Guidelines for Trials of Behavioral Treatments for Recurrent Headache, First Edition: American Headache Society Behavioral Clinical Trials Workgroup

Guidelines for design of clinical trials evaluating behavioral headache treatments were developed to facilitate production of quality research evaluating behavioral therapies for management of primary headache disorders. These guidelines were produced by a Workgroup of headache researchers under auspices of the American Headache Society. The guidelines are complementary to and modeled after guidelines for pharmacological trials published by the International Headache Society, but they address methodologic considerations unique to behavioral and other nonpharmacological treatments. Explicit guidelines for evaluating behavioral headache therapies are needed as the optimal methodology for behavioral (and other nonpharmacologic) trials necessarily differs from the preferred methodology for drug trials. In addition, trials comparing and integrating drug and behavioral therapies present methodological challenges not addressed by guidelines for pharmacologic research. These guidelines address patient selection, trial design for behavioral treatments and for comparisons across multiple treatment modalities (eg, behavioral vs pharmacologic), evaluation of results, and research ethics. Although developed specifically for behavioral therapies, the guidelines may apply to the design of clinical trials evaluating many forms of nonpharmacologic therapies for headache.     

Deletion of aldose reductase leads to protection against cerebral ischemic injury.

Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR(-/-) brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR(-/-) brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron- and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.     

An update of treatment options for neovascular age-related macular degeneration.

OBJECTIVES: To review the role of conventional and new treatment modalities in the management of neovascular age-related macular degeneration. DATA SOURCES AND EXTRACTION: Literature search of Medline till March 2007, using the key words/terms 'treatment' and 'age-related macular degeneration' to retrieve relevant original papers and review articles. DATA SYNTHESIS: Age-related macular degeneration is the leading cause of irreversible visual loss in the elderly in developed countries. Neovascular age-related macular degeneration has a relentless course and the consequent visual loss is debilitating. Successful treatment has always been a challenge due to poor understanding of its pathogenesis. Laser photocoagulation and photodynamic therapy with verteporfin are the standard conventional treatments. However, these approaches do not prevent disease recurrence and repeated treatments are required. Recent advances in understanding the molecular pathway for the angiogenesis of neovascular age-related macular degeneration enables exploration of new treatment approaches. Antiangiogenic therapy with anti-vascular endothelial growth factor agents, such as pegaptanib and ranibizumab, have recently been approved for clinical practice. Other antiangiogenic agents include bevacizumab, triamcinolone, and anecortave are also being evaluated in clinical trials. Additional treatment modalities include transpupillary thermotherapy and surgical intervention. CONCLUSIONS: Regarding patients with neovascular age-related macular degeneration, increased understanding in its pathogenesis coupled with rapid development in instrumental technology and new/emerging medications greatly expands available treatment options. Despite these various therapeutic options, current treatment is mainly directed at achieving visual stabilisation. Restoration of vision with newer agents is limited and not possible in every patient. Thus, early recognition and treatment to arrest the progression of neovascular age-related macular degeneration is the preferred means of attaining the best visual outcome.     

3,4-Dichlorobenzyloxyacetic acid is extensively metabolized to a taurine conjugate in rats

The metabolism of the antisickling agent 3,4-dichlorobenzyloxyacetic acid (3,4-DCBAA) was examined after ip administration to rats. Within 5 days after administration of radiolabeled 3,4-DCBAA, 77.4 +/- 4.6% of the dose was recovered in the urine and only 3.2 +/- 0.5% was recovered in the feces. Metabolites in the urine were isolated and characterized by HPLC, electron impact MS, and LC/MS, and their identities were confirmed by comparing their spectra with those of synthetic standards. Quantitation of these urinary metabolites revealed that the majority of the radioactive dose was excreted as a taurine conjugate (60.1 +/- 4.4%), while lesser amounts were excreted as 3,4-dichlorohippurate, unchanged 3,4-DCBAA, the glycine conjugate of 3,4-DCBAA, and a polar unknown which is believed to be glycolic acid. A pathway involving an initial O-dealkylation at the benzyl carbon of 3,4-DCBAA and proceeding through the glycine conjugation of 3,4-dichlorobenzoic acid has been proposed to explain the formation of 3,4-dichlorohippurate and the polar unknown. The extensive conjugation of 3,4-DCBAA with taurine is an unprecedented observation in rats, which usually utilize glycine for amino acid conjugation reactions. Further studies with 3,4-DCBAA may provide insight into the enzymatic mechanisms of taurine conjugation, which are not well defined at this time.     

Further morphological and biochemical observations on early low dose streptozocin diabetes in mice.

Conflicting published data regarding the role of macrophages and other cell types during the early stages of diabetes mellitus led us to further study this problem. To this end we diabetized mice, using low doses of streptozocin (STZ), 40 mg/kg body wt/day/5 days, and processed their pancreatic tissue for immunocytochemistry and ultrastructural observations; immunohistochemistry was performed on days 5 and 18 after the first STZ injection, and islets were observed ultrastructurally on days 5, 9, 10, and 18. Animals were tested for fasting serum glucose, and isolated islets were assayed for insulin secretion capacity. Immunohistology demonstrated that expression of major histocompatability complex class 2 antigens is strongly induced by multiple, low dose STZ treatments prior to impaired insulin release, and that different types of cells within the islet are capable of expressing Ia molecules. Ultrastructurally we found (a) a small number of macrophages (most probably resident monocytes/macrophages) containing B-cell debris, that were located close to either damaged or intact B cells; (b) a large number of recruited macrophages in a vascular or perivascular position; and (c) macrophages recognizable in the exocrine portion, close to the islets, occasionally containing exocrine cell debris. This led us to believe that recruited macrophages play an important role in the early islet-infiltrating stage.