, and choice of species.

Pending updates to ICH S7B/E14 guidelines will enable the substitution of human TQT studies with support from concomitant negative hERG and non-rodent CV studies. This retrospective analysis compared the effects of thioridazine (THD) (5-20 mg/kg) on heart rate (HR), blood pressure (BP), body temperature (Tc), and QT in the dog (n = 6), cynomolgus monkey (n = 4), and Goettingen minipig (n = 4) with data from previously completed studies employing crossover designs. As QT measurements are confounded by HR and Tc changes, QT effects were individually corrected for changes in HR (QTca) and Tc (QTcaT). THD-induced hemodynamic changes seen in humans were most accurately reflected in the monkey and, to a lesser extent, the dog, but not in the minipig. The minipig was most sensitive to THD QTc effects. When QTca was adjusted for THD-associated Tc decreases in minipigs and monkeys, the minipig revealed a lessened but pronounced QTcaT increase (48 ms). In the monkey, a persistent QTca increase was reduced to only a transient (0.5-3 h) QTcaT increase (20 ms). The dog's lack of THD QTca effects triggered co-administration of atenolol (AT) to attenuate THD-induced HR increases in the dog and monkey. THD + AT revealed peak QTcaT increases of 32 ms in the dog and 40 ms in the monkey, suggesting potential autonomic nervous system (ANS) interference in detecting repolarization changes. These results highlight critical species-specific differences in the outcome of parallel safety investigations. Species selection for nonclinical safety studies should consider the potential impact of Tc and ANS effects to avoid false-negative or overly positive outcomes.

A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia.

We completed a phase 1 dose-escalation trial to evaluate the safety of a dopamine receptor D2 (DRD2) antagonist thioridazine (TDZ), in combination with cytarabine. Thirteen patients 55 years and older with relapsed or refractory acute myeloid leukemia (AML) were enrolled. Oral TDZ was administered at 3 dose levels: 25 mg (n = 6), 50 mg (n = 4), or 100 mg (n = 3) every 6 hours for 21 days. Intermediate-dose cytarabine was administered on days 6 to 10. Dose-limiting toxicities (DLTs) included grade 3 QTc interval prolongation in 1 patient at 25 mg TDZ and neurological events in 2 patients at 100 mg TDZ (gait disturbance, depressed consciousness, and dizziness). At the 50-mg TDZ dose, the sum of circulating DRD2 antagonist levels approached a concentration of 10 µM, a level noted to be selectively active against human AML in vitro. Eleven of 13 patients completed a 5-day lead-in with TDZ, of which 6 received TDZ with hydroxyurea and 5 received TDZ alone. During this period, 8 patients demonstrated a 19% to 55% reduction in blast levels, whereas 3 patients displayed progressive disease. The extent of blast reduction during this 5-day interval was associated with the expression of the putative TDZ target receptor DRD2 on leukemic cells. These preliminary results suggest that DRD2 represents a potential therapeutic target for AML disease. Future studies are required to corroborate these observations, including the use of modified DRD2 antagonists with improved tolerability in AML patients. This trial was registered at www.clinicaltrials.gov as #NCT02096289.

Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity.

INTRODUCTION: Conservative treatment solutions against aortic prosthetic vascular graft infection (APVGI) for inoperable patients are limited. The combination of antibiotics with antibacterial helper compounds, such as the neuroleptic drug thioridazine (TDZ), should be explored. AIM: To investigate the efficacy of conservative systemic treatment with dicloxacillin (DCX) in combination with TDZ (DCX+TDZ), compared to DCX alone, against early APVGI caused by methicillin-sensitive Staphylococcus aureus (MSSA) in a porcine model. METHODS: The synergism of DCX+TDZ against MSSA was initially assessed in vitro by viability assay. Thereafter, thirty-two pigs had polyester grafts implanted in the infrarenal aorta, followed by inoculation with 106 CFU of MSSA, and were randomly administered oral systemic treatment with either 1) DCX or 2) DCX+TDZ. Treatment was initiated one week postoperatively and continued for a further 21 days. Weight, temperature, and blood samples were collected at predefined intervals. By termination, bacterial quantities from the graft surface, graft material, and perigraft tissue were obtained. RESULTS: Despite in vitro synergism, the porcine experiment revealed no statistical differences for bacteriological endpoints between the two treatment groups, and none of the treatments eradicated the APVGI. Accordingly, the mixed model analyses of weight, temperature, and blood samples revealed no statistical differences. CONCLUSION: Conservative systemic treatment with DCX+TDZ did not reproduce in vitro results against APVGI caused by MSSA in this porcine model. However, unexpected severe adverse effects related to the planned dose of TDZ required a considerable reduction to the administered dose of TDZ, which may have compromised the results.

Hypothermia Associated With Thioridazine Use in an Intellectually Disabled Patient.

PURPOSE: To report a case of hypothermia in a patient with intellectual disability treated with thioridazine. SUMMARY: A 59-year-old female presented to the emergency department with altered mental status, generalized weakness, chills, and fatigue and was diagnosed with a urinary tract infection. Upon completion of a history and physical examination, the patient was found to be hypothermic with a temperature of 91 F. A Bair Hugger protocol was initiated to manage hypothermia, and a taper schedule for thioridazine was initiated as it was identified as a possible culprit for the patient's hypothermia. According to the Naranjo probability scale, thioridazine was a possible cause of this adverse effect. Other patient-specific risk factors for hypothermia were evaluated and ruled out. CONCLUSION: This case indicates a possible correlation between hypothermia and the use of phenothiazine antipsychotics such as thioridazine. Appropriate measures, including early detection and identification of possible causative agents, should be taken to prevent and treat this adverse event in patients taking these medications, specifically in patients with the inability to participate in self-care.

Efficacy and safety of World Health Organization group 5 drugs for multidrug-resistant tuberculosis treatment.

The efficacy and toxicity of several drugs now used to treat multidrug-resistant tuberculosis (MDR-TB) have not been fully evaluated. We searched three databases for studies assessing efficacy in MDR-TB or safety during prolonged treatment of any mycobacterial infections, of drugs classified by the World Health Organization as having uncertain efficacy for MDR-TB (group 5). We included 83 out of 4002 studies identified. Evidence was inadequate for meropenem, imipenem and terizidone. For MDR-TB treatment, clarithromycin had no efficacy in two studies (risk difference (RD) -0.13, 95% CI -0.40-0.14) and amoxicillin-clavulanate had no efficacy in two other studies (RD 0.07, 95% CI -0.21-0.35). The largest number of studies described prolonged use for treatment of non-tuberculous mycobacteria. Azithromycin was not associated with excess serious adverse events (SAEs). Clarithromycin was not associated with excess SAEs in eight controlled trials in HIV-infected patients (RD 0.00, 95% CI -0.02-0.02), nor in six uncontrolled studies in HIV-uninfected patients, whereas six uncontrolled studies in HIV-infected patients clarithromycin caused substantial SAEs (proportion 0.20, 95% CI 0.12-0.27). For most group 5 drugs we found inadequate evidence of safety for prolonged use or for efficacy for MDR-TB, although macrolides appeared to be safe in prolonged use.

Dark adaptation abnormalities and recovery in acute thioridazine toxicity.

PUPOSE: To document acute thioridazine toxicity from the symptoms only, through the development of ophthalmoscopic signs and recovery of dark adaptation and electroretinogram responses. These findings support the thesis that visual loss is metabolic and reversible if diagnosed early. METHODS: Case Report. RESULTS: A case is presented of acute thioridazine toxicity with documentation of the development of symptoms before any ophthalmoscopic evidence of toxicity. This case uniquely shows the time course of dark adaptation, showing both delay in adaptation and elevated final threshold, it includes full electrophysiologic studies from within the first weeks of symptoms and regular follow-up demonstrating marked recovery of dark adaptation in terms of both delay and final threshold, a nearly normal electroretinography and normal color vision within 10 months. CONCLUSION: Our findings give support to the thesis that functional visual disturbance is primarily metabolic and reversible if detected early in the course of toxicity.

Sudden cardiac death & the Reverse Dodo Verdict.

Adverse effects of treatment on cardiac QT intervals were first reported 50 years ago. A clear link to sudden death was established, but the problem remained relatively unknown. The issue of treatment related effects on the heart, and the contribution this might make to sudden cardiac deaths in general, came more clearly into focus 20 years ago, linked to regulatory actions. In an era of polypharmacy, and mixing of prescribed and non-prescribed pharmacologically active agents it is now becoming increasingly clear that unanticipated cardiac effects may be common and a significant cause of mortality. There is likely underreporting and also underdiagnosis, as recognition requires a timely ECG. This paper proposes two methods to handle the problem.

Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis.

The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (TRZ) in combination with the standard regimen in a well-validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB/c mice to establish human-equivalent doses of TRZ. To determine the bactericidal activity of TRZ against TB in BALB/c mice, three separate studies were performed, including a dose-ranging study of TRZ monotherapy and efficacy studies of human-equivalent doses of TRZ with and without isoniazid (INH) or rifampin (RIF). Therapeutic efficacy was assessed by the change in mycobacterial load in the lung. The human-equivalent dose of thioridazine was determined to be 25 mg/kg of body weight, which was well tolerated in mice. TRZ was found to accumulate at high concentrations in lung tissue relative to serum levels. We observed modest synergy during coadministration of TRZ with INH, and the addition of TRZ reduced the emergence of INH-resistant mutants in mouse lungs. In conclusion, this study further illustrates the opportunity to reevaluate the contribution of TRZ to the sterilizing activity of combination regimens to prevent the emergence of drug-resistant M. tuberculosis.

Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis.

OBJECTIVES: The antipsychotic drug thioridazine is active in the murine model of tuberculosis infection, which is predominantly intracellular in nature. Recent clinical reports suggest that thioridazine may play a role in the treatment of drug-resistant tuberculosis. We studied the tuberculocidal activity of thioridazine in guinea pigs, which develop necrotic lung granulomas histologically resembling their human counterparts. METHODS: Pharmacokinetic studies were performed in guinea pigs to establish human-equivalent doses of thioridazine. Guinea pigs were aerosol-infected with ∼100 bacilli of Mycobacterium tuberculosis and single-drug treatment was started 4 weeks later with a range of thioridazine doses daily (5 days/week) for up to 4 weeks. Control animals received no treatment or 60 mg/kg isoniazid. RESULTS: The human-equivalent dose of thioridazine was determined to be 5 mg/kg with saturable absorption noted above 50 mg/kg. At the start of treatment, the lung bacterial burden was ∼6.2 log10 cfu. Although isoniazid reduced bacillary counts more than 10-fold, thioridazine monotherapy showed limited killing over the range of doses tested, reducing lung bacillary counts by 0.3-0.5 log10 following 1 month of treatment. Thioridazine was tolerated up to 40 mg/kg. CONCLUSIONS: Thioridazine has limited bactericidal activity against extracellular bacilli within necrotic granulomas. Its contribution to the sterilizing activity of combination regimens against drug-susceptible and drug-resistant tuberculosis remains to be determined.

Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort.

OBJECTIVE: Thioridazine is a first-generation antipsychotic drug that was withdrawn from the market worldwide in 2005. The outcome of clinically stable schizophrenia patients who used thioridazine before market withdrawal was evaluated. METHODS: Nationwide registers in Finland were utilized to study thioridazine use, hospitalization rate and length of hospital stay. RESULTS: Although thioridazine use continued to diminish year after year, the hospitalization rate remained constant until the withdrawal year of 2005, when the percentage of patients hospitalized for schizophrenia doubled. CONCLUSION: The market withdrawal of thioridazine predisposed many stable patients towards psychotic relapses. In order to minimize this kind of risk, an overall risk-benefit assessment and a clear-cut plan for the replacement of an antipsychotic should be established before market withdrawal.

Potential therapy of multidrug-resistant and extremely drug-resistant tuberculosis with thioridazine.

Multidrug-resistant tuberculosis (MDRTB) infections that continue to increase in frequency globally have progressed to become extremely drug-resistant tuberculosis (XDRTB). The therapeutic problems associated with MDRTB pale in comparison to those for XDRTB where mortality is high. This mini-review highlights the evidence that supports the use of the phenothiazine neuroleptic thioridazine for the therapy of XDRTB. Although thioridazine does produce some serious side-effects, the poor prognosis associated with an XDRTB infection of a patient that presents with AIDS merits that the use of thioridazine for therapy of XDRTB is seriously considered. A recommended protocol is presented.

Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine.

OBJECTIVES: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are scarce; therefore, information on the safety, tolerability and efficacy of alternative regimens is of utmost importance. The aim of this study was to describe the management, drug adverse effects and outcome of alternative combined treatment in a series of XDR-TB patients. PATIENTS AND METHODS: A retrospective study was performed on 17 non-AIDS, pulmonary adult patients with XDR-TB admitted to a referral treatment centre for infectious diseases in Buenos Aires from 2002 through 2008. Drug susceptibility testing was performed under regular proficiency testing and confirmed at the national TB reference laboratory. RESULTS: Linezolid was included in the drug regimens of all patients; moxifloxacin and/or thioridazine were included in the regimens of 14 patients. Clinically tractable drug adverse effects were observed in nine patients, the most frequent being haematological disorders and neurotoxicity. In two patients, thioridazine was discontinued. Negative culture conversion was achieved in 15 patients, 11 completed treatment meeting cure criteria, 4 are still on follow-up with good evolution, 1 defaulted treatment and 1 was lost to follow-up. CONCLUSIONS: The combination of linezolid, moxifloxacin and thioridazine is recommended for compassionate use in specialized centres with expertise in the management of XDR-TB.

Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB.

New drugs are desperately needed to combat XDR-TB as effective treatment involves at least four drugs to which the patient is sensitive or has never received in the past. Most Indian patients have received almost all second line drugs and have amplified resistance to most of the available drugs. Thioridazine has proven anti tuberculous effects in vitro and in vivo mouse models and we used this drug as salvage therapy in 4 Indian patients with XDR (near total drug resistance) with advanced disease. We found this drug to be well tolerated, even in this malnourished and ill patient population. It also resulted in clinical improvement in 3 of the 4 patients. Larger studies are being planned with this drug being added on to standardized or individualized XDR-TB regimens at an earlier stage. Because thioridazine has been used successfully for therapy of XDR-TB when in combination with antibiotics to which the patients were nonresponsive, the suggestion has been made that Thioridazine is eligible for patent as "New Use".

Thioridazine: the good and the bad.

Thioridazine is a phenothiazine drug which has previously been extensively used for its antipsychotic properties as it is associated with a low risk of extra-pyramidal side-effects. There is good evidence to suggest that, in common with other phenothiazine drugs, thioridazine has important anti-microbial activity and is a potential candidate for development as an anti-microbial drug against multi-resistant organisms, including drug-resistant strains of M. tuberculosis. The clinical pharmacology and toxicity profile of thioridazine are reviewed in this article and the implications for future drug development along with the patent are discussed.

Global clinical trials for the treatment of TB with thioridazine.

Current evidence shows that thioridazine (THZ) is ready for global clinical evaluation, while some of its derivatives and other efflux pump inhibitors reach the end stage of preclinical evaluation. In this paper, a clinical trial plan is described that investigates the antituberculosis potency, the safety profile and the role of THZ and/or its derivatives in the treatment of TB in humans, both in patients infected with drug sensitive strains as in patients infected with multi or extensive drug resistant strains of Mycobacterium tuberculosis and some of the patents related to thioridazine are also discussed.

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.

New patentable use of an old neuroleptic compound thioridazine to combat tuberculosis: a gene regulation perspective.

Use of the old antipsychotic phenothiazine thioridazine (THZ) for therapy of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) infection is now being seriously considered. It is reported that THZ primarily acts on enzymes involved in fatty acid metabolism and membrane proteins, particularly efflux pumps, as well as oxidoreductases and proteins involved in aerobic respiration that overlap with a number of conventional antituberculous drugs. It targets the products of the Rv3160c-Rv3161c operon, which are perhaps required for the detoxification of THZ, members of the sigma factor SigB regulon that play a crucial role in protecting the pathogen against cell envelope damage, and Rv2745c, a transcription factor that regulates ATP-dependent proteolysis. Some of these genes have been shown to be essential for the survival or persistence of Mycobacterium tuberculosis in the infected host. Since THZ targets multiple pathways, including those involved in cell wall processes and respiratory chain components, it may serve as a model for multi-target drug development, as well as constitute a highly potent addition to a combination of antituberculous drug regimens. The discussion of some of the patents relevant to thioridazine to combat tuberculosis is also included in the present manuscript.

Therapy Of XDR TB with thioridazine a drug beyond patent protection but eligible for patent "as new use".

Mycobacterium tuberculosis that is resistant to Isoniazid (INH) and Rifampin (Rif) and hence, multi-drug resistant (MDR) has progressed to extensive drug resistant (XDR) status. XDR strains of Mycobacterium tuberculosis (XDR Mtb) are resistant, in addition to INH and Rif, to any fluoroquinolone, streptomycin and to any of the injectable anti-TB drugs kanamycin, amikacin and capreomycin. Therapy of the XDR TB patient, even under the best conditions, is problematic and at least 20% of XDR TB patients die within one year after diagnosis. Mortality among XDR TB patients co-infected with HIV or presenting with AIDS is considerably higher reaching levels of 80% or higher. Drugs that are to prove effective against XDR Mtb must be able to reach the organism at the site where it mainly resides-the pulmonary macrophage. However, experience tells us that no matter how effective a drug may be, it will be followed by resistance. We have been able to demonstrate that thioridazine, a neuroleptic in safe use for over forty years, enhances the killing of phagocytosed Mycobacterium tuberculosis regardless of its antibiotic susceptibility profile and cure the mouse of a Mycobacterium tuberculosis pulmonary infection. Most recently, others have employed our studies for the therapy of the XDR TB patient with thioridazine and cured 10 out of 12 XDR TB patients of an XDR Mtb infection. Although thioridazine is beyond patent protection, its use for the therapy of XDR TB is new and therefore, a patent may be sought for "use as an anti-XDR TB agent".