Selective modulation of nicotinic receptors of the guinea pig ileum by NSAIDS: Implication of COX -1 isoform

Prostaglandins have been shown to modulate nicotinic receptors in the myenteric plexus of the guinea pig ileum. The present study investigated the effects of selective and non-selective Cox inhibitors on DMPP- and ACh-induced contraction of the isolated guinea pig ileal muscle strips. 1. Diclofenac Na [5-40 micro M], Indomethacin Na [10-80 micro M], piroxicam [20-80 micro M], ketoprofen [100-800 micro M] or hexamethonium [2.5-20 micro M] produced a dose dependent inhibition of DMPP-induced contractions. The IC50 was 5.15 +/- 1.08, 24.84 +/- 2.51, 31.37 +/- 7.25, 156.04 +/- 28.2 and 5.89 +/- 0.74 for each drug respectively. 2. values of the pD showed that diclofenac was the most potent followed by hexamethonium, indomethacin, piroxicam and Ketoprofen. pD values amounted 5.29, 5.23, 4.6, 4.5, and 3.81 for each drug respectively. 3. The selective Cox-2 inhibitors celecoxib [10-40 micro M] and Nimesulide [20-160 micro M] but not Rofecoxib [10-40 micro M] showed also similar inhibitory activity against DMPP-induced contractions. The IC50 amounted 9.66 +/- 0.89, 122.49 +/- 12.37 and pD values were 5.02 and 3.91 for celecoxib and nimesulide respectively. 4. NSAIDs and hexamethonium affected slightly ACh-evoked contraction in a dose-independent manner. 5. All of the studied non-selective NSAIDs failed to reduce DMPP- or ACh- evoked contracture of the frog rectus abdominis muscle. In conclusion, all the tested NSAIDs, except rofecoxib, showed significant inhibition of contraction evoked by the ganglion stimulant DMPP. This may reflect the involvement of Cox-1, rather than Cox-2, metabolites in the process of ACh release due to nicotinic receptor stimulation. This mechanism, however, is not applicable to the nicotinic skeletal muscle receptors at the motor end plate

Effects of cypermethrin on lipid peroxidation and some antioxidant defense mechanisms in rats

Reactive oxygen species [ROS] have been implicated in the toxicity of various insecticides. Pyrethroids, though having the advantage of low mammalian toxicity, have been reported to produce signs of toxicity Most of these are linked to skeletal muscles. The present study tests the ability of single or repeated administration of Cypermethrin, a type II pyrethroids. to induce lipid peroxidation [LPO] in die rat brain, liver and diaphragm tissues. The study included the effect on antioxidant parameters, reduced glutathione [GSH], glutathione peroxidase [GPX], superoxide dismutase [SOD], and the protective effect of vitamin E. Single and repeated [7 days] administration of Cypermethrin [1/10 LD] induced lipid peroxidation in the rat diaphragm, while the brain and liver showed significant lipid peroxidation upon repeated administration only. This was manifested as elevation of the marker malondialdehyde [MDA]. The antioxidant defense parameter. GSH. GPX and SOD were not affected by single dose of Cypennethrin. in the rat brain or liver tissues. while, in the rat diaphragm a significant reduction in glutathione peroxidase was evident. In the rat diaphragm, repeated administration of Cypermethrin increased the level of GSH while decreased GPX activity. No significant effect was shown on the rat brain or iiver tissues. SOD activity was significantly reduced ia he diaphragm while the brain and the liver showed significant increase in the enzyme activity. Prior administration of vitamin E effectively antagonized the changes in LPO and the antioxidant parameters GSH, GPX and SOD induced by Cypennethrin. In conclusion, Cypermethrin induced LPO and an increase in the ROS. This may be linked to the mechanism underlying its insecticidal action as well as its adverse effects. Vitamin E is an effective agent to protect against the lipid peroxydative s power of Cypermethrin

Topical capsaicin-curcumin combination: an effective therapy for chronic painful distal symmetric polyneuropathy in diabetic patients

Chronic distal symmetric polyneuropathy [CDP] is the most common form of diabetic neuropathy. In chronic [lasting>12 months] painful CDP, the patient suffers from paresthesia and pain, that may lead to disability with daily activities and even sleep. In this work, evaluation of the efficacy of topical application of a curcumin cream formula [0.05%], as a novel indication for treatment of CDP, was guarantied. The efficacy of a capsaicin-curcumin combination [CCC] cream was also tested. Subjects and This study included 120 known diabetic patients coming for follow up, aged 23-63 years, 37 with type 1 and 83 with type 2 DM. The patients were randomly allocated into 4 groups: group 1 applied topical cream base and served as controls. Group 2 applied topical 0.075% capsaicin cream. Group 3 applied topical 0.05% curcumin cream and group 4 applied topical cream containing 0.075% capsaicin plus 0.05% curcumin [combination]. All groups were given the medication as water washable cream, applied topically, 4 times daily for 2 months. The two cream formulas showed a remarkable relief of CDP associated symptoms. As compared to a standard capsaicin cream [0.075%] and a cream base that served as placebo. At the end of study period of 2 months, the overall percentage of patients showing improved and 89.3% for placebo, capsaicin, curcumin and neuropathic symptoms was 20.7%, 70%, 78.5% curcumin-capsaicin combination, respectively [P<0.0001]. The percentage of patients without neuropathic symptoms was 3.4%, 20%, 26% and 42.9% for the four groups, respectively [P<0.0001]. Moreover, pain score declined from 4.2 +/- 0.5, 4. 3 +/- 0.3, 3.9 +/- 0.6 and 4.2 +/- 0.4 [P>0.05] before treatment to 4.0 +/- 0.5, 3.1 +/- 0.3, 2.9 +/- 0.5 and 1.2 +/- 0.3 [P<0.0001] after treatment with placebo, capsaicin, curcumin or their combination, respectively. The onset of gaining pain relief was evident from the first week of treatment, with the highest number of patients reporting pain relief with the combination therapy. Conclusions: Our clinical observations report, for the first time, that topical application of curcumin cream [0.05%] has a beneficial effect in alleviating symptoms associated with CDP. The clinical observations also suggest that a cream containing a combination of 0.075% capsaicin plus 0.05% curcumin is an effective, noninvasive treatment modality for the management of CDP