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1993
Khayyal, M. T., A. S. el-Khatib, M. El-Ghazaly, and A. Hatem, "Inhibition of leukotriene release by mofebutazone: a possible clinical advantage.", International journal of clinical pharmacology research, vol. 13, issue 5, pp. 255-61, 1993. Abstract

The isolated perfused lung preparation from actively sensitized guinea-pigs was used; after it was challenged with antigen, mediators such as histamine, prostaglandins and leukotrienes were released into the lung effluent. It was found that treatment of the perfused lungs before and during challenge with mofebutazone (10 micrograms/ml) inhibited the immunological release of prostaglandins as well as leukotrienes. Phenylbutazone, on the other hand, at the same dose level inhibited the release of prostaglandins, whereas the release of leukotrienes was much less affected by the drug. Histamine release was not altered by either drug. When clinically mofebutazone tablets (300 mg) were given as an analgesic twice daily for 15 days to a number of asthmatic volunteers including 3 aspirin-sensitive individuals, there was no increase in the incidence or intensity of the asthmatic attacks, even in the aspirin-sensitive patients. Pulmonary ventilatory functions which showed a certain obstructive pattern were not worsened by the treatment and even tended to be somewhat improved.

Khayyal, M. T., M. A. El-Ghazaly, and A. S. el-Khatib, "Mechanisms involved in the antiinflammatory effect of propolis extract.", Drugs under experimental and clinical research, vol. 19, issue 5, pp. 197-203, 1993. Abstract

Propolis is a natural product produced by the honey bee. The extract contains amino acids, flavanoids, terpenes and cinnamic acid derivatives. In various in vitro models propolis extract was shown to inhibit platelet aggregation and to inhibit eicosanoid synthesis, suggesting that it might have potent antiinflammatory properties. A 13% aqueous extract was tested orally in three dose levels (1, 5 and 10 ml/kg) on the carrageenan rat paw oedema model and on adjuvant-induced arthritis in rats. In both models, the extract showed potent dose-related antiinflammatory activity, which compared well with that of diclofenac (as a reference standard). The extract was then tested on an isolated sensitized guinea pig lung preparation to study its effect on the release of prostaglandins, leukotrienes and histamine. It is concluded that propolis extract has potent antiinflammatory properties in vivo. Its activity can be well correlated with its effects on the release of various mediators of inflammation.

1995
el-Khatib, A. S., and A. E. Khaleel, "EVALUATION OF SOME PHARMACOLOGICAL PROPERTIES OF DIFFERENT EXTRACTS OF BAUHINIA RACEMOSA LAM. LEAF AND BASSIA MURICATA L. WHOLE PLANT", Bull. Fac. Pharm. Cairo Uni, vol. 33, issue 2, pp. 59-65, 1995.
Mansour, M., A. S. el-Khatib, and O. El-Ahmady, "INHIBITED GENERATION OF LEUKOTRIENES FROM STIMULATED HUMAN LEUKOCYTES BY THE AQUEOUS EXTRACT OF PROPOLIS", Bull. Fac. Pharm. Cairo Uni, vol. 33, issue 2, pp. 75-79, 1995.
Khayyal, M. T., M. El-Ghazaly, A. S. el-Khatib, and A. Hatem, "Tolerability of mofebutazone in asthmatic patients.", International journal of clinical pharmacology research, vol. 15, issue 4, pp. 145-51, 1995. Abstract

Twenty-seven human volunteer asthmatic patients were each given one tablet of mofebutazone (300 mg) twice daily for 15 days. Pulmonary ventilatory function test (forced expiratory volume test) as well as bronchoalveolar lavage (BAL) were performed one day before initiation of treatment and one day after completion of the course; in the BAL, prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha) and leukotrienes (LTs) were also estimated. It was found that there was no increase in the incidence or severity of the asthmatic attacks during the course of mofebutazone treatment. The drug tended to improve the tested pulmonary ventilatory functions or at least to leave them unchanged. All the mofebutazone-treated individuals showed a dramatic reduction in the concentrations of PGE2, PGF2alpha and LTs in their BAL, but there was no consistent correlation between the extent of reduction and the degree of benefit or worsening sustained by any individual patient. It is evident from the present study that mofebutazone has shown good tolerability which was associated with an improvement in the pulmonary ventilatory functions, a fact that would seem to advocate the use of this non-steroidal antiinflammatory drug (NSAID) in asthmatic patients whenever a need for such therapy becomes necessary.

Agha, A. M., A. S. el-Khatib, S. A. Kenawy, and M. T. Khayyal, "The influence of carbon tetrachloride-induced liver damage on the inflammatory reaction elicited by carrageenan and its treatment with diclofenac.", Pharmacological research, vol. 32, issue 1-2, pp. 75-84, 1995 Jul-Aug. Abstract

The effect of impaired hepatic function on the development of the inflammatory process as well as on treatment with diclofenac was investigated. Carbon tetrachloride was used to induce liver injury and the elevation of serum transaminases was taken as evidence for impaired hepatic function. The carrageenan-induced rat hind paw oedema and the granuloma pouch were chosen as models of inflammation. The results of the study revealed that: (1) The intensity of inflammation in both models was markedly attenuated in CCl4-treated animals. (2) Serum total proteins were decreased in liver-injured animals particularly in acute experiments. (3) In liver-injured groups diclofenac showed more pronounced anti-inflammatory activity in chronic experiments, but not in acute ones. (4) Neither CCl4 nor diclofenac affected the levels of histamine and serotonin in the granuloma pouch exudate. The level of prostaglandins was decreased in CCl4 and in diclofenac-treated animals. At the same time, the leukotriene content was elevated. The mechanism by which CCl4 induced liver injury attenuates inflammatory response to carrageenan is not entirely understood. Its effect on protein metabolism and extravasation as well as on PG synthesis could play a possible role. Decreased drug metabolism may be, at least in part, responsible for the enhanced response of diclofenac in the cases of liver-injured animals. Dose adjustment of the drug in case of hepatic impairment might be necessary.

1996
Mahran, L. G., A. S. el-Khatib, A. M. Agha, and M. T. Khayyal, "The protective effect of aqueous propolis extract on isolated rat hepatocytes against carbon tetrachloride toxicity.", Drugs under experimental and clinical research, vol. 22, issue 6, pp. 309-16, 1996. Abstract

The protective effect of honeybee aqueous propolis extract (APE) against the hepatotoxicity of carbon tetrachloride was investigated using isolated liver-cell suspensions as the experimental model. Various concentrations of the extract were preincubated with the hepatocyte suspensions for 30 min before being subjected to the hepatotoxin for a further 30 min. The hepatocyte toxicity was assessed using three parameters, namely, the release of lactate dehydrogenase, the formation of lipid peroxides and the depletion of intracellular reduced glutathione. It was found that a dose-related protection against the induced cell injury was conferred by APE as evidenced by its inhibitory influence on the changes induced by CCl4 on the measured parameters. The hepatocyte protective effect of APE is probably a result of its antioxidant and free-radical-scavenging properties which in turn help to maintain the intracellular level of reduced glutathione.

1997
el-Khatib, A. S., "BIOLOGICALLY ACTIVE FREE RADICALS AND THEIR SCAVENGERS: A REVIEW", Saud. Pharm. J, vol. 5, issue 2-3, pp. 78-89, 1997.
1999
Agha, A. M., A. S. el-Khatib, and H. Al-Zuhair, "Modulation of oxidant status by meloxicam in experimentally induced arthritis.", Pharmacological research, vol. 40, issue 4, pp. 385-92, 1999 Oct. Abstract

Meloxicam is a new non-steroidal anti-inflammatory drug, that possesses a selective inhibition of the inducible isoform of cyclooxygenase enzyme (COX-2) relative to the constitutive one, COX-1. Oxidative stress has been documented to be involved in the aetiology of many pathological conditions. The present study aims to further explore the relationship between free radical generation and the inflammatory process, and extends more to investigate the effect of meloxicam on the oxidant status in experimentally induced arthritis, namely, Freund's adjuvant-induced arthritis in rats. Results of the present investigation revealed that animals inoculated with Freund's complete adjuvant showed a biphasic response regarding changes in the right hind paw oedema volume. During the chronic phase of the disease, arthritic animals showed an elevated plasma level of lipid peroxides, enhanced blood glutathione peroxidase activity, with depletion of plasma total thiols and albumin; while no significant effects have been observed on erythrocytic superoxide dismutase activity and plasma total proteins content, as compared to normal untreated rats. Long-term administration of meloxicam, at two dose levels, produced significant antioedemetous effect and succeeded in modulating the altered parameters affected during arthritis. The selected dose regimens of meloxicam did not show any apparent lesions in the gastric mucosa. The results of the present investigation lend further support to the reported observations concerning selective COX-2 inhibitors. The modulatory influence of meloxicam on the oxidant status, particularly on lipid peroxidation and thiols might be a relevant effect accounting for its anti-inflammatory properties.

2001
el-Khatib, A. S., A. M. Agha, and M. M. A. Elmazar, "CAFFEINE-INDUCED FETAL NEURAL TUBE DEFECTS IN MICE AND ITS INFLUENCE ON VALPROATE TERATOGENESIS", New Egypt. J. Med, vol. 25, issue 2, pp. 90-98, 2001.
Mansour, M. A., O. T. Ginawi, T. El-Hadiyah, A. S. el-Khatib, O. A. Al-Shabanah, and H. A. Al-Sawaf, "Effects of volatile oil constituents of Nigella sativa on carbon tetrachloride-induced hepatotoxicity in mice: evidence for antioxidant effects of thymoquinone.", Research communications in molecular pathology and pharmacology, vol. 110, issue 3-4, pp. 239-51, 2001. Abstract

Effects of the volatile oil constituents of Nigella sativa, namely, thymoquinone (TQ), p-cymene and alpha-pinene, on carbon tetrachloride (CCl4-indued acute liver injury were investigated in mice. A single dose of CCl4 (15 microl/Kg i.p.) induced hepatotoxicity 24 h after administration manifested biochemically as significant elevation of the enzymes activities of serum alanine transaminase (ALT, EC:2.6.1.2), asparate transaminase (AST, EC:2.6.1.1) and lactate dehydrogenase (LDH, EC: 1.1.1.27). The toxicity was further evidenced by a significant decrease of non-protein sulfhydryl(-SH) concentration, and a significant increase of lipid peroxidation measued as malondialdhyde (MDA) in the liver tissues. Administration of different doses of the TQ (4, 8, 12.5, 25 and 50 mg/Kg i.p.) did not alter the chosen biochemical parameters measured, while higher doses of TQ were lethal. The LD50 was 90.3 mg/Kg (77.9-104.7, 95% CL). Pretreatment of mice with different doses of TQ 1 h before CCl4 injection showed that the only dose of TQ that ameliorated hepatotoxicity of CCl4 was 12.5 mg/Kg i.p. as evidenced by the significant reduction of the elevated levels of serum enzymes as well as hepatic MDA content and significant increase of the hepatic nonprotein sulfhydryl(-SH) concentration. Treatment of mice with the other volatile oil constituents, p-cymene or alpha-pinene did not induce any changes in the serum ALT measured. In addition, i.p. administration of these compounds 1 h before CCl4 injection, did not protect mice against CC4-induced hepatotoxicity. The results of the present study indicate that TQ (12.5 mg/Kg, i.p.) may play an important role as antioxidant and may efficiently act as a protective agent against chemically-induced hepatic damage. In contrast, higher doses of TQ were found to induce oxidative stress leading to hepatic injury.

el-Khatib, A. S., and M. A. Mansour, "Prior treatment with captopril attenuates carbon tetrachloride-induced liver injury in mice.", Research communications in molecular pathology and pharmacology, vol. 110, issue 1-2, pp. 3-16, 2001 Jul-Aug. Abstract

The present investigation focused on the possible hepatoprotective potential of captopril on carbon tetrachloride (CCl4)-induced acute liver injury in mice. Twenty-four hours after a single intraperitoneal injection of CCl4 (20 microl/Kg), hepatotoxicity was evidenced in the serum by elevated levels of aspartate transaminase (AST; EC: 2.6.1.1), alanine transaminase (ALT; EC: 2.6.1.2) and lactate dehydrogenase (LDH; EC: 1.1.1.27) and in the liver by depleted level of reduced glutathione (GSH), enhanced activity of glutathione peroxidase (GSH-Px; EC: 1I.11.1.9) and elevated level of lipid peroxides (LP). Captopril was given orally at three dose levels viz., 10, 25 and 50 mg/Kg/day for three consecutive days before subjecting the animals to the hepatotoxin. With the exception of the lowest dose namely, 10 mg/Kg/day, captopril afforded protection against CCl4-induced hepatotoxicity to different extents. Thus, the elevated activities of the enzymes AST, ALT, LDH and GSH-Px as well as the enhanced lipid peroxidation were markedly reduced below those elicited by the hepatotoxin, reaching values closer to the control, though still statistically higher. Captopril, however, did not ameliorate the depletion of GSH produced by CCl4. The data reported herein reveal a protective potential of captopril against the acute hepatotoxicity induced by CCl4 in mice. This hepatoprotection could be attributed, at least in part, to the free radical scavenging properties of the drug.

el-Khatib, A. S., A. M. Moustafa, A. A. Abd El-Aziz, O. A. Al-Shabanah, and H. A. El-Kashef, "Effects of aminoguanidine and desferrioxamine on some vascular and biochemical changes associated with streptozotocin-induced hyperglycaemia in rats.", Pharmacological research, vol. 43, issue 3, pp. 233-40, 2001 Mar. Abstract

The effects of aminoguanidine (AG; 100 mg x kg(-1)) and desferrioxamine (DFO; 50 mg x kg(-1)) on some vascular and biochemical changes associated with streptozotocin (STZ; 65 mg x kg(-1); i.p.)-induced hyperglycaemia were investigated in rats. Both AG and DFO were administered i.p., once daily, for 14 consecutive days to normal and hyperglycaemic animals. The responsiveness of the isolated aortic rings to phenylephrine (PE) was tested. In addition, biochemical markers for oxidative stress such as plasma levels of lipid peroxides and total thiols, as well as the activities of erythrocytic superoxide dismutase (SOD) and whole blood glutathione peroxidase (GSH-Px) were assessed. Results of the present study indicated that induction of hyperglycaemia was associated with increased aortic ring responsiveness to PE, loss in body weight, increase in urine volume, elevation of plasma total thiols and lipid peroxide levels and elevated SOD and GSH-Px enzymatic activities. Treatment of normal rats with AG reduced the response of their aortae to PE. Furthermore, a profound increase in body weight without any significant change in the measured biochemical parameters was observed. In hyperglycaemic animals, AG tended to normalize the enhanced aortic response to PE and modulated STZ-induced biochemical changes without affecting the elevated plasma glucose level. Treatment of normal rats with DFO reduced the response of their aortae to PE and decreased their body weight without altering any of the chosen biochemical parameters. In hyperglycaemic animals, DFO attenuated the responsiveness of their aortae to PE and at the same time, did not affect the loss in body weight and the elevation of plasma glucose level observed in the hyperglycaemic group. Additionally, DFO normalized the elevated plasma level of total thiols and exerted a modulatory influence on the enhanced activities of SOD and GSH-Px as well as on the increased levels of lipid peroxides. Our data lend further credence for the contribution of oxidative stress in the vascular and biochemical changes associated with STZ-induced hyperglycaemia. It is also apparent that advanced glycosylation end products and nitric oxide might be involved. Until clinical studies prove the efficacy and safety of these drugs, specific agents which could scavenge free radicals and block protein glycosylation seem beneficial as a helpful adjunct to the therapy of diabetes.

el-Khatib, A. S., A. M. Moustafa, A. A. Abd El-Aziz, O. A. Al-Shabanah, and H. A. El-Kashef, "Ginkgo biloba extract (EGb 761) modulates bleomycin-induced acute lung injury in rats.", Tumori, vol. 87, issue 6, pp. 417-22, 2001 Nov-Dec. Abstract

The effect of Ginkgo biloba extract (EGb 761) on bleomycin (BLM)-induced acute lung injury was studied in rats. The responsiveness of isolated pulmonary arterial rings to 5-hydroxytryptamine (5-HT) as well as the levels of some relevant biochemical markers in the lung tissue were taken as evidence for the acute lung injury. BLM was given intraperitoneally at a dose of 15 mg/kg/day for five consecutive days. It was found that BLM treatment attenuated the vasoconstrictor effect of 5-HT on the isolated pulmonary arteries. In lung tissues BLM also elevated the level of lipid peroxides and enhanced the activity of glutathione peroxidase. On the other hand, the level of glutathione and the activity of alkaline phosphatase were reduced. Body weight, lung weight and tissue glutathione-S-transferase activity were, however, not altered. Oral administration of EGb 761 at a dose of 100 mg/kg/day for five consecutive days did not alter any of the chosen biochemical parameters in the lung tissue except for a slight reduction in alkaline phosphatase activity. However, treatment with EGb 761 reduced the responsiveness of the pulmonary artery to 5-HT. Administration of EGb 761 (100 mg/kg/day; po) two hours prior to BLM (15 mg/kg/day; ip), for five consecutive days blunted the occurrence of further reduction in the vasoconstrictor response of the pulmonary artery to 5-HT. Furthermore, EGb 761 tended to normalize BLM-induced alterations in the measured biochemical markers in the lung tissue. The apparent modulatory influence of EGb 761 on BLM-induced acute lung injury stems, at least in part, from its beneficial free radical scavenging properties that provide the extract with antioxidant activity.

2002
Khattab, M. M., A. M. Moustafa, O. A. Al-Shabanah, and A. S. el-Khatib, "INVOLVEMENT OF NITRIC OXIDE IN CARBON TETRACHLORIDE-INDUCED ACUTE HEPATOTOXICITY IN MICE", Res. Commun. Pharmacol. Toxicol, vol. 7, issue 1-2, pp. 53-64, 2002.
El-Khatib, A. S., "Possible modulatory role of nitric oxide in lung toxicity induced in rats by chronic administration of bleomycin.", Chemotherapy, vol. 48, issue 5, pp. 244-51, 2002 Dec. Abstract

BACKGROUND: The present study was undertaken to evaluate whether stimulation or inhibition of nitric oxide (NO) synthesis could affect lung toxicity induced by chronic administration of bleomycin (BLM). L-arginine (ARG) and N(G)-nitro-L-arginine methyl ester (L-NAME) were employed as NO precursor and NO synthesis inhibitor, respectively.

METHODS: BLM was administered intraperitoneally to male Wistar rats at a dose of 15 mg/kg, 3 times a week, for a total period of 4 weeks. ARG (500 mg/kg/day) and L-NAME (100 mg/kg/day) were given in drinking water, the treatments commenced with BLM and continued up to the end of the experiment. Appropriate controls were performed.

RESULTS: BLM treatment resulted in a pronounced fall in the average body weight of animals, together with a rise in the lung weight/body weight ratio. In the lung tissue, elevated levels of hydroxyproline (HP) and lipid peroxides (LP) as well as decreased activity of angiotensin converting enzyme (ACE) further evidenced the toxicity. Pulmonary level of NO end products, nitrite and nitrate, tended to rise but did not reach a significant level. Glutathione (GSH) content and GSH-peroxidase activity measured in the lung remained unaltered. In animals given concurrent treatment of BLM and ARG, a remarkable rise in the pulmonary level of nitrite and nitrate was observed. Average body weight was still decreased when compared with the untreated control group, but the decrease was significantly less than that observed in the BLM group. In addition, ARG decreased the extent of BLM-induced elevations of lung HP and LP levels. Meanwhile, ARG failed to significantly affect the BLM-evoked decrease in pulmonary ACE activity and increase in lung weight/body weight ratio. In animals given simultaneous treatment of BLM and L-NAME, noticeable reductions in the pulmonary levels of nitrite/nitrate and GSH were detected. BLM-induced decrease in body weight and increase in lung weight/body weight ratio were accentuated by L-NAME co-treatment. Furthermore, administration of L-NAME led to more profound elevations in lung HP and LP levels, without affecting the decrease in pulmonary ACE activity elicited by BLM.

CONCLUSION: In principle, the present findings indicate that the lung toxicity exerted by chronic administration of BLM is alleviated by ARG, but exacerbated by L-NAME supplementation. This could indicate a possible protective role of NO.

Mansour, M. A., M. N. Nagi, A. S. El-Khatib, and A. M. Al-Bekairi, "Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action.", Cell biochemistry and function, vol. 20, issue 2, pp. 143-51, 2002 Jun. Abstract

The present investigation focused, firstly, on the effects of oral administration of thymoquinone (TQ) on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase activity in hepatic, cardiac and kidney tissues of normal mice. Superoxide dismutase (SOD; E.C:1.15.1.1), catalase (CAT; E.C:1.11.1.6), glutathione peroxidase (GSH-Px; E.C:1.11.1.9), glutathione-S-transferase (GST; E.C:2.5.1.18), and DT-diaphorase (E.C:1.6.99.2) enzyme activities in each tissue type were determined. Treatment of mice with the different doses of TQ (25, 50 and 100 mg kg(-1) day(-1) orally) for 5 successive days, produced significant reductions in hepatic SOD, CAT and GSH-Px activities. In addition cardiac SOD activity was markedly inhibited with the higher doses of TQ, (namely 50 and 100 mg kg(-1)). Moreover, TQ (100 mg kg(-1)) significantly reduced hepatic and cardiac lipid peroxidation as compared with the respective control group. Conversely, TQ (50,100 mg kg(-1)) and TQ (100 mg kg(-1)) enhanced cardiac and renal DT-diaphorase activity respectively. However, the selected doses of TQ neither produced any change in GST activity nor influenced reduced glutathione content in all tissues studied. TQ was tested, secondly, as a substrate for hepatic, cardiac and renal DT-diaphorase of normal mice in the presence of NADPH. Kinetic parameters for the reduction of TQ to dihydrothymoquinone (DHTQ) indicated that DT-diaphorase of different tissues can efficiently reduce TQ to DHTQ. K(m) and V(max) values revealed that hepatic DT-diaphorase exhibited the higher values, while the lower values were associated with renal DT-diaphorase. TQ and DHTQ were tested, thirdly, as specific scavengers for superoxide anion (generated biochemically) or as general scavengers for free radicals (generated photochemically). The results revealed that TQ and DHTQ acted not only as superoxide anion scavengers but also as general free radical scavengers. The IC(50) for TQ and DHTQ in biochemical and photochemical assays were in the nanomolar and micromolar range respectively. Our data may explain at least partly the reported beneficial in vivo protective effects of TQ through the combined antioxidant properties of TQ and its metabolite DHTQ.

El-Khatib, A. S., A. M. Agha, L. G. Mahran, and M. T. Khayyal, "Prophylactic effect of aqueous propolis extract against acute experimental hepatotoxicity in vivo.", Zeitschrift für Naturforschung. C, Journal of biosciences, vol. 57, issue 3-4, pp. 379-85, 2002 Mar-Apr. Abstract

Propolis has been extensively used in folk medicine for the management of a wide spectrum of disorders. In a previous study, we demonstrated the protective effect of the aqueous propolis extract (APE) against the injurious effects of carbon tetrachloride (CCl4) on hepatocytes in vitro. The present investigation was carried out to show whether the hepatoprotective effect of the extract could also be manifested in vivo. Rats were given APE orally for 14 consecutive days, before being subjected to a single intraperitoneal injection of CCl4. One day after the CCl4 injection, the animals were sacrificed, hepatocytes were isolated and liver homogenates were prepared for the assessment of liver injury. In isolated hepatocytes, APE afforded protection against CCl4-induced injury as manifested by a decrease in the leakage of the cytosolic enzyme lactate dehydrogenase (LDH), decreased generation of lipid peroxide and maintenance of cellular reduced glutathione (GSH) content. In principle, similar findings were observed in liver homogenates. The present findings show that APE has in vivo hepatoprotective potential which could be attributed at least in part to the maintenance of cellular GSH content. The latter effect seems to play an important role in conserving the integrity of biomembranes as it was associated with a decrease in lipid peroxidation and reduced leakage of cytosolic LDH.

2003
Khayyal, M. T., M. A. El-Ghazaly, A. S. el-Khatib, A. M. Hatem, P. J. F. de Vries, S. el-Shafei, and M. M. Khattab, "A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients.", Fundamental & clinical pharmacology, vol. 17, issue 1, pp. 93-102, 2003 Feb. Abstract

The aqueous extract of propolis has been formulated as a nutritional food product and administered, as an adjuvant to therapy, to patients with mild to moderate asthma daily for 2 months in the framework of a comparative clinical study in parallel with a placebo preparation. The diagnosis of asthma was made according to the criteria of patient classification of the National Institutes of Health and Global Initiative for Asthma Management. At inclusion, the pulmonary forced expiratory volume in the first second (FEV1) as a percentage of the forced vital capacity (FVC) was more than 80% in mild persistent cases, and between 60 and 80% in moderate persistent cases, showing an increase in the degree of reversibility of > 15% in FEV1. All patients were on oral theophylline as controller therapy, none was receiving oral or inhaled corticosteroids, none had other comorbidities necessitating medical treatment, and all were from a middle-class community and had suffered from asthma for the last 2-5 years. Twenty-four patients received the placebo, with one drop-out during the study, while 22 received the propolis extract, with no drop-outs. The age range of the patients was 19-52 years; 36 were male and 10 female. The number of nocturnal attacks was recorded on a weekly basis, while pulmonary function tests were performed on all patients at the beginning of the trial, 1 month later and at the termination of the trial. Immunological parameters, including various cytokines and eicosanoids known to play a role in asthma, were measured in all patients at the beginning of the trial and 2 months later. Analysis of the results at the end of the clinical study revealed that patients receiving propolis showed a marked reduction in the incidence and severity of nocturnal attacks and improvement of ventilatory functions. The number of nocturnal attacks dropped from an average of 2.5 attacks per week to only 1. The improvement in pulmonary functions was manifested as a nearly 19% increase in FVC, a 29.5% increase in FEV1, a 30% increase in peak expiratory flow rate (PEFR), and a 41% increase in the forced expiratory flow rate between 25 and 75% of the vital capacity (FEF25-75). The clinical improvement was associated with decreases by 52, 65, 44 and 30%, respectively, of initial values for the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, ICAM-1, interleukin (IL)-6 and IL-8, and a 3-fold increase in the 'protective' cytokine IL-10. The levels of prostaglandins E2 and F2alpha and leukotriene D4 were decreased significantly to 36, 39, and 28%, respectively, of initial values. Patients on the placebo preparation showed no significant improvement in ventilatory functions or in the levels of mediators. The findings suggest that the aqueous propolis extract tested is potentially effective as an adjuvant to therapy in asthmatic patients. The benefits may be related to the presence in the extract of caffeic acid derivatives and other active constituents.

2008
Bahgat, A., H. Abdel-Aziz, M. Raafat, A. Mahdy, A. S. El-Khatib, A. Ismail, and M. T. Khayyal, "Solanum indicum ssp. distichum extract is effective against L-NAME-induced hypertension in rats.", Fundamental & clinical pharmacology, vol. 22, issue 6, pp. 693-9, 2008 Dec. Abstract

Solanum indicum ssp. distichum is used as a vegetable in some parts of Africa and claimed in folk medicine to guard against cardiovascular disorders. It was of interest to study the potential blood pressure lowering effects of a standardized extract of the fruit. An ethanolic extract of the fruit, standardized to contain > 0.15% chlorogenic acids, was tested orally in both normotensive rats and in those rendered hypertensive by twice daily intraperitoneal injection of N(W)-nitro-L-arginine methylester (L-NAME) for 1 week. The extract was either given at the same time as l-NAME or after the establishment of hypertension. The systolic blood pressure (SBP) was measured non-invasively using a tail cuff computer-aided monitoring device. Treatment of normotensive rats with the extract (30-300 mg/kg) for 4 weeks showed no hypotensive effect. Giving the extract (100 and 300 mg/kg) orally once daily during the 1 week hypertension induction period with L-NAME prevented the development of hypertension. Administration of the extract orally for 1 week after the establishment of hypertension tended to normalize the blood pressure. Pharmacological evidence for the antihypertensive activity of S. distichum is hereby reported for the first time. The extract showed good prophylactic as well as curative effect against L-NAME-induced hypertension, whereby its content of chlorogenic acids may play a minor role. Other constituents may be responsible for the antihypertensive action. The findings support further development of the extract as a potential therapeutically useful antihypertensive agent.

2011
Mansour, S. M., A. K. Bahgat, A. S. El-Khatib, and M. T. Khayyal, "Ginkgo biloba extract (EGb 761) normalizes hypertension in 2K, 1C hypertensive rats: role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction.", Phytomedicine : international journal of phytotherapy and phytopharmacology, vol. 18, issue 8-9, pp. 641-7, 2011 Jun 15. Abstract

The 2 kidney, 1-clip (2K, 1C) model of hypertension was used to investigate the potential antihypertensive effect of a standardized leaf extract of Ginkgo biloba (EGb 761). Clipping of the renal artery resulted in gradual elevation of the systolic blood pressure (SBP) reaching a plateau after 4 weeks of surgery. Treatment of hypertensive rats with EGb 761 (60, 90, 180 mg/kg/day orally) was therefore started 4 weeks after surgery and continued for 3 weeks. This led to a dose-dependent reduction in SBP with no significant change in heart rate. Control hypertensive rats showed a significant elevation of total protein thiols (Pr-SHs level) in both clipped and non-clipped kidneys as well as in the serum. However, glutathione peroxidase (GSH-Px) activity was decreased in the clipped kidneys but elevated in the non-clipped ones and in the blood. The malondialdehyde (MDA) level was raised in clipped kidneys but not in non-clipped ones nor in the serum. Nitric oxide (NO level) and angiotensin converting enzyme (ACE) activity were increased in both clipped and non-clipped kidneys but not in the serum. Endothelium-dependent and -independent relaxation of aortic rings towards acetylcholine (Ach) and sodium nitroprusside (SNP) were impaired. Treatment with EGb 761 (180 mg/kg/day for 3 weeks) was associated with recovery of GSH-Px activity in clipped kidneys, inhibition of ACE activity in both kidneys and a reduction in the elevated NO level of the non-clipped kidneys, decreased responsiveness to the vasoconstrictor NE and improvement of endothelial function as evidenced by restoration of endothelium-dependent vasorelaxation induced by Ach. The observed beneficial effects of the EGb 761 may be attributed to different factors, including ACE inhibition and maintenance of cellular antioxidant capacity as well as preserving vascular reactivity towards endothelium-dependent and -independent vasodilators while inhibiting responses to vasoconstrictors.

2012
El-Marasy, S. A., S. M. El-Shenawy, A. S. el-Khatib, O. A. El-Shabrawy, and S. A. Kenawy, "EFFECT OF NIGELLA SATIVA AND WHEAT GERM OILS ON SCOPOLAMINE-INDUCED MEMORY IMPAIRMENT IN RATS", Bull. Fac. Pharm. Cairo Uni, vol. 50, pp. 81-88, 2012.
2013
Saleh, D. O., A. R. Bayoumi, W. I. El-Eraky, and A. S. El-Khatib, "Streptocin-induced vascular and biochemical changes in rats: Effects of rosiglitazone vs. metformin", Bulletin of Faculty of Pharmacy, Cairo University, vol. 51, pp. 131-138, 2013.
Attia, Y. M., E. F. Elalkamy, O. A. Hammam, S. S. Mahmoud, and A. S. El-Khatib, "Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection.", Parasites & vectors, vol. 6, pp. 199, 2013. Abstract

BACKGROUND: Hepatic schistosomiasis is considered to be one of the most prevalent forms of chronic liver disease in the world due to its complication of liver fibrosis. The demonstration of the pro-fibrogenic role of angiotensin (Ang) II in chronic liver disease brought up the idea that anti-Ang II agents may be effective in improving hepatic fibrosis by either blocking Ang II type 1 (AT1) receptors or inhibiting the angiotensin converting enzyme. Peroxisome proliferator-activated receptors gamma (PPARγ) activation has been also shown to inhibit hepatic stellate cell activation and progression of fibrosis. The present study has aimed at testing the anti-fibrogenic effects of telmisartan; an AT1 receptor blocker and a PPARγ partial agonist, alone or combined with praziquantel (PZQ) on Schistosoma mansoni-induced liver fibrosis in mice.

METHODS: To achieve the aim of the study, two sets of experiments were performed in which telmisartan was initiated at the 5th (set 1) and the 10th (set 2) weeks post infection to assess drug efficacy in both acute and chronic stages of liver fibrosis, respectively. Schistosoma mansoni-infected mice were randomly divided into the following four groups: infected-control (I), telmisartan-treated (II), PZQ-treated (III), and telmisartan+PZQ-treated (IV). In addition, a normal non-infected group was used for comparison. Parasitological (hepatomesenteric worm load and oogram pattern), histopathological, morphometric, immunohistochemical (hepatic expressions of matrix metalloproteinase-2; MMP-2 and tissue inhibitor of metalloproteinase-2; TIMP-2), and biochemical (serum transforming growth factor beta 1; TGF-β1 and liver function tests) studies were performed.

RESULTS: Telmisartan failed to improve the parasitological parameters, while it significantly (P<0.05) decreased the mean granuloma diameter, area of fibrosis, and serum TGF-β1. Additionally, telmisartan increased MMP-2 and decreased TIMP-2 hepatic expression. Combined treatment failed to show any additive properties, yet it did not affect the anti-schistosomal activity of PZQ.

CONCLUSIONS: These results suggest potential anti-fibrotic effects of telmisartan, an AT1 receptor blocker and a PPARγ partial agonist, in acute and chronic stages of Schistosoma mansoni-induced liver fibrosis in mice.

2014
El-Marasy, S. A., H. M. I. Abdallah, S. M. El-Shenawy, A. S. El-Khatib, O. A. El-Shabrawy, and S. A. Kenawy, "Anti-depressant effect of hesperidin in diabetic rats.", Canadian journal of physiology and pharmacology, vol. 92, issue 11, pp. 945-52, 2014 Nov. Abstract

This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.

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