Harpagophytum procumbens (Hp), commonly known as Devil's Claw is a perennial plant which thrives in arid conditions. For centuries, it has been used as a traditional treatment for a variety of illnesses, including fevers, skin complaints, arthritis and diseases of the digestive tract as well as an appetite stimulant. Since its introduction to Europe in the early twentieth century, it has become a popular antiinflammatory and analgesic preparation amongst herbalists for supportive or adjuvant treatment of degenerative joint diseases, tendonitis, headache, backache and menstrual pain. The validity of Hp as an effective antiinflammatory and analgesic preparation, particularly in the relief of arthritic symptoms, has been investigated in numerous animal, clinical and in vitro studies. Although some contradictory evidence exists, the majority of animal studies appear to indicate Hp as an effective antiinflammatory and analgesic preparation in the treatment of acute and subacute inflammation. Clinical trials support Hp as a beneficial treatment for the alleviation of pain and improvement of mobility in a variety of musculoskeletal conditions. Analysis of the in vitro and ex vivo studies that currently exist, indicate that Hp has significant effects on numerous proinflammatory markers. However, the exact mechanism(s) by which Hp may reduce inflammation remain to be elucidated.

This study provides clear evidence that acute exposure to MDMA results in cerebrovascular dysfunction. The uncoupling of LCBF from underlying metabolic demand, possibly due to the vasoconstrictor action of 5-HT, could provide the basis for oligaemia-induced pathological changes in the brain.

The effect of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), upon integrated cerebral function was measured in rats using the quantitative [14C]deoxyglucose autoradiographic technique. Animals were injected with MDMA (20 mg/kg sc) twice daily for 4 days. Fourteen days after the final administration, [3H]-paroxetine binding to 5HT uptake sites was reduced by 89% in membranes prepared from tissue samples of frontal cortex. In the same rats [3H]-paroxetine binding autoradiography revealed heterogeneity in the regional distribution of 5-HT uptake site depletion within neocortex (0-92%) and hippocampus (30-95%). Despite these profound reductions in 5-HT uptake sites no significant alterations were found in glucose utilisation in any area of neocortex examined. However, significant increases in glucose use were found in subregions of the hippocampus, most notably within the pyramidal cell layer of CA2 and CA3 (25-35%). This study provides direct evidence that the loss of 5-HT innervation caused by exposure to MDMA results in lasting functional changes in hippocampus.

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1 In this study we have examined methylenedioxymethamphetamine (MDMA)-induced toxicity in perinatal rat brain, related this to normal development of serotonin transporter sites (SERT), and determined whether early exposure to MDMA subsequently alters cerebral function in adults. 2 Perinatal development of SERT was visualized and quanti®ed using [ 3 H]-paroxetine binding autoradiography in embryonic and neonatal rat brain from embryonic day 15 (E15) to postnatal day 30 (P30). Cerebral glucose utilization (lCMR glu ) was measured by 2-deoxyglucose autoradiography in adult rats. 3 [ 3 H]-Paroxetine binding was observed in forebrain from E18. From birth (P0), binding was organized into neocortical columns (75% higher at P10 than in adult) which declined toward adult levels between P20 and P25. 4 MDMA treatment (20 mg kg 71 s.c. twice daily for four days) commencing at developmental stages from E15 (treatment given to dams) to P20, had no e ect upon [ 3 H]-paroxetine binding measured at P40. Treatments started on P25 or later resulted in signi®cant decreases in [ 3 H]-paroxetine binding (546%). This was coincident with the development of adult patterns of binding in forebrain. 5 Despite the lack of MDMA-induced neurotoxicity, rats treated in utero (E15) showed increased lCMR glu in locus coeruleus (+37%), and in areas receiving ascending noradrenergic innervation, such as anterior thalamus (+44%) and septal nucleus (+24%). 6 These studies con®rm that the susceptibility of serotonergic terminals to the neurotoxic properties of MDMA is absent in the immediate perinatal period, but also suggests that in utero MDMA exposure produces signi®cant long-term e ects on cerebral function by a mechanism as yet unknown.

Acutely, 3,4,-methylenedioxymethamphetamine (MDMA) induces cerebrovascular dysfunction [Quate et al., (2004)Psychopharmacol., 173, 287-295]. In the longer term the same single dose results in depletion of 5-hydroxytrptamine (5-HT) nerve terminals. In this study we examined the cerebrovascular consequences of this persistent neurodegeneration, and the acute effects of subsequent MDMA exposure, upon the relationship that normally exists between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu). Dark agouti (DA) rats were pre-treated with 15 mg/kg i.p. MDMA or saline. Three weeks later, rats from each pre-treatment group were treated with an acute dose of MDMA (15 mg/kg i.p.) or saline. Quantitative autoradiographic imaging was used to measure LCBF or LCMRglu with [(14)C]-iodoantipyrine and [(14)C]-2-deoxyglucose, respectively. Serotonergic terminal depletion was assessed using radioligand binding with [(3)H]-paroxetine and immunohistochemistry. Three weeks after MDMA pre-treatment there were significant reductions in densities of 5-HT transporter (SERT)-positive fibres (-46%) and [(3)H]-paroxetine binding (-47%). In animals pre-treated with MDMA there were widespread significant decreases in LCMRglu, but no change in LCBF indicating a persistent loss of cerebrovascular constrictor tone. In both pre-treatment groups, acute MDMA produced significant increases in LCMRglu, while LCBF was significantly decreased. In 50% of MDMA-pre-treated rats, random areas of focal hyperaemia indicated a loss of autoregulatory capacity in response to MDMA-induced hypertension. These results suggest that cerebrovascular regulatory dysfunction resulting from acute exposure to MDMA is not diminished by previous exposure, despite a significant depletion in 5-HT terminals. However, there may be a sub-population, or individual circumstances, in which this dysfunction develops into a condition that might predispose to stroke.

Arthritis and other rheumatic conditions (AORC) are the leading cause of disability, are associated with poor quality of life and incur considerable direct and indirect costs. It is considered that the instance of AORC will continue to increase. To assess the effectiveness, safety and tolerability of Harpagophytum (Bioforce) in the treatment of AORC, a single group open study of 8 weeks duration (259 patients) was performed in the United Kingdom. Effectiveness was assessed by numeric rating scales, the Western Ontario and McMasters Universities Osteoarthritis (WOMAC) Index and the Algofunctional Hand Osteoarthritis Index. Tolerance was measured by a numeric rating scale and safety by self-reporting, blood analysis and liver function tests. Quality of life was measured by SF-12 questionnaire. There were statistically significant (p < 0.0001) improvements in patient assessment of global pain, stiffness and function. There were also statistically significant reductions in mean pain scores for hand, wrist, elbow, shoulder, hip, knee and back pain. Quality of life measurements (SF-12) were significantly increased from baseline and 60% patients either reduced or stopped concomitant pain medication. Harpagophytum is an effective and well-tolerated serious treatment option for mild to moderate degenerative rheumatic disorders providing improved quality of life measure.

1 A new, modified rat two vessel occlusion model (with hypotension) was established and the neuroprotective efficacy of the novel agent lifarizine (RS-87476) was examined. 2 The two vessel occlusion model used in the study was a modification of the model described in the literature, whereby we have obviated the need to use a muscle relaxant and intubate the trachea to provide ventilatory support by providing a tight fitting face mask attached to the ventilator. Furthermore, the need to combine exsanguination and additional pharmacological means of inducing the mandatory hypotension (50 mmHg), required to decrease brain blood perfusion pressure, has been removed by simply manipulating the concentration of the already present halothane anaesthetic. 3 The appropriate level of hypotension having been reached, microvascular clips were applied to bilaterally occlude the common carotid arteries for 12 min. This resulted in a loss of the cortical EEG activity. Local cerebral blood flow was measured 6 min into the occlusion period, using the fully quantitative ["4C]-iodoantipyrine autoradiographic technique, in a separate group of rats (n = 5). This illustrated the lack of any blood flow, in the areas under study, during the period when there was an isoelectric cortical EEG pattern. 4 The high grade global ischaemic lesion which occurred gave quantifiable neuronal damage in several vulnerable regions of the brain, namely, the hippocampal CA, sub-field, cortex, thalamus, striatum, and cerebellar brain stem (Purkinje cells). 5 Following the global ischaemic insult the rats were allowed to recover for 72 h before assessment of the damage, during which time one group of rats (n = 11) received 100 jig kg-1 lifarizine i.a. 5 min postocclusion, 500 jig kg-' lifarizine i.p. 15 min post-occlusion, and 500 jug kg-' lifarizine i.p. twice daily for 72 h. A second group of rats (n = 12) was treated with appropriate volumes of vehicle (0.4 ml kg-' i.a. and 2 ml kg-' i.p.) at identical time points. 6 Histopathological damage was assessed, from cresyl violet and haematoxyline/eosin stained sections, using a scoring system of 0-6 (no damage -complete neuronal death). The dosing regimen of lifarizine gave reduced damage in the hippocampal CA, sub-field (4.1 0.3 to 2.8 + 0.6) and striatum (1.7 0.3 to 1.2+0.3) and significant neuroprotection in the anterior cortex (2.0+0.2 to 1.2+0.2; P<0.05), thalamus (1.5+0.2 to 0.8+0.2; P<0.01), posterior cortex (1.5±0.2 to 1.0+0.2; P<0.05) and cerebellar brain stem (0.9+0.2 to 0.4+0.1; P<0.01). The overall mean brain score was significantly reduced (from 1.5+0.1 to 0.9+0.2). 7 These data show that the newly modified 2 vessel occlusion model produced a quantifiable level of ischaemic damage and that the novel agent lifarizine is neuroprotective in the model.