Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study.

BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study.

BACKGROUND: Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. METHODS: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. RESULTS: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). CONCLUSIONS: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Towards new business models for R&D for novel antibiotics.

In the face of a growing global burden of resistance to existing antibiotics, a combination of scientific and economic challenges has posed significant barriers to the development of novel antibacterials over the past few decades. Yet the bottlenecks at each stage of the pharmaceutical value chain-from discovery to post-marketing-present opportunities to reengineer an innovation pipeline that has fallen short. The upstream hurdles to lead identification and optimization may be eased with greater multi-sectoral collaboration, a growing array of alternatives to high-throughput screening, and the application of open source approaches. Product development partnerships and South-South innovation platforms have shown promise in bolstering the R&D efforts to tackle neglected diseases. Strategies that delink product sales from the firms' return on investment can help ensure that the twin goals of innovation and access are met. To effect these changes, both public and private sector stakeholders must show greater commitment to an R&D agenda that will address this problem, not only for industrialized countries but also globally.

Male reproductive hormones in patients treated with pretomanid.

BACKGROUND: Pretomanid (Pa) is a nitroimidazole-class drug recently approved by the US Food and Drug Administration and other regulatory authorities as part of a regimen for treating highly drug-resistant pulmonary Mycobacterium tuberculosis infections. Studies in rodents identified the testis as a target organ of concern, which led to monitoring of reproductive hormones in >800 male patients enrolled in four clinical trials of Pa-containing regimens and the HRZE (isoniazid+rifampin+pyrazinamide+ethambutol) control regimen.METHODS: Serum hormone levels relevant to male reproductive health - follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (InhB) and total testosterone (T) - from the four clinical trials were summarized numerically and analyzed by repeated-measures modeling.RESULTS: Hormone levels generally behaved similarly in Pa-containing and HRZE arms. Relative to baseline, serum T and InhB levels generally increased at the end of treatment and follow-up. FSH and LH levels were variable, but were generally at or below baseline levels by follow-up. Before treatment, many patients were borderline hypogonadal, with T levels near the lower limits of the normal range.CONCLUSION: Changes in male hormones in four clinical trials studying patients with TB indicate that Pa-containing treatment was not associated with testicular toxicity but rather led to improvement in the underlying hypogonadism.

Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.

BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Etoposide induced blood-brain barrier disruption in rats: duration of opening and histological sequelae.

The intracarotid infusion of the antineoplastic compound etoposide enhances blood-brain barrier (BBB) permeability. In a rat model system, the functional reversibility and anatomic sequelae of etoposide induced BBB disruption were investigated. Etoposide, in a dose range from 3.0 to 22.5 mg/kg, was infused into the left internal carotid artery of Sprague-Dawley rats. BBB disruption was evaluated by the appearance in the infused hemisphere of systemically administered Evans blue dye and quantitatively by the ratio of counts of the technetium labeled chelate of diethylenetriaminepentaacetic acid in the infused to the noninfused hemisphere. Functional reversibility of altered BBB permeability was investigated at three dose levels of etoposide (3.0, 15.0, and 22.5 mg/kg) by the administration of Evans blue dye at the time of etoposide infusion and the administration of the technetium labeled chelate of diethylenetriamine-pentaacetic acid at varying time intervals after etoposide infusion. Fourteen groups of 12 rats each were studied to define the time course of altered BBB permeability at these three doses. The anatomic sequelae of etoposide induced BBB disruption were investigated at varying time intervals (up to 3 weeks) after intracarotid etoposide infusion. Nineteen rats were examined after sacrifice by intracardiac fixation perfusion with 10% formalin. Each brain was sectioned coronally and examined under light microscopy after hematoxylin and eosin staining. Evidence of BBB disruption was seen at all dose levels of etoposide. The degree of BBB disruption increased with increasing doses of etoposide. The duration of altered BBB permeability increased from less than 1 day at 3.0 mg/kg to between 3 and 4 days at 22.5 mg/kg. Histological studies revealed no evidence of parenchymal damage, although at 4 days postdisruption, a mild perivascular lymphocytic infiltration was noted in the infused hemisphere. Etoposide infusion and subsequent BBB disruption were well tolerated by all test animals. In a rat model system the intracarotid infusion of etoposide is capable of producing prolonged reversible BBB disruption.

TB Alliance regimen development for multidrug-resistant tuberculosis.

The recent approval of new tuberculosis (TB) drugs raises hope for new and more effective anti-tuberculosis treatment regimens. The Global Alliance for TB Drug Development (TB Alliance) is committed to ensuring that new anti-tuberculosis drugs fulfill the needs of patients, their families and the local health services that serve the communities. Here we present highlights of the TB Alliance's pipeline of regimen development, with novel regimens for patients with drug-susceptible, multidrug-resistant and extensively drug-resistant TB. The ongoing clinical trials (STAND, NC-005, Nix-TB and LIN-CL001) are outlined and their rationale and goals presented.

Evidence of probable tuberculosis in Lithuanian mummies.

Tuberculosis has affected Europe for millennia and continues to be a burden upon modern society. It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of this condition. Despite the introduction of control strategies, the disease continues to be one of the most common causes of death globally. Within the framework of the Lithuanian Mummy Project, seven spontaneously mummified human bodies from a church crypt in Vilnius, dating from the 18th and 19th century, were CT-scanned to assess the presence of tuberculosis or other lung diseases. We encountered pulmonary lesions suggestive of cases of pulmonary tuberculosis. In addition, one case might have been affected by extra-pulmonary tuberculosis. This report replicates the image findings from previous studies on ancient mummies that provided evidence of tuberculosis in soft tissues, thus helping reconstruct the history of this disease over time.

Fulminant disseminated carcinomatosis arising from squamous cell carcinoma of the tongue.

Squamous cell carcinoma of the tongue tends to be an indolent disease. Tumors that present as small, localized lesions of the anterior tongue have a median five-year survival greater than 70 percent whether treated by irradiation or surgery. Distant metastases occur in only 7.5 percent. This report describes a well-differentiated T1N0M0 squamous cell carcinoma of the anterior tongue that progressed from diagnosis to death of the patient in less than nine months. At autopsy, the tumor had disseminated widely, including simultaneous metastases to all layers of the heart. It is concluded that factors other than morphology and anatomic extent at presentation may modify prognosis in squamous cell carcinoma of the tongue.

PCR primers that can detect low levels of Mycobacterium leprae DNA.

There are several specific PCR-based methods to detect Mycobacterium leprae DNA, but the amplicons are quite large. For example, primers that target the 36-kDa antigen gene and are in common diagnostic use yield a 530-bp product. This may be a disadvantage when examining samples in which the DNA is likely to be damaged and fragmented. Therefore, two sets of M. leprae-specific nested primers were designed, based on existing primer pairs which have been shown to be specific for M. leprae. Primers that targeted the 18-kDa antigen gene gave an outer product of 136 bp and inner product of 110 bp. The primers based on the RLEP repetitive sequence yielded a 129-bp outer product and 99-bp nested product. With dilutions of a standard M. leprae killed whole-cell preparation as the source of DNA, both single-stage and nested PCR were performed after optimisation of the experimental conditions. Compared with the 36-kDa antigen gene primers, the 18-kDa antigen gene outer primers were 100-fold more sensitive and the RLEP outer primers were 1000-fold more sensitive. As an illustration of two possible applications of these new primers, positive results were obtained from three skin slit samples from treated lepromatous leprosy patients and three archaeological samples from human remains showing typical leprosy palaeopathology. It was concluded that these new primers are a useful means of detecting M. leprae DNA which is damaged or present at a very low level.

Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: report of a case and review of the literature.

Although systemic metastases from transitional cell carcinoma of the bladder occur frequently, involvement of the central nervous system is uncommon. We describe a patient with an isolated cerebral metastasis who had previously undergone resection of a Grade III, Stage B2 carcinoma of the bladder. We have been able to find only one previous case report of a solitary intracerebral metastasis from transitional cell carcinoma of the bladder without evidence of primary recurrence or additional sites of spread. Central nervous system metastasis from bladder carcinoma must be considered in the differential diagnosis of solitary intracerebral lesions.

Electroencephalographic consequences of sodium dehydrocholate-induced blood-brain barrier disruption: Part 1. Acute and chronic effects of intracarotid sodium dehydrocholate.

Prior work has shown that the intracarotid infusion of sodium dehydrocholate can produce prolonged reversible blood-brain barrier (BBB) disruption. Associated with barrier disruption is the occasional presence of behavioral seizure activity. Electroencephalographic changes were monitored in 32 rats after BBB disruption by the left internal carotid artery infusion of sodium dehydrocholate. The electroencephalogram (EEG) was monitored for 3 hours after disruption in 20 animals, and the remaining 12 animals were followed for 24 hours. The EEG was also monitored in 8 additional control animals: 4 had undergone carotid artery infusion with normal saline, and 4 had received sodium dehydrocholate intravenously. The 20 rats monitored for up to 3 hours postinfusion were found to have varying grades of BBB disruption as measured by the presence of Evans blue staining of the brain. EEG alterations in this group included decreased amplitude and slowing as well as the presence of spike activity over the disrupted and the nondisrupted hemispheres. The more extensive the disruption, the more severe the EEG changes. In animals with minimal to moderate disruption, the EEG usually returned to base line levels within 3 hours after infusion. Animals with marked disruption usually had bilaterally flat EEGs before the end of the observation period. The remaining 12 animals were followed for 24 hours postinfusion. Of 9 animals surviving 24 hours, 1 animal had a decrease in amplitude over the disrupted hemisphere; in the remaining 8 animals, the spontaneous EEG was unchanged from predisruption levels except for occasional spikes in 2 animals. Animals infused with intracarotid saline or intravenous sodium dehydrocholate demonstrated no EEG changes or Evans blue staining.(ABSTRACT TRUNCATED AT 250 WORDS)

Electroencephalographic consequences of sodium dehydrocholate-induced blood-brain barrier disruption: Part 2. Generation and propagation of spike activity after the topical application of sodium dehydrocholate.

Sodium dehydrocholate was applied topically to the right hemispheric cortex of eight rats and the electrocorticogram was monitored from both the treated cortex and the homotopic cortex of the contralateral hemisphere. All animals developed blood-brain barrier (BBB) disruption in the treated cortex as evidenced by cortical staining with systemically administered Evans blue dye. Spike activity developed in three of eight animals after the topical application of dehydrocholate. The subsequent intravenous injection of sodium dehydrocholate provoked spike activity in both hemispheres in all eight animals. Dependent and independent spike activity was recorded in the nondisrupted hemisphere. The intravenous administration of gamma-aminobutyric acid (GABA) resulted in alterations in spike activity in four of five animals because of penetration of the GABA through the altered BBB. These findings demonstrate that sodium dehydrocholate can result in increased BBB permeability when applied directly to the cortical surface. Spike activity subsequent to the topical application of dehydrocholate can be enhanced by systemic loading with dehydrocholate. Spike activity occurring over the nontreated cortex (secondary focus) represents interhemispheric propagation of spike activity from the disrupted hemisphere (primary focus). The lack of Evans blue staining in the actively discharging secondary focus suggests that spike activity does not account for the increases in BBB permeability observed with dehydrocholate treatment.

Physiological and electrophysiological consequences of etoposide-induced blood-brain barrier disruption.

The present study investigates the effects of etoposide-induced blood-brain barrier (BBB) disruption on systemic blood pressure (SBP), intracranial pressure (ICP), and electroencephalographic (EEG) activity. A total of 29 rats were divided into two groups. In Group 1, 8 control animals received intracarotid normal saline; in Group 2, 21 animals received intracarotid etoposide. SBP, ICP, and EEG were monitored continuously under general anesthesia and controlled ventilation after tracheostomy. Intravenous Evans blue dye was used for determination of BBB disruption. Although none of the Group 1 animals showed BBB disruption, 57% of the animals in Group 2 showed marked BBB disruption (3+). A slight but statistically significant increase in ICP was noted in the Group 2 animals with 3+ BBB disruption, although lesser degrees of barrier disruption (1+ or 2+) resulted in no significant alteration in ICP. The amplitude and frequency of the EEG decreased significantly ipsilateral to the side of intracarotid infusion in all animals with 3+ barrier disruption with a tendency to return toward normal within 2 hours. The degree of transient EEG change observed correlates well with the degree of barrier disruption, potentially allowing clinical determination of BBB disruption by this method.

Intracarotid dehydrocholate infusion: a new method for prolonged reversible blood-brain barrier disruption.

An animal model for prolonged reversible blood-brain barrier (BBB) disruption has been developed. The external carotid arteries of Osborn-Mendel rats were catheterized in a retrograde manner. Varying concentrations of sodium dehydrocholate were infused into the internal carotid artery by this technique. BBB disruption was evaluated qualitatively by the appearance in the infused hemisphere of the systemically administered dyes Evans blue and sodium fluorescein and quantitatively by the ratio of counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the infused to the noninfused hemisphere. The ability of sodium dehydrocholate to disrupt the BBB was documented with all three markers. As the concentration of the infused dehydrocholate was increased, both the incidence and the degree of BBB disruption increased. Reversibility of BBB disruption was evaluated by the administration of sodium fluorescein and 99mTc-DTPA at varying times after BBB disruption. Depending on the concentration of the infused sodium dehydrocholate, altered BBB permeability can be maintained for over 3 days. This new model of prolonged reversible BBB disruption deserves further investigation both for basic studies of the BBB and for therapeutic studies of drug delivery into the central nervous system.

Etoposide-induced blood-brain barrier disruption. Effect of drug compared with that of solvents.

The intracarotid infusion of the anti-neoplastic compound, etoposide, has been shown to exert a dose-dependent effect on blood-brain barrier (BBB) permeability. Etoposide, however, is formulated in a complex solvent solution containing alcohol, Tween 80, polyethylene glycol 300, and citric acid. To investigate the contribution of the solvent solution to BBB disruption, the authors studied Sprague-Dawley rats after the internal carotid artery infusion of the solvent solution with and without the addition of etoposide. Experiments were performed at four doses of drug and/or solvent. Disruption of the BBB was evaluated qualitatively by the appearance of the systemically administered dye, Evans blue, in the cerebral hemispheres and quantitatively by the ratio of gamma counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the ipsilateral:contralateral hemisphere. Significant barrier opening was obtained in all four groups of animals infused with solvent plus etoposide. In the corresponding groups of rats infused with the solvent solution alone, BBB disruption was markedly lower. Only in the group infused with the largest dose of solvent was the hemispheric ratio of 99mTc-DTPA significantly different from saline-infused animals. Each of the groups with solvent plus etoposide had 99mTc-DTPA ratios significantly different from the control group. Intracarotid infusion and subsequent BBB disruption were well tolerated by the animals receiving either solvent alone or solvent and etoposide. Disruption of the BBB secondary to the intracarotid infusion of etoposide is primarily caused by the drug itself and not by the solvent solution.

Caloric vs. pharmacologic effects of ethanol consumption on activity anorexia in rats.

Food restriction, combined with access to a running wheel, produces "activity anorexia" (self-starvation) in rats. The relative effects of ethanol and propylene glycol on activity-maintained self-starvation were examined. Young male rats were provided with access to a running wheel while on a 22.5-h food deprivation schedule. One-third were concurrently provided with a 7% solution of ethanol, one-third with a (pharmacologically weak) 7% solution of propylene glycol, and one-third with water. Results indicated that neither survival rate nor running activity were affected significantly by ethanol consumption, relative to water-drinking controls. However, increased survival rates and decreased activity were observed for those animals which consumed propylene glycol. Antagonistic effects of ethanol on energy metabolism, stress responses, and the preservation of body weight are considered in light of these findings.