Study objective Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering ...progesterone to patients with acute traumatic brain injury. Methods This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale–Extended 30 days postinjury. Results Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale–Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. Conclusion In this small study, progesterone caused no discernible harm and showed possible signs of benefit.
Does Progesterone Have Neuroprotective Properties? Stein, Donald G., PhD; Wright, David W., MD; Kellermann, Arthur L., MD, MPH
Annals of emergency medicine,
02/2008, Letnik:
51, Številka:
2
Journal Article
Recenzirano
In this article, we review published preclinical and epidemiologic studies that examine progesterone’s role in the central nervous system. Its effects on the reproductive and endocrine systems are ...well known, but a large and growing body of evidence, including a recently published pilot clinical trial, indicates that the hormone also exerts neuroprotective effects on the central nervous system. We now know that it is produced in the brain, for the brain, by neurons and glial cells in the central and peripheral nervous system of both male and female individuals. Laboratories around the world have reported that administering relatively large doses of progesterone during the first few hours to days after injury significantly limits central nervous system damage, reduces loss of neural tissue, and improves functional recovery. Although the research published to date has focused primarily on progesterone’s effects on blunt traumatic brain injury, there is evidence that the hormone affords protection from several forms of acute central nervous system injury, including penetrating brain trauma, stroke, anoxic brain injury, and spinal cord injury. Progesterone appears to exert its protective effects by protecting or rebuilding the blood-brain barrier, decreasing development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis. All are plausible mechanisms of neuroprotection.
There is growing recognition that traumatic brain injury is a highly variable and complex systemic disorder that is refractory to therapies that target individual mechanisms. It is even more complex ...in elderly persons, in whom frailty, previous comorbidities, altered metabolism, and a long history of medication use are likely to complicate the secondary effects of brain trauma. Progesterone, one of the few neuroprotective agents that has shown promise for the treatment of acute brain injury, is now in national and international phase 3 multicenter trials. New findings show that vitamin D hormone (VDH) and VDH deficiency in the aging process (and across the developmental spectrum) may interact with progesterone and treatment for traumatic brain injury. In this article we review the use of progesterone and VDH as biologics-based therapies along with recent studies demonstrating that the combination of progesterone and VDH may promote better functional outcomes than either treatment independently.
Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide ...investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.
The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.
Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).
Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.
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