Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B).

Neurogenic orthostatic hypotension (nOH) results from failure of norepinephrine responses to postural change to maintain standing systolic blood pressure (s-SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinson's disease (PD) and symptomatic nOH. Subjects underwent up to 2 weeks of double-blind titration of droxidopa or placebo, followed by 8 weeks of double-blind maintenance treatment (100-600 mg thrice-daily). For the initial 51 subjects (study nOH306A, previously reported), the primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate significant change versus placebo at maintenance week 8. For the subsequent 171 subjects (study nOH306B, reported here), the primary efficacy measure was change versus placebo on item 1 ("dizziness, lightheadedness, feeling faint, or feeling like you might black out") of the Orthostatic Hypotension Symptom Assessment (OHSA) subsection of the OHQ at maintenance week 1. At week 1, mean (standard deviation) improvement on OHSA item 1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P = 0.018). In addition, mean increase in s-SBP at week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18) mmHg for placebo (nominal P value: 0.032). Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse-event (AE) incidence was similar across groups, but 12.4% of droxidopa and 6.1% of placebo subjects withdrew because of AEs. The most common AEs on droxidopa (vs. placebo) were headache (13.5% vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study nOH306B demonstrated subjective (OHSA item 1) and objective (s-SBP) evidence of short-term droxidopa efficacy (vs. placebo) for symptomatic nOH in PD.

Induction of CD4-independent E7-specific CD8+ memory response by heat shock fusion protein.

Infection with human papillomavirus type 16 (HPV16) is strongly associated with a number of disease states, of which cervical and anal cancers represent the most drastic endpoints. Induction of T-cell-mediated immunity, particularly cytotoxic T lymphocytes (CTL), is important in eradication of HPV-induced lesions. Studies have shown that heat shock protein fusion proteins are capable of inducing potent antigen-specific CTL activity in experimental animal models. In addition, E7-expressing tumors in C57BL/6 mice can be eradicated by treatment with HspE7, an Hsp fusion protein composed of Mycobacterium bovis BCG Hsp65 linked to E7 protein of HPV16. More importantly, HspE7 has also displayed significant clinical benefit in phase II clinical trials for the immunotherapy of HPV-related diseases. To delineate the mechanisms underlying the therapeutic effects of HspE7, we investigated the capability of HspE7 to induce antigen-specific protective immunity. Here, we demonstrate that HspE7 primes potent E7-specific CD8(+) T cells with cytolytic and cytokine secretion activities. These CD8(+) T cells can differentiate into memory T cells with effector functions in the absence of CD4(+) T-cell help. The HspE7-induced memory CD8(+) T cells persist for at least 17 weeks and confer protection against E7-positive murine tumor cell challenge. These results indicate that HspE7 is a promising immunotherapeutic agent for treating HPV-related disease. Moreover, the ability of HspE7 to induce memory CD8(+) T cells in the absence of CD4(+) help indicates that HspE7 fusion protein may have activity in individuals with compromised CD4(+) functions, such as those with invasive cancer and/or human immunodeficiency virus infection.