Drug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male Volunteers.

E1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti-Trypanosoma cruzi activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers. This open-label, single-center, sequential, single- and multiple-oral-dose study enrolled 28 healthy male subjects. These subjects received BNZ (2.5 mg/kg) once daily on days 1 and 9 and twice daily from day 12 to day 15 and E1224 once daily from day 4 to day 15 (loading dose of 400 mg for 3 days and maintenance dose of 100 mg for 9 days). The maximum concentration (Cmax) and area under the concentration curve from zero to infinity for BNZ were comparable, whether BNZ was given alone or with E1224 at steady state, with ratios of geometric means for BNZ-RVZ to BNZ of 0.96 and 0.83 and corresponding 90% confidence intervals (CIs) of 0.91 to 1.10 and 0.80 to 0.87, respectively. However, RVZ Cmax and area under the concentration curve from zero to 24 h increased by about 35% when concomitantly administered with BNZ at steady state (ratio of geometric means for RVZ-BNZ/RVZ of 1.31 and 1.36 and corresponding 90% CIs of 1.23 to 1.39 and 1.31 to 1.41, respectively). Both compounds were well tolerated. There were no clinically relevant safety interactions between E1224 and BZN. Given these results, coadministration of RVZ and BNZ should not require any adaptation of E1224 dosing.

Diabetes Exacerbates Infection via Hyperinflammation by Signaling through TLR4 and RAGE.

For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. We confirmed that diabetic mice were hypersusceptible to bacteremia caused by Gram-negative bacteria (GNB), dying at inocula nonlethal to nondiabetic mice. Contrary to the pervasive paradigm that diabetes impedes phagocytic function, the bacterial burden was no greater in diabetic mice despite excess mortality. However, diabetic mice did exhibit dramatically increased levels of proinflammatory cytokines in response to GNB infections, and immunosuppressing these cytokines with dexamethasone restored their resistance to infection, both of which are consistent with excess inflammation. Furthermore, disruption of the receptor for advanced glycation end products (RAGE), which is stimulated by heightened levels of AGEs in diabetic hosts, protected diabetic but not nondiabetic mice from GNB infection. Thus, rather than immunosuppression, diabetes drives lethal hyperinflammation in response to GNB by signaling through RAGE. As such, interventions to improve the outcomes from GNB infections should seek to suppress the immune response in diabetic hosts.IMPORTANCE Physicians and scientists have subscribed to the dogma that diabetes predisposes the host to worse outcomes from infections because it suppresses the immune system. This understanding was based largely on ex vivo studies of blood from patients and animals with diabetes. However, we have found that the opposite is true and worse outcomes from infection are caused by overstimulation of the immune system in response to bacteria. This overreaction occurs by simultaneous ligation of two host receptors: TLR4 and RAGE. Both signal via a common downstream messenger, MyD88, triggering hyperinflammation. In summary, contrary to hundred-year-old postulations about immune suppression in diabetic hosts, we find that diabetes instead predisposes to more severe infections because of additional inflammatory output through dual activation of MyD88 by not only TLR4 but also RAGE. It is the activation of RAGE during GNB infections in those with diabetes that accounts for their heightened susceptibility to infection compared to nondiabetic hosts.

The investigational agent E1210 is effective in treatment of experimental invasive candidiasis caused by resistant Candida albicans.

The in vitro and in vivo activity of the inositol acyltransferase inhibitor E1210 was evaluated against echinocandin-resistant Candida albicans. E1210 demonstrated potent in vitro activity, and in mice with invasive candidiasis caused by echinocandin-resistant C. albicans, oral doses of 10 and 40 mg E1210/kg of body weight twice daily significantly improved survival and reduced fungal burden compared to those of controls and mice treated with caspofungin (10 mg/kg/day). These results demonstrate the potential use of E1210 against resistant C. albicans infections.

Benefits and harms of doxycycline treatment for Gulf War veterans' illnesses: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. OBJECTIVE: To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs. DESIGN: A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up. SETTING: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. PARTICIPANTS: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. INTERVENTION: Doxycycline, 200 mg, or matching placebo daily for 12 months. MEASUREMENTS: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. RESULTS: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, -6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. LIMITATIONS: Adherence to treatment after 6 months was poor. CONCLUSION: Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.

Cognitive behavioral therapy and aerobic exercise for Gulf War veterans' illnesses: a randomized controlled trial.

CONTEXT: Gulf War veterans' illnesses (GWVI), multisymptom illnesses characterized by persistent pain, fatigue, and cognitive symptoms, have been reported by many Gulf War veterans. There are currently no effective therapies available to treat GWVI. OBJECTIVE: To compare the effectiveness of cognitive behavioral therapy (CBT), exercise, and the combination of both for improving physical functioning and reducing the symptoms of GWVI. DESIGN, SETTING, AND PATIENTS: Randomized controlled 2 x 2 factorial trial conducted from April 1999 to September 2001 among 1092 Gulf War veterans who reported at least 2 of 3 symptom types (fatigue, pain, and cognitive) for more than 6 months and at the time of screening. Treatment assignment was unmasked except for a masked assessor of study outcomes at each clinical site (18 Department of Veterans Affairs [VA] and 2 Department of Defense [DOD] medical centers). INTERVENTIONS: Veterans were randomly assigned to receive usual care (n = 271), consisting of any and all care received from inside or outside the VA or DOD health care systems; CBT plus usual care (n = 286); exercise plus usual care (n = 269); or CBT plus exercise plus usual care (n = 266). Exercise sessions were 60 minutes and CBT sessions were 60 to 90 minutes; both met weekly for 12 weeks. MAIN OUTCOME MEASURES: The primary end point was a 7-point or greater increase (improvement) on the Physical Component Summary scale of the Veterans Short Form 36-Item Health Survey at 12 months. Secondary outcomes were standardized measures of pain, fatigue, cognitive symptoms, distress, and mental health functioning. Participants were evaluated at baseline and at 3, 6, and 12 months. RESULTS: The percentage of veterans with improvement in physical function at 1 year was 11.5% for usual care, 11.7% for exercise alone, 18.4% for CBT plus exercise, and 18.5% for CBT alone. The adjusted odds ratios (OR) for improvement in exercise, CBT, and exercise plus CBT vs usual care were 1.07 (95% confidence interval [CI], 0.63-1.82), 1.72 (95% CI, 0.91-3.23), and 1.84 (95% CI, 0.95-3.55), respectively. The OR for the overall (marginal) effect of receiving CBT (n = 552) vs no CBT (n = 535) was 1.71 (95% CI, 1.15-2.53) and for exercise (n = 531) vs no exercise (n = 556) was 1.07 (95% CI, 0.76-1.50). For secondary outcomes, exercise alone or in combination with CBT significantly improved fatigue, distress, cognitive symptoms, and mental health functioning, while CBT alone significantly improved cognitive symptoms and mental health functioning. Neither treatment had a significant impact on pain. CONCLUSION: Our results suggest that CBT and/or exercise can provide modest relief for some of the symptoms of chronic multisymptom illnesses such as GWVI.

Immunological responses are not abnormal in symptomatic Gulf War veterans.

The underlying etiology and pathogenesis of Gulf War veterans' illnesses continue to be under intense investigation. Reports have suggested the basis for these illnesses may be an altered immune system, but compelling evidence is lacking. We sought to determine whether in vitro immune responses were abnormal in symptomatic Gulf War veterans relative to matched controls. A randomized case-control study was conducted by blinded comparison of laboratory measures of in vitro immune responses in blood samples obtained from veterans in an outpatient facility of a Veterans Affairs medical center. Symptomatic Gulf War veterans with otherwise undefined illnesses (52 symptomatic subjects), asymptomatic Gulf War veterans (31 asymptomatic controls), and veterans who had applied for disability compensation and had not participated in the Gulf War (21 disability controls) represented the volunteer sample. In vitro cellular and humoral immune responses were measured to detect functional abnormalities in antigen presenting cells (autologous mixed leukocyte reactions and expression of interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor-alpha); T cells (lymphocyte proliferation using the polyclonal T-cell activators phytohemagglutinin and Concanavalin A; primary immune responses in allogeneic mixed leukocyte reactions; secondary immune response using the recall antigens tetanus toxoid, Candida albicans, and anthrax vaccine; and soluble IL-2 receptor expression); type-1 T-helper cells (gamma interferon expression); type-2 T-helper cells (IL-4 and IL-10 expression); and B cells (polyclonal B-cell activator pokeweed mitogen-induced immunoglobulin production). In general, immune response measures did not differ significantly between groups. Heightened responses observed in the disability control group (sporadically greater responses to one mitogen and two antigens) and the Gulf War participation control group (greater recall responses to anthrax vaccine) did not suggest impaired immune cell function in symptomatic veterans when compared with controls. We conclude that in vitro immunological responses are not abnormal in symptomatic Gulf War veterans.

Misoprostol Modulation of Dendritic Cell Function in Immune Responses.

Dendritic cells (DC) from blood and other tissues are potent accessory cells for primary immune responses. Because prostaglandins from monocytes and macrophages can suppress DC and T-cell function, we sought to investigate the binding properties of misoprostol (MPL), a prostaglandin E(1) analog, and its regulation of DC function. Results of mouse and human experiments have suggested 1) that MPL could significantly inhibit DC-induced T-cell proliferation in oxidative mitogenesis and allogeneic mixed leukocyte reactions by decreasing interleukin-2 production in DC-T cell cocultures, and 2) that MPL could bind to human peripheral blood mononuclear cells via specific high-affinity MPL binding sites as well as through nonspecific MPL uptake. Taken together, these data suggest that MPL can bind high-affinity and/or nonspecific cell surface receptors and subsequently regulate T-cell growth and cytokine production such as that induced by DC and associated with primary immune responses.