Adel A. Gomaa

A selective phosphodiesterase IV inhibitor, rolipram blocks both withdrawal behavioral manifestations, and c-Fos protein expression in morphine dependent mice

We investigated the effect of rolipram, a selective phosphodiesterase IV inhibitor, on morphine dependence in mice. The withdrawal manifestations were significantly reduced in mice that were treated with rolipram in combination with morphine repeatedly, compared to the mice treated with morphine and saline. Immunohistochemical study of c-Fos protein revealed a significant increase in the protein expression, 1 h after naloxone induced withdrawal manifestations. A combination of rolipram and morphine treatment for 5 days prevented the increase of c-Fos protein expression. Acute rolipram treatment prior to the naloxone challenge had no effect. Repeated treatment with rolipram itself had no effect either on behavior, or on c-Fos protein expression. These results suggest that chronic rolipram treatment in combination with morphine in mice will abolish the development of morphine dependence and the expression of c-Fos protein induced by naloxone challenge.

Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence: an association with cortical Ca2+/calmodulin-dependent signal cascade.

We investigated how dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, affects the development of morphine dependence in mice. Co-administration of dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days attenuated the development of tolerance to the antinociceptive effects of morphine. The withdrawal manifestation induced by the naloxone-challenge (5 mg/kg) was significantly reduced in mice that were treated with a combination of dizocilpine and morphine, compared to the mice treated with morphine and saline. The present study revealed a significant increase in c-Fos protein expression in the cortex and thalamus of mice showing naloxone-precipitated withdrawal syndrome. The combination of dizocilpine and morphine prevented the increase of c-Fos protein expression in the cortex and thalamus. Interestingly, repeated co-administration of dizocilpine and morphine prevented the withdrawal-induced phosphorylation of Ca2+/calmodulin kinase II (p-CaMK II) in the cortex, but not in the thalamus. Acute dizocilpine treatment prior to the naloxone-challenge and repeated treatment with dizocilpine alone had no effect on analgesia, withdrawal manifestations, p-CaMK II levels or c-Fos protein levels. These results showed that co-administration of dizocilpine and morphine prevented the development of morphine tolerance and dependence and suggested that the preventive effect of dizocilpine results from the regulation of c-Fos protein expression, which is possibly involved in the activation of the Ca2+/calmodulin-dependent signal cascade in the cortex.

Hormonal changes during the first year of use of subdermal levonoregestrel implants, NORPLANT®

Sixty-three women had NORPLANT implants inserted during the first eight days of the menstrual cycle. Blood specimens were withdrawn at the time of insertion and every three days during one of the following months of observation; the first, third, sixth, ninth and twelfth month after insertion. Ten subjects were sampled at multiple times during implant use. A total of 83 months of observation was available. The serum concentrations of levonorgestrel (LNG), FSH, LH, prolactin (PRL), estradiol (E2) and progesterone (prog) were measured in each specimen. LNG concentration rapidly declined during the first 15 days of use, the decline became more gradual during the subsequent two weeks, and an almost steady level was reached during the remainder of the year. There were no significant trends of change in the levels of FSH, LH, E2 and prog during the year. Frequent peaks in E2 concentration were observed and were generally associated with or followed by LH surges. PRL concentration showed a slight but significant rise during the second half of the year. Rises in prog concentration suggestive of ovulation occurred in 36 percent of the months of observation. However, in all these instances, there were evidences suggestive of deficient luteal phase. The bleeding episodes were usually, but not always, related to decline in E2 and prog concentrations.

Modification of morphine-induced analgesia, tolerance and dependence by bromocriptine

The effect of two doses of bromocriptine, a dopamine agonist, on morphine-induced analgesia, tolerance and dependence was investigated in mice. Bromocriptine at doses of 0.04 and 0.08 mg/kg did not affect the baseline tail flick latency of mice but potentiated the morphine analgesia. Pretreatment of mice with 5 mg/kg of sulpiride, a D-2 antagonist, not only blocked the effect of 0.08 mg/kg of bromocriptine but also antagonized the morphine analgesia. Control animals given daily injections of 10 mg/kg of morphine rapidly developed tolerance to the analgesic effect. A combined treatment of bromocriptine with morphine given daily suppressed the development of tolerance to morphine analgesia. However, development of tolerance to morphine analgesia was not significantly modified in the animals treated daily with bromocriptine (0.08 mg/kg) plus sulpiride (5 mg/kg). Acute dependence was induced by the administration of 100 mg/kg of morphine. The administration of bromocriptine 30 min before naloxone significantly decreased the ED50 value for naloxone for inducing jumping in mice. Coadministration of sulpiride and bromocriptine attenuated the ability of bromocriptine to potentiate the withdrawal syndrome of morphine dependence. The results indicate that bromocriptine potentiates morphine analgesia, suppresses the development of tolerance to morphine analgesia but exacerbates opiate withdrawal signs in morphine-dependent mice. These effects of bromocriptine appear to be mediated via D-2 receptors.

Levonorgestrel concentrations in maternal and infant serum during use of subdermal levonorgestrel contraceptive implants Norplant by nursing mothers.

The transfer of levonorgestrel to infants was studied in 42 lactating women in whom the contraceptive subdermal implants, Norplant, were inserted 30 to 40 days postpartum. The women breastfed their infants for one year. Simultaneous mother and infant blood samples were taken once during the year. The levonorgestrel serum concentrations were measured by radioimmunoassay. During the first postinsertion month, the levonorgestrel concentration in the infants serum amounted, on the average, to 5% of the maternal concentration. Thereafter, the ratio ranged from 8 to 13%. The implications of this finding are discussed.

Dual effect of nitric oxide donor on adjuvant arthritis

The effect of medical use of NO donors on the pathogenesis of arthritis is still yet unclear. We investigated the effects of the NO donor, sodium nitroprusside (SNP), on the pathogenesis of adjuvant-induced arthritis in rats. Rats were given SNP intraperitoneally either from day 5 to day 14 (as a prophylactic protocol) or from day 16 to day 25 (as a therapeutic protocol) after inoculation of adjuvant. SNP administration, whether prophylactic or therapeutic, in doses of 0.1 and 1 mg/kg/d significantly aggravated pathogenesis of adjuvant arthritis in rats. SNP-treated rats showed significant (P<0.05) increase in arthritis index, hind paw volume, ankle joint diameter and hyperalgesia compared with control adjuvant arthritic rats. However, in adjuvant rats given the smallest dose of SNP (0.01 mg/kg/d), arthritis index, volume of hind paws, ankle joint diameter, body weight loss, and hyperalgesia were significantly lower than that of control adjuvant rats. After 30 d of the induction of adjuvant arthritis, TNF alpha levels exhibited insignificant changes either in control adjuvant rats or in rats given SNP compared with control non adjuvant rats. IL-10 levels in adjuvant control rats and adjuvant rats given 1 mg or 0.1 mg/kg/d from day 15 to day 25 were significantly lower than that of control non adjuvant rats. Histopathology examination of ankle joint showed that large doses of SNP (1 mg or 0.1 mg/kg/d) increased the mononuclear cells infiltration and erosion of cartilage induced by adjuvant while the infiltration of the inflammatory cells in the synovium of adjuvant rats treated with 0.01 mg/kg/d was minimal and the pannus was inhibited with alleviation of erosion of articular cartilage. Prophylactic small dose of SNP improved the histological status more than the therapeutic small dose. The present work reveals that SNP administration, either prophylactic or therapeutic, was deleterious in higher doses. However, the smallest dose used 0.01 mg/kg/d attenuates joint inflammation, hyperalgesia and body weight loss in adjuvant arthritic rats. These results suggest that small dose of NO donor may exert partial protective effects while the safety of the clinical use of NO donors, in higher doses, in patients with rheumatoid arthritis is questioned.

The effect of topically applied vasoactive agents and testosterone versus testosterone in the treatment of erectile dysfunction in aged men with low sexual interest

The objective was to evaluate the efficacy and safety of topically applied cream containing testosterone, isosorbide dinitrate and co-dergocrine mesylate compared to testosterone cream in the treatment of erectile dysfunction in aged men with low sexual interest. A randomised double-blind crossover trial was performed over two months. The subjects were 42 men with erectile dysfunction and low normal or slightly depressed testosterone level randomly allocated to two equal groups. Polypharmacy cream containing testosterone 0.8%, isosorbide dinitrate 0.5% and co-dergocrine mesylate 0.06% was applied for one month, and testosterone 0.8% cream for another month. The serum level of total testosterone was measured before and after each phase of treatment. Response to each therapy was assessed by a sexual questionnaire, measurement of tumescence and repeat penile duplex ultrasonography. Twenty-eight patients reported full erection and satisfactory intercourse with the polypharmacy cream. Thirteen men reported full erection and satisfactory intercourse with either cream. Polypharmacy cream increased penile arterial flow (P<0.001) and induced tumescence in 34 patients in lab. No patient in either phase of the study has tumescence or a significant increase in cavernous arterial peak systolic velocities after the application of testosterone cream. Serum level of total testosterone increased in all patients (P<0.05). Sexual desire was improved in 85% and 62% of patients during the treatment with polypharmacy cream and testosterone cream, respectively. No marked side effects were reported after either of them. Topical treatment with cream containing testosterone and vasoactive agents may represent a new effective treatment for erectile dysfunction associating with aging.

Enhancement of the anti‐inflammatory and anti‐arthritic effects of theophylline by a low dose of a nitric oxide donor or non‐specific nitric oxide synthase inhibitor

Background and purpose:  Although there are many new specific phosphodiesterase inhibitors with anti‐inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti‐inflammatory and anti‐arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L‐NG‐monomethyl arginine (L‐NMMA) on its actions.

Influence of dipyridamole and its combination with NO donor or NO synthase inhibitor on adjuvant arthritis

The anti-arthritic and anti-inflammatory effects of dipyridamole and the possible involvement of NO in the dipyridamole action are not yet clear. The aim of this study was to evaluate the effects of dipyridamole alone and in combination with either the nitric oxide donor, sodium nitroprusside (SNP) or the non-selective nitric oxide synthase inhibitor, L-NG- monomethyl arginine (L-NMMA), on pathogenesis of adjuvant-induced arthritis model in rats. The results of the present work showed that prophylactic administration of dipyridamole alone and dipyridamole administration in combination with either low dose of SNP or L-NMMA significantly ameliorated pathogenesis of adjuvant arthritis in rats as evidenced by significant decrease in arthritis index, hind paws volume, loss of body weight, hyperalgesia compared with control vehicle (1% DMSO) treated adjuvant arthritic rats. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10(IL-10) levels were significantly increased in these groups of animals. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of dipyridamole. The inhibitory effect of therapeutic administration of dipyridamole alone on adjuvant arthritis syndrome was not significantly different from that of vehicle administration. In conclusion, dipyridamole has prophylactic but not therapeutic anti-arthritic and anti-inflammatory effects that appear to be dependent on inhibition of NO synthase. A synergistic combination between dipyridamole and NO synthase inhibitor or low dose of NO donor may have prophylactic and therapeutic values in autoimmune diseases like RA.

Inhibition of adiposity and related metabolic disturbances by polyphenol-rich extract of Boswellia serrata gum through alteration of adipo/cytokine profiles

BackgroundThe role of proinflammatory cytokines in adiposity is well established. The anti-inflammatory and antihyperglycemia effects of Boswellia serrata (B. Serrata) gum have been demonstrated by many investigators. The present study aimed to investigate the anti-obesity potential of B. serrata extract.MethodsThe effects of B. serrata extract on lipase activity and acute food intake were investigated. The present study aimed to investigate the anti-obesity potential of B. serrata extract. The effects on lipase activity and acute food intake were investigated. Body weight changes, biochemical and histopathological markers were demonstrated in rats fed a high-fat diet.ResultsBoswellia serrata extract inhibited alterations in pancreatic lipase activity, but orlistat was more efficacious. B. serrata and ephidrene, but not orlistat, significantly suppressed cumulative food intake in mice. In obese rats, B. serrata or orlistat significantly decreased weight gain and weight of visceral white adipose tissue. B. serrata-treated animals exhibited a significant reduction in serum glucose, TC, TG, LDL-C, FFA, IL-1β, TNF-α, insulin and leptin levels of obese rat groups while HDL-C and adiponectin levels were significantly increased by orlistat or B. serrata extract. Histopathological examination of the liver revealed that B. serrata was more effective than orlistat in alleviating steatosis and adipocyte hypertrophy shown in obese control rats.ConclusionsBoswellia serrata is as effective as orlistat in preventing obesity, hyperlipidemia, steatosis and insulin resistance. These actions may be mediated by suppression of food intake and decrease levels of TNF-α, IL-1β and leptin resistance along with increasing adiponectin.