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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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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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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.

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.
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.

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.

Abdel-Wahab, L. A., A. I. El-Brairy, G. G. El-Hossary, and A. S. el-Khatib, "EFFECT OF GINKGO BILOBA AND GREEN TEA EXTRACTS ON CORTICOSTEROID-INDUCED OCULAR HYPERTENSION IN RABBITS", Rev. Res. J, vol. 5, pp. 1-17, 2015.
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., "BIOLOGICALLY ACTIVE FREE RADICALS AND THEIR SCAVENGERS: A REVIEW", Saud. Pharm. J, vol. 5, issue 2-3, pp. 78-89, 1997.
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. 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.
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.

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.
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