Combination of thioridazine and dicloxacillin as a possible treatment strategy of staphylococci.

We have previously shown that the phenothiazine, thioridazine, acts in synergy with the beta-lactam antibiotic, dicloxacillin, to kill methicillin-resistant Staphylococcus aureus. In this study, we investigated whether synergy by combining these two drugs could also be observed in vancomycin intermediate susceptible S. aureus (VISA) and methicillin-resistant Staphylococcus epidermidis (MRSE). Synergy was observed in three of four tested VISA strains, suggesting that the thickening of cell wall does not interfere with the effects of thioridazine. In S. epidermidis, no synergy was observed in all tested strains, suggesting that synergy by combining thioridazine and dicloxacillin is isolated to S. aureus species.

Chemotherapeutic efficacy of thioridazine as an adjunct drug in a murine model of latent tuberculosis.

Thioridazine, a potent phenothiazine compound was evaluated for its chemotherapeutic efficacy against experiment model of tuberculosis. Thioridazine potentiated the activities of both isoniazid and rifampicin (>1 log CFU reduction) against the in vitro latent Mycobacterium tuberculosis bacilli. Further, a murine model of latent tuberculosis was used and the standard 9-month isoniazid and 4-month rifampicin regimen along with thioridazine as an adjunct drug were evaluated. Thioridazine led to an accelerated clearance of bacilli with both the regimen, thereby leading to completion of therapy much earlier than the standard end-point. In the case of 9-month isoniazid regimen, when thioridazine was used along with isoniazid as an adjunct drug, complete clearance was observed as early as 24 weeks as compared to the 36 week standard isoniazid monotherapy regimen. Also, in the 4-month rifampicin regimen, it was observed that the bacillary clearance was more robust when rifampicin was used along with thioridazine (>3 log CFU reduction) than rifampicin alone (>2 log CFU reduction). Our findings implicate that thioridazine, when used as an adjunct drug along with isoniazid or rifampicin has the potential to augment their chemotherapeutic efficacy against experimental latency.

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.

Enhancement of in vitro activity of tuberculosis drugs by addition of thioridazine is not reflected by improved in vivo therapeutic efficacy.

OBJECTIVES: Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), in vitro and in vivo as a single drug and in combination with tuberculosis (TB) drugs. METHODS: The in vitro activity of thioridazine as single drug or in combination with TB drugs was assessed in terms of MIC and by use of the time-kill kinetics assay. Various Mtb strains among which the Beijing genotype strain BE-1585 were included. In vivo, mice with TB induced by BE-1585 were treated with a TB drug regimen with thioridazine during 13 weeks. Therapeutic efficacy was assessed by the change in mycobacterial load in the lung, spleen and liver during treatment and 13 weeks post-treatment. RESULTS: In vitro, thioridazine showed a concentration-dependent and time-dependent bactericidal activity towards both actively-replicating and slowly-replicating Mtb. Thioridazine at high concentrations could enhance the activity of isoniazid and rifampicin, and in case of isoniazid resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants. Thioridazine had no added value in combination with moxifloxacin or amikacin. In mice with TB, thioridazine was poorly tolerated, limiting the maximum tolerated dose (MTD). The addition of thioridazine at the MTD to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy. CONCLUSIONS: Thioridazine is bactericidal towards Mtb in vitro, irrespective the mycobacterial growth rate and results in enhanced activity of the standard regimen. The in vitro activity of thioridazine in potentiating isoniazid and rifampicin is not reflected by improved therapeutic efficacy in a murine TB-model.

Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis.

Over a period of 14 years, the authors have studied thioridazine, an old neuroleptic, that has been shown to have in vitro activity against intracellular Mycobacterium tuberculosis, regardless of its antibiotic resistance status, thioridazine cures infected mice of antibiotic-susceptible and multidrug-resistant tuberculosis (TB) infections and, when used in combination with antibiotics used for therapy of TB, renders the organism significantly more susceptible. This article will describe the authors' further work and the mechanisms by which thioridazine alone and in combination with antibiotics cures an extensively drug-resistant infection and why it is expected to cure totally drug-resistant TB infections as well. The concepts presented are entirely new and because they focus on the activation of killing by nonkilling macrophages where M. tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic-resistant status, effective therapy of any antibiotic-resistant TB infection is possible.

The broad-spectrum antimycobacterial activities of phenothiazines, InVitro: somewhere in all of this there may be patentable potentials.

The phenothiazines are neuroleptic drugs that have long been known to have antimycobacterial activity, in vitro. Of the various commercially available phenothiazines, thioridazine, chlorpromazine and trifluoperazine are most active against mycobacteria, in vitro. Their MICs for Mycobacterium tuberculosis are in the 8-16 µg/ml range and MICs for Mycobacterium avium in the 10-32 µg/ml range, depending on methods and media. These concentrations cannot be safely attained in humans, where maximum serum concentrations are 0.5 µg/ml (thioridazine) to 1 µg/ml (chlorpromazine) or 4 µg/ml (trifluoperazine). Phenothiazines still have potential as antimycobacterial drugs because they accumulate in macrophages; concentrations inside macrophages are at least 10 fold higher than in serum. When applied to mycobacteria inside macrophages, concentrations as low as 0.1 µg/ml (thioridazine) or 0.1-3.6 µg/ml (chlorpromazine) kill phagocytized M. tuberculosis and M. avium in 3-7 days. Owing to their multiple and novel drug targets, phenothiazine resistance has not been observed. The drug targets and less toxic phenothiazine derivatives (patents include WO2005105145A and WO2010122012A) provide excellent patentable potentials. Thioridazine itself may be patented as "new use". New drugs for treatment of mycobacterial disease, most notable multidrug- and extensively drug-resistant tuberculosis, are urgently needed; phenothiazines and their targets should be exploited for this use.

[Predictors of the efficacy of methods for psychocorrection in patients with irritable bowel syndrome and constipation].

Prognostic factors that predict the efficiency of autogenous training and psychopharmacotherapy were detected in 90 women with irritable bowel syndrome and constipation. A multifactor personality questionnaire, Spielberg's state-trait anxiety test, Beck's depression inventory scale, and visual analog scale were used for the purpose of psychodiagnosis. The efficiency of autogenous training was found to be higher in patients with irritable bowel syndrome and mildly or moderately compromised psychological adaptation associated with a moderately elevated level of anxiety. Psychopharmacotherapy proved to be especially efficacious in patients with hypochondriac, depressive, and manifest anxiety disorders. It was found that the pronouncedness of rigidity, tension, fixation-proneness, and the degree of depression could be used as predictors of positive effects of psychopharmacotherapy on stool patterns while hypochondriac trends served as predictors of the alleviation of pain syndrome in patients with irritable bowel syndrome and constipation.

Treatment with benznidazole or thioridazine in the chronic phase of experimental Chagas disease improves cardiopathy.

Mice infected with Trypanosoma cruzi Tulahuen strain or SGO-Z12 isolate were treated at 180 days post infection (p.i.) (i.e. chronic phase) with benznidazole (for 30 days) or thioridazine (for 12 days). Both drugs produced a decrease in electrocardiographic alterations, fewer modifications in the affinity and density of cardiac beta-receptors, and few isolated areas of fibrosis in the heart, whereas untreated mice presented areas of necrosis and fibre fragmentation 350 days p.i. (P<0.01). Survival in treated mice was 100% for benznidazole and 88% for thioridazine, independent of the parasite strain; survival for untreated mice was 30% and 40% for Tulahuen strain and SGO-Z12 isolate, respectively (P<0.01). No cardiotoxic effects of thioridazine were detected at the dose and treatment schedule used. These results show the benefit of treatment in the chronic phase of Chagas disease and that thioridazine should be considered as a promising agent for the treatment of Chagas disease.

"Non-Antibiotics": alternative therapy for the management of MDRTB and MRSA in economically disadvantaged countries.

The antibiotic resistance is now common place throughout the globe. Two highly problematic antibiotic resistant infections are those produced by multi-drug resistant Mycobacterium tuberculosis (MDRTB) and methicillin resistant Staphylococcus aureus (MRSA). Although vancomycin is useful for therapy of MRSA, there is now evidence that resistance to this antibiotic is taking place. Intracellular infections of MRSA are very difficult to manage and are recurrent especially when invasive prosthetic devices are employed. This mini-review provides cogent evidence that both intracellular MDRTB and intracellular MRSA can be killed by concentrations of the non-antibiotic phenothiazine, Thioridazine, at concentrations in the medium that are below those present in the plasma of patients treated with this agent. Although thioridazine has been claimed to cause arrhythmias and even sudden death, the frequencies of these episodes are rare and when present, they are related to the patients underlying cardiac status as opposed to the direct effect of the agent itself. The authors do not suggest that thioridazine be used indiscriminately for MDRTB or intracellular infections produced by MRSA. However, there are circumstances where there are no alternative forms of therapy and the patient faces an unfavourable prognosis. For these highly selective and controlled situations, the use of thioridazine in the manner employed for the therapy of psychosis is recommended (compassionate therapy).

[Polymorphic ventricular tachycardia of torsade de pointes type in patient with schizophrenia treated with thioridazine]. / Wieloksztaltny czestoskurcz komorowy typu torsade de pointes u pacjentki ze schizofrenia leczonej tiorydazyna.

A case of 82 year-old female with schizophrenia treated with thioridazine with a long QT syndrome and polymorphic ventricular tachycardia of torsade de pointes type was presented. Additional predisposing factor for cardiac arrhythmia was diarrhea with subsequent hypokalemia. Infusion of magnesium sulphate, potassium supplementation and thioridazine discontinuation was effective management of the pathient.

The in vitro activity of phenothiazines against Mycobacterium avium: potential of thioridazine for therapy of the co-infected AIDS patient.

Patients presenting with Acquired Immune Deficiency Syndrome (AIDS) are predisposed to co-infection with Mycobacterium avium. The management of such patients is problematic due to underlying immuno-incompetence and the high resistance of M. avium to most non-toxic compounds. Therefore, the need for effective agents is obvious. Because phenothiazines, especially the relatively mild thioridazine, have significant activity against Mycobacterium tuberculosis, we investigated the in vitro activity of chlorpromazine, thioridazine, promazine, promethazine and desipramine against a reference and clinical strains of M. avium. The results obtained show that whereas all of the phenothiazines employed in this study had an minimum inhibitory concentration (MIC) against the strains studied that ranged from ca. 10 to > 50 mg/L, as was previously shown for M. tuberculosis, thioridazine was the most active of the group against M. avium.

Thioridazine treatment modifies the evolution of Trypanosoma cruzi infection in mice.

Thioridazine, a tricyclic drug, is known to have a direct effect on Trypanosoma cruzi, disrupting the parasites' mitochondria and kinetoplasts. In the present study, the drug was used orally, at 80 mg/kg.day for 3 days, to treat mice inoculated with low numbers of T. cruzi. The drug caused no apparent toxicity in the host. It cleared trypomastigotes from the bloodstream, prevented the histological and functional alterations of the heart normally observed in the chronic phase of the experimental disease, and greatly reduced the mortality rate compared with that in untreated, infected controls. When checked 135 days post-infection, the density of cardiac beta receptors and the cardiac histology of the treated mice were indistinguishable from those of uninfected, untreated controls. The drug is already used to treat humans, as a neuroleptic drug. It appears to be able to prevent acute infection with T. cruzi evolving into chronic disease, at least in mice, and may be a useful base from which to design new agents for the treatment of Chagas disease.

Controversies in the treatment of autistic children: vitamin and drug therapy.

A survey of approximately 4,000 questionnaires completed by parents of autistic children provided ratings on a variety of treatments and interventions. Among the biomedical treatments, the use of high-dosage vitamin B6 and magnesium (n = 318) received the highest ratings, with 8.5 parents reporting behavioral improvement to every one reporting behavioral worsening. Deanol (n = 121) was next most highly rated, with 1.8 parents reporting improvement to each one reporting worsening. Fenfluramine (n = 104) was third, with a ratio of 1.5:1. Thioridazine hydrochloride (Mellaril), by far the most often used drug on the list (n = 724), was fourth with a helped-worsened ratio of 1.4:1. The research literature on the use of vitamin B6-magnesium is briefly reviewed, and mention is made of recent findings regarding high-dosage folic acid in autism and biotin in Rett syndrome.

Mania following head injury. A report of two cases and a review of the literature.

Secondary mania has been described in association with a variety of physical conditions. While there have been a number of reports of mania occurring in individuals with intracranial cerebral lesions, there have been few reporting its occurrence in association with non-penetrating cerebral trauma. Two further cases of mania following non-penetrating head injury and the efficacy of ECT in its management are reported, and a brief review of the literature relating to the subject is given.

Social skills training for patients with schizophrenia: a controlled clinical trial.

Twenty-eight schizophrenic male patients, diagnosed by the Present State Examination and Catego criteria, and from families high on "expressed emotion," were randomly assigned to either intensive social skills training or holistic health therapy. A multidimensional evaluation was conducted before and after 9 weeks of inpatient treatment and for 24 months in the community. Patients exposed to social skills training evidenced significantly greater acquisition, generalization, and durability of social skills; their social adjustment in the community was rated as better by significant others; and they experienced fewer relapses and rehospitalizations.

Subjective response to antipsychotic drugs: failure to replicate predictions of outcome.

Twenty male schizophrenic patients were given a test dose of chlorpromazine and their subjective response, graded on a syntonic-dysphoric continuum, was recorded at 4, 24, and 48 hours following the test dose. All patients were subsequently treated with an optimal dose of chlorpromazine or thioridazine plus either social skills training or holistic health therapy for a fixed inpatient period of 10 weeks. Patients were maintained on neuroleptics for a 9-month follow-up period. Subjective response to the test dose was not found to be significantly correlated to any of the outcome measures. This study's failure to replicate previously published findings that subjective response to test doses of neuroleptics predict outcome may stem from differences in patients population, treatment milieu, and compliance with drug regimen.

A plea for comprehensive treatment for the hyperkinetic child.

Having a multimodality approach to the hyperkinetic child may make the difference between success or failure in the management of the child. Frequently, one or two modes of intervention alone will not be sufficient. Although several modes of intervention have been described, the helping professional must exercise his own creativity in order to assist specific children.

A neurological form of schizophrenia.

A case is described of a young woman who first showed manifestations of schizophrenia in childhood. At the age of 13 years evidence was present of what was authoritatively diagnosed as a progressive degenerative cerebellar syndrome and her condition continued to deteriorate. Improvement commenced shortly after the institution of megavitamin therapy, notably nicotinic acid 3 grams daily. Her subsequent educational progress was satisfactory and her social rehabilitation is now complete. No medication other than nicotinic acid is required.