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Hammam, O. A., N. Elkhafif, Y. M. Attia, M. T. Mansour, M. M. Elmazar, R. M. Abdelsalam, S. A. Kenawy, and A. S. El-Khatib, "Wharton's jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis.", Scientific reports, vol. 6, pp. 21005, 2016. Abstract

Liver fibrosis is one of the most serious consequences of S. mansoni infection. The aim of the present study was to investigate the potential anti-fibrotic effect of human Wharton's jelly-derived mesenchymal stem cells (WJMSCs) combined with praziquantel (PZQ) in S. mansoni-infected mice. S. mansoni-infected mice received early (8(th) week post infection) and late (16(th) week post infection) treatment with WJMSCs, alone and combined with oral PZQ. At the 10(th) month post infection, livers were collected for subsequent flow cytometric, histopathological, morphometric, immunohistochemical, gene expression, and gelatin zymographic studies. After transplantation, WJMSCs differentiated into functioning liver-like cells as evidenced by their ability to express human hepatocyte-specific markers. Regression of S. mansoni-induced liver fibrosis was also observed in transplanted groups, as evidenced by histopathological, morphometric, and gelatin zymographic results besides decreased expression of three essential contributors to liver fibrosis in this particular model; alpha smooth muscle actin, collagen-I, and interleukin-13. PZQ additionally enhanced the beneficial effects observed in WJMSCs-treated groups. Our results suggest that combining WJMSCs to PZQ caused better enhancement in S. mansoni-induced liver fibrosis, compared to using each alone.

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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.

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.

Rasheed, N. A. O., N. S. El Sayed, and A. S. El-Khatib, "Targeting central $\beta$2 receptors ameliorates streptozotocin-induced neuroinflammation via inhibition of glycogen synthase kinase3 pathway in mice", Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 86: Elsevier, pp. 65–75, 2018. Abstract
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Attia, Y. M., O. A. Hammam, N. Elkhafif, T. Mansour, M. M. Elmazar, R. A. Mohsen, S. A. Kenawy, and A. S. el-Khatib, "SUCCESSFUL INTEGRATION OF TRANSPLANTED MESENCHYMAL STEM CELLS INTO THE LIVERS OF S. MANSONI-INFECTED MICE", Int. J. Develop. Res, vol. 5, issue 3, pp. 3847-3851, 2015.
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.
Raafat, S. N., R. M. Amin, M. M. Elmazar, M. M. Kattab, and A. El-Khatib, "The sole and combined effect of simvastatin and platelet rich fibrin as a filling material in induced bone defect in tibia of albino rats", Bone, vol. 711: Elsevier, pp. 12–34, 2018. Abstract
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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.

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El-Ganainy, S. O., A. El-Mallah, D. Abdallah, M. M. Khattab, M. M. Mohy El-Din, and A. S. El-Khatib, "Rosuvastatin safety: An experimental study of myotoxic effects and mitochondrial alterations in rats.", Toxicology letters, vol. 265, pp. 23-29, 2017 Jan 04. Abstract

Myopathy is the most commonly reported adverse effect of statins. All statins are associated with myopathy, though with different rates. Rosuvastatin is a potent statin reported to induce myopathy comparable to earlier statins. However, in clinical practice most patients could tolerate rosuvastatin over other statins. This study aimed to evaluate the myopathic pattern of rosuvastatin in rats using biochemical, functional and histopathological examinations. The possible deleterious effects of rosuvastatin on muscle mitochondria were also examined. The obtained results were compared to myopathy induced by atorvastatin in equimolar dose. Results showed that rosuvastatin induced a rise in CK, a slight increase in myoglobin level together with mild muscle necrosis. Motor activity, assessed by rotarod, showed that rosuvastatin decreased rats' performance. All these manifestations were obviously mild compared to the prominent effects of atorvastatin. Parallel results were obtained in mitochondrial dysfunction parameters. Rosuvastatin only induced a slight increase in LDH and a minor decrease in ATP (∼14%) and pAkt (∼12%). On the other hand, atorvastatin induced an increase in LDH, lactate/pyruvate ratio and a pronounced decline in ATP (∼80%) and pAkt (∼65%). These findings showed that rosuvastatin was associated with mild myotoxic effects in rats, especially when compared to atorvastatin.

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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.

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.

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., "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.

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El-Mezayen, N. S., W. F. El-Hadidy, W. M. El-Refaie, T. I. Shalaby, M. M. Khattab, and A. S. El-Khatib, "Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence.", Journal of controlled release : official journal of the Controlled Release Society, vol. 283, pp. 32-44, 2018 Aug 10. Abstract

So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (V) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to V and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled V-coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, V-coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity.

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El-Ganainy, S. O., A. El-Mallah, D. Abdallah, M. M. Khattab, A. S. El-Khatib, and M. M. Mohy El-Din, "A novel investigation of statins myotoxic mechanism: effect of atorvastatin on respiratory muscles in hypoxic environment.", Toxicology letters, vol. 305, pp. 58-64, 2019 May 01. Abstract

Myopathy is a well-known adverse effect of statins, affecting a large sector of statins users. The reported experimental data emphasized on mechanistic study of statin myopathy on large muscles. Clinically, both large muscles and respiratory muscles are reported to be involved in the myotoxic profile of statins. However, the experimental data investigating the myopathic mechanism on respiratory muscles are still lacking. The present work aimed to study the effect of atorvastatin treatment on respiratory muscles using rat isolated hemidiaphragm in normoxic & hypoxic conditions. The contractile activity of isolated hemidiaphragm in rats treated with atorvastatin for 21 days was investigated using nerve stimulated technique. Muscle twitches, train of four and tetanic stimulation was measured in normoxic, hypoxic and reoxygenation conditions. Atorvastatin significantly increased the tetanic fade, a measure of muscle fatigability, in hypoxic conditions. Upon reoxygenation, rat hemidiaphragm regains its normal contractile profile. Co-treatment with coenzyme Q10 showed significant improvement in defective diaphragmatic contractility in hypoxic conditions. This work showed that atorvastatin treatment rapidly deteriorates diaphragmatic activity in low oxygen environment. The mitochondrial respiratory dysfunction is probably the mechanism behind such finding. This was supported by the improvement of muscle contractile activity following CoQ10 co-treatment.

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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.

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.

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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.
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.

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.
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.

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El-Mezayen, N. S., W. F. El-Hadidy, W. M. El-Refaie, T. I. Shalaby, M. M. Khattab, and A. S. El-Khatib, "Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.", Journal of controlled release : official journal of the Controlled Release Society, vol. 266, pp. 226-237, 2017 Nov 28. Abstract

Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (V) storage cells, they can be actively targeted by coupling liposomes to V. In this study, novel V-coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding V-coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected V-coupled liposomes loaded with Nile Red (LCNR) to rats with CCl-induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional imatinib. It can represent a promising novel approach for liver fibrosis treatment.

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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.

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.

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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.