Eucalyptol potentiates antianginal effect while blunts tachycardia of nifedipine in rats via nitric oxide, antioxidant, and anti-inflammatory pathways: In vivo and in vitro study
Objective: Statins' therapy in osteoporosis can aggravate muscle damage. This study was designed ... more Objective: Statins' therapy in osteoporosis can aggravate muscle damage. This study was designed to assess which agent, L-carnitine or coenzyme Q10, could enhance the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. Methods: Forty-eight female Sprague Dawley rats were used; forty rats were ovariectomized while eight were sham-operated. Eight weeks post-ovariectomy, rats were divided into ovariectomized-untreated group and four ovariectomized-treated groups (n=8) which received by gavage (mg/(kg•d), for 8 weeks) 17β-estradiol (0.1), atorvastatin (50), atorvastatin (50)+L-carnitine (100), or atorvastatin (50)+coenzyme Q10 (20). At the end of therapy, bone mineral density (BMD), bone mineral content (BMC), and serum levels of bone metabolic markers (BMMs) and creatine kinase (CK) were measured. Femurs were used for studying the breaking strength and histopathological changes. Results: Treatment with atorvastatin+L-carnitine restored BMD, BMC, and bone strength to near normal levels. Estrogen therapy restored BMD and BMC to near normal levels, but failed to increase bone strength. Although atorvastatin and atorvastatin+coenzyme Q10 improved BMD, BMC, and bone strength, they failed to restore levels to normal. All treatments decreased BMMs and improved histopathological changes maximally with atorvastatin+L-carnitine which restored levels to near normal. Atorvastatin aggravated the ovariectomy-induced increase in CK level while estrogen, atorvastatin+L-carnitine, and atorvastatin+coenzyme Q10 decreased its level mainly with atorvastatin+L-carnitine which restored the level to near normal. Conclusions: Coadministration of L-carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. This could be valuable in treatment of osteoporotic patients. However, further confirmatory studies are needed.
Background and aim: Inflammatory cells involved in the pathophysiology of asthma express nicotini... more Background and aim: Inflammatory cells involved in the pathophysiology of asthma express nicotinic receptor. Therefore 1,1 dimethyl(-4-)phenylpiperazinium (DMPP) in two doses were compared to dexamethasone in asthmatic guinea pigs. Materials and methods: Six groups were included; Normal control and five asthmatic (OVA-sensitized and challenged) groups; which were treated for 10 days as follows: two vehicles, dexamethasone (DEXA, 1 mg/kg) and DMPP (0.4 and 0.8 mg/kg) groups. Pulmonary functions and airway hyper-responsiveness were assessed. Leukocytic count, tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6) and immunoglobulin E (IgE) were measured in both blood and bronchoalveolar lavage fluid (BALF). Histopathological examination of the lung tissues was conducted. Results: Asthmatic untreated animals exhibited significant increase in early and late airway resistance (RxV) and airway hyper-responsiveness, with reduction in tidal volume. Both blood and BALF showed significant increase in total leukocytic count (TLC), eosinophils, lymphocytes, monocytes, TNF-α, IL-6 and IgE with significant decrease in neutrophils. Airway inflammatory cell infiltration and smooth muscle thickness significantly increased. DMPP 0.4 mg/kg significantly decreased late phase RXV, TLC, BALF lymphocytes, TNF-α, smooth muscle thickness and increased neutrophils in BALF over both DEXA and DMPP 0.8 mg/kg. Moreover, DMPP 0.4 mg/kg significantly decreased IL-6 and BALF eosinophils than DMPP 0.8 mg/kg and decreased serum IgE and parenchymal inflammatory infiltration than DEXA. Conclusions: Low dose DMPP has more anti-inflammatory effect than a high dose in most parameters and sometimes than dexamethasone. Cholinergic anti-inflammatory pathway may therefore represent a potential drug target for allergic asthma. The dose related effect of DMPP and the mechanism underlying this effect require further evaluation.
Ethnopharmacological relevance: Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditio... more Ethnopharmacological relevance: Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditional medicine in treatment of many gastrointestinal disorders. 2 Aim of the study: This study aimed to evaluate potential protecting effect of ML and its major constituent, eucalyptol, against acetic acid-induced colitis in rats, a model of human inflammatory bowel disease (IBD). Materials and Methods: Rats were divided into ten groups (n=8) given orally for three days (mg/kg/day) the following: normal control, acetic acid-induced colitis (un-treated, positive control), vehicle (DMSO), sulfasalazine (500), ML extract (100, 500, 1000), and eucalyptol (100, 200, 400). After 24 h-fasting, two ml of acetic acid (3%) was administered intrarectally. On the fifth day, serum and colonic biochemical markers, and histopathological changes were evaluated. Results: Colitis significantly increased colonic myeloperoxidase activity and malonaldehyde level, and serum tumour necrosis factor-α, interleukin-6, and malonaldehyde levels while significantly decreased colonic and serum glutathione levels. All treatments (except ML 100, ML 1000, and eucalyptol 100) significantly reversed these changes where eucalyptol (400) showed the highest activity in a dose-dependent manner. The colitis-induced histopathological changes were mild in sulfasalazine and eucalyptol 400 groups, moderate in ML 500 and eucalyptol 200 groups, and severe in ML 100, ML 1000, and eucalyptol 100 groups nearly similar to colitis-untreated rats. Conclusion: ML (in moderate doses) and eucalyptol (dose-dependently) exerted protective effects against acetic acid-induced colitis in rats possibly through antioxidant and antiinflammatory properties suggesting a potential benefit in treatments of IBD. To our knowledge this is the first report addressing this point.
International Journal of General Medicine, Aug 1, 2022
Unplanned hospital readmission forms costly, but preventable burdens on healthcare system. This s... more Unplanned hospital readmission forms costly, but preventable burdens on healthcare system. This study was designed to evaluate cardiovascular-related readmission rate after discharge of acute coronary syndrome (ACS) patients and its relationship with medication adherence at a university hospital, Saudi Arabia. Methods: A total of 370 consecutive patients presenting with ACS were involved. The inclusion criteria were clinical and coronary angiography diagnostic data of ACS. Exclusion criteria included heart valve disease, myocarditis, hepatic disease, and history of acute infection during the previous two weeks. Patients were divided into index admission group (n = 291) and unplanned readmission group (n = 79). Readmission and medication adherence rates were evaluated during 1-30, 31-180, 181-365, and 366-548 days post-ACS discharge. Medication adherence was estimated with a (yes/no) questionnaire. Results: The overall readmission rate was 21.4%; individual rates were 30.4%, 38.0%, 27.8%, and 3.8% and the overall medication adherence rate was 62.03%, while individual rates were 54.2%, 70.0%, 63.6%, and 33.3% during the four periods, respectively. There were strong correlations between medication non-adherence and readmission rates. Heart failure, ST-elevated myocardial infarction, unstable angina, cerebrovascular accident, and arrhythmia represented the top causes. Body mass index was higher in readmission group. There were significant correlations between smoking, hypertension, cerebrovascular accident, ischemic heart disease, previous stent, instent restenosis, and LDL-cholesterol as predictor factors and readmission rate. Conclusion: The cardiovascular-related unplanned readmission rate post-ACS discharge was 21.4%, and medication non-adherence rate was 37.97%. There were strong correlations between them in the time frames from 1-month to 1.5-year post-discharge. The individual rates decreased by time, but the first month showed lower rates than the following 5 months and this indicated the role of factors other than medication non-adherence in readmission. The rates are generally consistent with the international levels but utilizing technology can further improve medication adherence and reduce readmission rates.
Nateglinide is suggested to have a glucose-dependent insulinotropic effect. We recently compared ... more Nateglinide is suggested to have a glucose-dependent insulinotropic effect. We recently compared serum insulin levels in fasting and non-fasting elderly diabetic patients following nateglinide administration and did not find a significant difference. Insulin, but not c-peptide is subjected to a significant first pass hepatic metabolism. Given the inclusion of 2 patients with liver dysfunction in the study, we estimated serum c-peptide levels in the same samples to further investigate this finding. Eight elderly diabetics underwent a fixed dose single blinded, placebo controlled, cross-over study. They received either nateglinide 120 mg or a placebo, both under fasting and non-fasting states. Serum c-peptide levels were measured at 30 minutes intervals for four hours, following drug or placebo administration. None of the eight patients developed hypoglycemia under the non-fasting state and only one patient developed mild hypoglycemia (66 mg/dl) under the fasting state in response to nateglinide. Area under the serum c-peptide concentration-time curve was not significantly different between the fasting and non-fasting states, following nateglinide, though it was significantly different in case of placebo. There was no correlation between serum c-peptide levels and serum glucose levels, in either of the 4 days. The present results are possibly explained by the lower mean fasting serum glucose levels, which would lead to the relatively lower insulin secretory effect of nateglinide and thus the insignificant difference in insulin secretion between the fasting and the fed state.
BMC complementary medicine and therapies, Feb 4, 2022
Background: The chemokine CXCL12 and its two receptors (CXCR4 and CXCR7) are involved in inflamma... more Background: The chemokine CXCL12 and its two receptors (CXCR4 and CXCR7) are involved in inflammation and hematopoietic cell trafficking. This study was designed to investigate molecular docking interactions of four popular cardiovascular-active natural compounds; curcumin, resveratrol, quercetin, and eucalyptol; with these receptors and to predict their drug-like properties. We hypothesize that these compounds can modify CXCL12/CXCR4/CXCR7 pathway offering benefits for coronary artery disease patients. Methods: Docking analyses were carried and characterized by Molecular Environment (MOE) software.Protein Data Bank (http:// www. rcsb. org/) has been retrieved from protein structure generation and crystal structures of CXCR4 and CXCR7 receptors (PDB code = 3ODU and 6K3F). The active sites of these receptors were evaluated and extracted from full protein and molecular docking protocol was done for compounds against them. The presented parameters included docking scores, ligand binding efficiency, and hydrogen bonding. The pharmacokinetic/toxic properties (ADME/T) were calculated using SwissADME, ProTox-II, and Pred-hERG softwares to predict drug-like properties of the compounds. The thermochemical and molecular orbital analysis, and molecular dynamics simulations were also done. Results: All compounds showed efficient interactions with the CXCR4 and CXCR7 receptors. The docking scores toward proteins 3ODU of CXCR4 and 6K3F of CXCR7 were − 7.71 and − 7.17 for curcumin, − 5.97 and − 6.03 for quercetin, − 5.68 and − 5.49 for trans-resveratrol, and − 4.88 and − 4.70 for (1 s,4 s)-eucalyptol respectively indicating that all compounds, except quercetin, have more interactions with CXCR4 than with CXCR7. The structurally and functionally important residues in the interactive sites of docked CXCR4-complex and CXCR7-complex were identified. The ADME analysis showed that the compounds have drug-like properties. Only (1 s,4 s)-Eucalyptol has potential weak cardiotoxicity. The results of thermochemical and molecular orbital analysis and molecular dynamics simulation validated outcomes of molecular docking study.
In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins... more In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins, its main polyphenolic pigments, will improve sildenafil-induced delay in gastric emptying (GE) and small intestinal transit (SIT) in mice. Twenty groups of mice (n = 8) were given a phenol red meal, and three sets of experiments were performed. In the first and second sets, effects of different concentrations of BTE, thearubigins (TRs), and sildenafil (SLD), alone and in combinations, on GE and SIT were measured. In the third set, influence of N ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) pretreatment on effects of these treatments was tested. Black tea extract (3% and 4.5%) and thearubigins (50 and 60 mg/kg) dose-dependently increased GE and SIT, whereas BTE 6% and thearubigins 70 mg/kg did not affect them. Sildenafil dose-dependently reduced both GE and SIT. Combination of metoclopramide, BTE 4.5%, thearubigins 60, or L-NAME with sildenafil (5 mg/kg) reversed its motility-delaying effects. Pretreatment with L-NAME followed by BTE 4.5%, thearubigins 60, BTE 4.5% + sildenafil 5, or thearubigins 60 + sildenafil 5 only partially affected the accelerating effects of BTE 4.5% and thearubigins 60. In conclusion, a standardized BTE and its thearubigins improve the sildenafil-induced delayed gut motility in mice. This improvement was partially blocked by L-NAME suggesting a possible role of nitric oxide. Thus, BTE 4.5% or TRs 60 mg/kg solution could be considered a reliever therapy for the sildenafil-induced dyspepsia.
Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats
Background: Chronic pain may be associated with diabetes mellitus and/or depression. Use of thera... more Background: Chronic pain may be associated with diabetes mellitus and/or depression. Use of therapies that target both comorbidities is encouraged. Objective: This study was designed to investigate the potential antinociceptive, neuroprotective, and antidepressant effects of combinations of pioglitazone or metformin with fluoxetine in chronic constriction injury (CCI) in rats. Study Design: Experimental trial in rats. Setting: University lab in Saudia Arabia. Methods: Two sets of experiments were performed. In each one, 9 groups of rats (n = 8) were used: sham, CCI, and 7 CCI-treated groups. Treatments were given orally starting on day 7 post-surgery as follows (mg/kg/day): fluoxetine (10, 20, and 40), pioglitazone (20), metformin (50), fluoxetine (20) + pioglitazone, and fluoxetine (20) + metformin. In the first set, on day 14 post-surgery mechanical allodynia, thermal hyperalgesia, and serum cytokines were measured. Moreover, immunoreactivity of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation) in the spinal cord was assessed and histopathological changes in the ipsilateral sciatic nerve were examined. In the second set, on days 14 and 21 post-surgery the forced swimming test was done. Results: In the first set, all treatments significantly decreased mechanical allodynia while all treatments except F10 and F20 significantly decreased thermal hyperalgesia compared to the CCI group. The F20+M group showed the highest decreases, however still significantly lower than those of the sham group. The treatments didn't impair motor function in the rotarod test. All treatments significantly decreased serum levels of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 while increasing the level of interleukin-10. The CCI-induced marked increase of GFAP immunoexpression has been reduced to moderate with fluoxetine (40) and pioglitazone, and to mild with metformin and the combination groups. The CCI-induced changes in sciatic nerve were less in fluoxetine (40), pioglitazone, and metformin groups, and least in the combination groups. In the second set, the immobility duration was significantly reduced by F20, F40, P, F20+P, and F20+M compared to the CCI group. The F20+P group showed the highest decrease, however still significantly lower than that of the sham group. The treatments didn't affect locomotor activity in the open field test. Limitations: Measuring the cytokines levels only in blood and not in the spinal cord and sciatic nerve and measuring the outcome measures in the first set of experiments at only one time-point. Conclusions: Co-administration of pioglitazone or metformin with low-dose fluoxetine improved mechanical allodynia, thermal hyperalgesia, and neurohistopathological changes while coadministration of pioglitazone, but not metformin, improved the depressive-like behavior in the peripheral nerve injury model of neuropathic pain in rats. Extrapolation of the current results to clinical reality could be beneficial for pain patients with diabetes and/or depression, however this needs further confirmatory studies.
Could Plasma CXCL12 Predict Ventricular Dysfunction in Patients with Severe Myocardial Infarction?
International Journal of Angiology, Sep 23, 2022
Plasma level of chemokine CXCL12 can predict adverse cardiovascular outcomes in patients with cor... more Plasma level of chemokine CXCL12 can predict adverse cardiovascular outcomes in patients with coronary artery disease, but data on its relationship with severity of coronary stenosis in cases of severe myocardial infarction (MI) are scarce and conflicting. The objective of this study was to investigate link between plasma CXCL12 levels and different grades of left ventricular ejection fraction (LVEF) in statin-treated and -untreated patients with severe MI. A total of 198 consecutive patients with first-time severe MI (ST-elevated myocardial infarction [STEMI], n = 121 and non-ST-elevated myocardial infarction [NSTEMI], n = 77) were recruited from Coronary Care Unit, King Abdulaziz University Hospital. They have one to two coronary arteries blocked ≥50%, or three arteries blocked 30 to 49%. Demographic and clinical criteria were collected and plasma CXCL12 level was measured. No correlations were detected between demographic and clinical criteria and CXCL12 level. While troponin peaks and LVEF significantly differed between STEMI and NSTEMI patients, CXCL12 level showed nonsignificant changes. Plasma CXCL12 levels decreased significantly in statin-treated patients compared with those untreated. From receiver operating characteristic (ROC) analysis, high CXCL12 levels were associated with no statin therapy. For STEMI and NSTEMI patients, area under the receiver operating characteristic curve for CXCL12 test were 0.685 and 0.820, while sensitivity and specificity values were 75.9 and 54.8%, and 73.1 and 84%, respectively. Plasma CXCL12 levels showed nonsignificant changes with different ranges of LVEF and troponin peaks. In patients with severe MI, irrespective of statin therapy, plasma CXCL12 showed no correlation with different ranges of LVEF suggesting that it cannot predict left ventricular dysfunction in these cases. However, cross-sectional design of this study is a limitation.
Brazilian Journal of Medical and Biological Research, 2022
Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and... more Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via offlabel routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mgÁkg-1 Áday-1), oral roflumilast (5 mgÁkg-1 Á day-1), or rectal roflumilast (5 mgÁkg-1 Áday-1) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-a, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-a. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-a, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.
Egyptian Journal of Basic and Clinical Pharmacology (Print), 2011
In this study, we examined the renoprotective effects of curative and prophylactic doses of epler... more In this study, we examined the renoprotective effects of curative and prophylactic doses of eplerenone and captopril in L-NAME-treated rats. Rats were divided into seven groups: The first and second (normal control and hypertensive control) groups received distilled water and L-NAME (L-nitro arginine methyl ester, 50 mg/kg per day), respectively, for eight weeks. The third and fourth groups received L-NAME (50 mg/kg per day) plus a prophylactic dose of eplerenone (50 mg/kg per day) or captopril (25 mg/kg per day), respectively, for eight weeks. The fifth, sixth and seventh groups received L-NAME (50 mg/kg per day) for eight weeks, followed by curative doses of eplerenone (100 mg/kg per day), captopril (50 mg/kg per day) or eplerenone plus captopril (50 + 25 mg/kg per day), respectively, for five weeks. The drugs were administered by gastric gavage. During prophylactic therapy, eplerenone and captopril decreased the L-NAME-induced rise in systolic blood pressure (SBP) and serum creatinine levels. Furthermore, both drugs improved microalbuminuria and renal histopathological changes and increased serum nitric oxide (sNO) levels. During curative therapy, eplerenone improved microalbuminuria and renal histopathological changes. Captopril or the combination of captopril and eplerenone improved all L-NAME-induced changes. The combination improved renal histopathological changes more significantly than each individual drug did. In conclusion, eplerenone and captopril have prophylactic and curative renoprotective effects in L-NAMEtreated rats, indicating the promising role of eplerenone as an add-on therapy to captopril in antihypertensive drug regimens.
Background: This study was designed to examine effects of telmisartan; an angiotensin receptor bl... more Background: This study was designed to examine effects of telmisartan; an angiotensin receptor blocker; self-nanoemulsifying drug delivery system (SNEDDS) in reversing already-established hepatic fibrosis. Method: Forty rats were given thioacetamide (200 mg/kg, intraperitoneally) twice/week for 8 weeks then divided into 5 groups (n ¼ 8), PC and 4 treated groups. Treatments were given orally for another 2 months as follows: telmisartan low and high doses (TL and TH: 1.8 and 3.6 mg/kg/day) and telmisartan SNEDDS at the same doses (TLS and THS). At end of treatment, blood was obtained and liver was isolated. Results: Rats showed significant elevations of plasma ALT and AST and hepatic IL-6, TNF-a, and MDA, significant reductions of plasma albumin, hepatic GSH, and body weight, and hepatic histopathological damage. All treatments except for TL significantly reversed these thioacetamide-induced changes. THS group showed significant differences from all groups. Regarding ratio of free telmisartan concentration in hepatic homogenate to that of plasma, TH and TLS groups showed non-significant variation between each other while THS group showed significant differences from them. No significant changes were detected in blood pressure, hemoglobin, white blood cells, and platelets. Conclusion: Telmisartan SNEDDS, compared with telmisartan, more effectively reversed chronic hepatic fibrosis with good safety profile.
Effect of eucalyptol on matrix metalloproteinase-9 and its tissue inhibitor in hypertensive rats
Bioinformation
Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP... more Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1), compared with lisinopril, were investigated in a model of hypertension induced by chronic intraperitoneal (IP) injection of low dose nicotine in rats. The hypertensive rats were randomly allocated to 4 groups (n=8): Positive control (PC, untreated), eucalyptol-treated group (1.0 mg/kg, IP), lisinopril-treated group (10 mg/kg, IP), and eucalyptol+lisinopril-treated group. Systolic blood pressure and plasma levels of MMP-9 and TIMP-1 were measured. All treatments decreased the elevated blood pressure and plasma levels of MMP-9 and TIMP-1 most significantly with the combination group which showed non-significant differences from the normal control group. Lisinopril reduced plasma levels of MMP-9 and TIMP-1 more significantly than eucalyptol. In conclusion, eucalyptol significantly decreased the increased plasma levels of MMP-9 and TIMP-1 in nicotine-in...
Background: T-box family members are transcription factors characterized by highly conserved resi... more Background: T-box family members are transcription factors characterized by highly conserved residues corresponding to the DNA-binding domain known as the T-box. TBX2 has been implicated in several developmental processes, such as coordinating cell fate, patterning, and morphogenesis of a wide range of tissues and organs, including lungs, limbs, heart, kidneys, craniofacial structures, and mammary glands.Methods: In the present study, we have clinically and genetically characterized a proband showing a severe form of chondrodysplasia with developmental delay. Whole-exome sequencing (WES), Sanger sequencing, and 3D protein modeling were performed in the present investigation.Results: Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2. 3D-TBX2 protein modeling revealed a substantial reduction of the mutated protein, which might lead to a loss of function (LOF) or nonsense-mediated decay (NMD).Conclusion: This study has not only expan...
Eucalyptol potentiates antianginal effect while blunts tachycardia of nifedipine in rats via nitric oxide, antioxidant, and anti-inflammatory pathways: In vivo and in vitro study
Objective: Statins' therapy in osteoporosis can aggravate muscle damage. This study was designed ... more Objective: Statins' therapy in osteoporosis can aggravate muscle damage. This study was designed to assess which agent, L-carnitine or coenzyme Q10, could enhance the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. Methods: Forty-eight female Sprague Dawley rats were used; forty rats were ovariectomized while eight were sham-operated. Eight weeks post-ovariectomy, rats were divided into ovariectomized-untreated group and four ovariectomized-treated groups (n=8) which received by gavage (mg/(kg•d), for 8 weeks) 17β-estradiol (0.1), atorvastatin (50), atorvastatin (50)+L-carnitine (100), or atorvastatin (50)+coenzyme Q10 (20). At the end of therapy, bone mineral density (BMD), bone mineral content (BMC), and serum levels of bone metabolic markers (BMMs) and creatine kinase (CK) were measured. Femurs were used for studying the breaking strength and histopathological changes. Results: Treatment with atorvastatin+L-carnitine restored BMD, BMC, and bone strength to near normal levels. Estrogen therapy restored BMD and BMC to near normal levels, but failed to increase bone strength. Although atorvastatin and atorvastatin+coenzyme Q10 improved BMD, BMC, and bone strength, they failed to restore levels to normal. All treatments decreased BMMs and improved histopathological changes maximally with atorvastatin+L-carnitine which restored levels to near normal. Atorvastatin aggravated the ovariectomy-induced increase in CK level while estrogen, atorvastatin+L-carnitine, and atorvastatin+coenzyme Q10 decreased its level mainly with atorvastatin+L-carnitine which restored the level to near normal. Conclusions: Coadministration of L-carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. This could be valuable in treatment of osteoporotic patients. However, further confirmatory studies are needed.
Background and aim: Inflammatory cells involved in the pathophysiology of asthma express nicotini... more Background and aim: Inflammatory cells involved in the pathophysiology of asthma express nicotinic receptor. Therefore 1,1 dimethyl(-4-)phenylpiperazinium (DMPP) in two doses were compared to dexamethasone in asthmatic guinea pigs. Materials and methods: Six groups were included; Normal control and five asthmatic (OVA-sensitized and challenged) groups; which were treated for 10 days as follows: two vehicles, dexamethasone (DEXA, 1 mg/kg) and DMPP (0.4 and 0.8 mg/kg) groups. Pulmonary functions and airway hyper-responsiveness were assessed. Leukocytic count, tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6) and immunoglobulin E (IgE) were measured in both blood and bronchoalveolar lavage fluid (BALF). Histopathological examination of the lung tissues was conducted. Results: Asthmatic untreated animals exhibited significant increase in early and late airway resistance (RxV) and airway hyper-responsiveness, with reduction in tidal volume. Both blood and BALF showed significant increase in total leukocytic count (TLC), eosinophils, lymphocytes, monocytes, TNF-α, IL-6 and IgE with significant decrease in neutrophils. Airway inflammatory cell infiltration and smooth muscle thickness significantly increased. DMPP 0.4 mg/kg significantly decreased late phase RXV, TLC, BALF lymphocytes, TNF-α, smooth muscle thickness and increased neutrophils in BALF over both DEXA and DMPP 0.8 mg/kg. Moreover, DMPP 0.4 mg/kg significantly decreased IL-6 and BALF eosinophils than DMPP 0.8 mg/kg and decreased serum IgE and parenchymal inflammatory infiltration than DEXA. Conclusions: Low dose DMPP has more anti-inflammatory effect than a high dose in most parameters and sometimes than dexamethasone. Cholinergic anti-inflammatory pathway may therefore represent a potential drug target for allergic asthma. The dose related effect of DMPP and the mechanism underlying this effect require further evaluation.
Ethnopharmacological relevance: Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditio... more Ethnopharmacological relevance: Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditional medicine in treatment of many gastrointestinal disorders. 2 Aim of the study: This study aimed to evaluate potential protecting effect of ML and its major constituent, eucalyptol, against acetic acid-induced colitis in rats, a model of human inflammatory bowel disease (IBD). Materials and Methods: Rats were divided into ten groups (n=8) given orally for three days (mg/kg/day) the following: normal control, acetic acid-induced colitis (un-treated, positive control), vehicle (DMSO), sulfasalazine (500), ML extract (100, 500, 1000), and eucalyptol (100, 200, 400). After 24 h-fasting, two ml of acetic acid (3%) was administered intrarectally. On the fifth day, serum and colonic biochemical markers, and histopathological changes were evaluated. Results: Colitis significantly increased colonic myeloperoxidase activity and malonaldehyde level, and serum tumour necrosis factor-α, interleukin-6, and malonaldehyde levels while significantly decreased colonic and serum glutathione levels. All treatments (except ML 100, ML 1000, and eucalyptol 100) significantly reversed these changes where eucalyptol (400) showed the highest activity in a dose-dependent manner. The colitis-induced histopathological changes were mild in sulfasalazine and eucalyptol 400 groups, moderate in ML 500 and eucalyptol 200 groups, and severe in ML 100, ML 1000, and eucalyptol 100 groups nearly similar to colitis-untreated rats. Conclusion: ML (in moderate doses) and eucalyptol (dose-dependently) exerted protective effects against acetic acid-induced colitis in rats possibly through antioxidant and antiinflammatory properties suggesting a potential benefit in treatments of IBD. To our knowledge this is the first report addressing this point.
International Journal of General Medicine, Aug 1, 2022
Unplanned hospital readmission forms costly, but preventable burdens on healthcare system. This s... more Unplanned hospital readmission forms costly, but preventable burdens on healthcare system. This study was designed to evaluate cardiovascular-related readmission rate after discharge of acute coronary syndrome (ACS) patients and its relationship with medication adherence at a university hospital, Saudi Arabia. Methods: A total of 370 consecutive patients presenting with ACS were involved. The inclusion criteria were clinical and coronary angiography diagnostic data of ACS. Exclusion criteria included heart valve disease, myocarditis, hepatic disease, and history of acute infection during the previous two weeks. Patients were divided into index admission group (n = 291) and unplanned readmission group (n = 79). Readmission and medication adherence rates were evaluated during 1-30, 31-180, 181-365, and 366-548 days post-ACS discharge. Medication adherence was estimated with a (yes/no) questionnaire. Results: The overall readmission rate was 21.4%; individual rates were 30.4%, 38.0%, 27.8%, and 3.8% and the overall medication adherence rate was 62.03%, while individual rates were 54.2%, 70.0%, 63.6%, and 33.3% during the four periods, respectively. There were strong correlations between medication non-adherence and readmission rates. Heart failure, ST-elevated myocardial infarction, unstable angina, cerebrovascular accident, and arrhythmia represented the top causes. Body mass index was higher in readmission group. There were significant correlations between smoking, hypertension, cerebrovascular accident, ischemic heart disease, previous stent, instent restenosis, and LDL-cholesterol as predictor factors and readmission rate. Conclusion: The cardiovascular-related unplanned readmission rate post-ACS discharge was 21.4%, and medication non-adherence rate was 37.97%. There were strong correlations between them in the time frames from 1-month to 1.5-year post-discharge. The individual rates decreased by time, but the first month showed lower rates than the following 5 months and this indicated the role of factors other than medication non-adherence in readmission. The rates are generally consistent with the international levels but utilizing technology can further improve medication adherence and reduce readmission rates.
Nateglinide is suggested to have a glucose-dependent insulinotropic effect. We recently compared ... more Nateglinide is suggested to have a glucose-dependent insulinotropic effect. We recently compared serum insulin levels in fasting and non-fasting elderly diabetic patients following nateglinide administration and did not find a significant difference. Insulin, but not c-peptide is subjected to a significant first pass hepatic metabolism. Given the inclusion of 2 patients with liver dysfunction in the study, we estimated serum c-peptide levels in the same samples to further investigate this finding. Eight elderly diabetics underwent a fixed dose single blinded, placebo controlled, cross-over study. They received either nateglinide 120 mg or a placebo, both under fasting and non-fasting states. Serum c-peptide levels were measured at 30 minutes intervals for four hours, following drug or placebo administration. None of the eight patients developed hypoglycemia under the non-fasting state and only one patient developed mild hypoglycemia (66 mg/dl) under the fasting state in response to nateglinide. Area under the serum c-peptide concentration-time curve was not significantly different between the fasting and non-fasting states, following nateglinide, though it was significantly different in case of placebo. There was no correlation between serum c-peptide levels and serum glucose levels, in either of the 4 days. The present results are possibly explained by the lower mean fasting serum glucose levels, which would lead to the relatively lower insulin secretory effect of nateglinide and thus the insignificant difference in insulin secretion between the fasting and the fed state.
BMC complementary medicine and therapies, Feb 4, 2022
Background: The chemokine CXCL12 and its two receptors (CXCR4 and CXCR7) are involved in inflamma... more Background: The chemokine CXCL12 and its two receptors (CXCR4 and CXCR7) are involved in inflammation and hematopoietic cell trafficking. This study was designed to investigate molecular docking interactions of four popular cardiovascular-active natural compounds; curcumin, resveratrol, quercetin, and eucalyptol; with these receptors and to predict their drug-like properties. We hypothesize that these compounds can modify CXCL12/CXCR4/CXCR7 pathway offering benefits for coronary artery disease patients. Methods: Docking analyses were carried and characterized by Molecular Environment (MOE) software.Protein Data Bank (http:// www. rcsb. org/) has been retrieved from protein structure generation and crystal structures of CXCR4 and CXCR7 receptors (PDB code = 3ODU and 6K3F). The active sites of these receptors were evaluated and extracted from full protein and molecular docking protocol was done for compounds against them. The presented parameters included docking scores, ligand binding efficiency, and hydrogen bonding. The pharmacokinetic/toxic properties (ADME/T) were calculated using SwissADME, ProTox-II, and Pred-hERG softwares to predict drug-like properties of the compounds. The thermochemical and molecular orbital analysis, and molecular dynamics simulations were also done. Results: All compounds showed efficient interactions with the CXCR4 and CXCR7 receptors. The docking scores toward proteins 3ODU of CXCR4 and 6K3F of CXCR7 were − 7.71 and − 7.17 for curcumin, − 5.97 and − 6.03 for quercetin, − 5.68 and − 5.49 for trans-resveratrol, and − 4.88 and − 4.70 for (1 s,4 s)-eucalyptol respectively indicating that all compounds, except quercetin, have more interactions with CXCR4 than with CXCR7. The structurally and functionally important residues in the interactive sites of docked CXCR4-complex and CXCR7-complex were identified. The ADME analysis showed that the compounds have drug-like properties. Only (1 s,4 s)-Eucalyptol has potential weak cardiotoxicity. The results of thermochemical and molecular orbital analysis and molecular dynamics simulation validated outcomes of molecular docking study.
In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins... more In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins, its main polyphenolic pigments, will improve sildenafil-induced delay in gastric emptying (GE) and small intestinal transit (SIT) in mice. Twenty groups of mice (n = 8) were given a phenol red meal, and three sets of experiments were performed. In the first and second sets, effects of different concentrations of BTE, thearubigins (TRs), and sildenafil (SLD), alone and in combinations, on GE and SIT were measured. In the third set, influence of N ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) pretreatment on effects of these treatments was tested. Black tea extract (3% and 4.5%) and thearubigins (50 and 60 mg/kg) dose-dependently increased GE and SIT, whereas BTE 6% and thearubigins 70 mg/kg did not affect them. Sildenafil dose-dependently reduced both GE and SIT. Combination of metoclopramide, BTE 4.5%, thearubigins 60, or L-NAME with sildenafil (5 mg/kg) reversed its motility-delaying effects. Pretreatment with L-NAME followed by BTE 4.5%, thearubigins 60, BTE 4.5% + sildenafil 5, or thearubigins 60 + sildenafil 5 only partially affected the accelerating effects of BTE 4.5% and thearubigins 60. In conclusion, a standardized BTE and its thearubigins improve the sildenafil-induced delayed gut motility in mice. This improvement was partially blocked by L-NAME suggesting a possible role of nitric oxide. Thus, BTE 4.5% or TRs 60 mg/kg solution could be considered a reliever therapy for the sildenafil-induced dyspepsia.
Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats
Background: Chronic pain may be associated with diabetes mellitus and/or depression. Use of thera... more Background: Chronic pain may be associated with diabetes mellitus and/or depression. Use of therapies that target both comorbidities is encouraged. Objective: This study was designed to investigate the potential antinociceptive, neuroprotective, and antidepressant effects of combinations of pioglitazone or metformin with fluoxetine in chronic constriction injury (CCI) in rats. Study Design: Experimental trial in rats. Setting: University lab in Saudia Arabia. Methods: Two sets of experiments were performed. In each one, 9 groups of rats (n = 8) were used: sham, CCI, and 7 CCI-treated groups. Treatments were given orally starting on day 7 post-surgery as follows (mg/kg/day): fluoxetine (10, 20, and 40), pioglitazone (20), metformin (50), fluoxetine (20) + pioglitazone, and fluoxetine (20) + metformin. In the first set, on day 14 post-surgery mechanical allodynia, thermal hyperalgesia, and serum cytokines were measured. Moreover, immunoreactivity of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation) in the spinal cord was assessed and histopathological changes in the ipsilateral sciatic nerve were examined. In the second set, on days 14 and 21 post-surgery the forced swimming test was done. Results: In the first set, all treatments significantly decreased mechanical allodynia while all treatments except F10 and F20 significantly decreased thermal hyperalgesia compared to the CCI group. The F20+M group showed the highest decreases, however still significantly lower than those of the sham group. The treatments didn't impair motor function in the rotarod test. All treatments significantly decreased serum levels of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 while increasing the level of interleukin-10. The CCI-induced marked increase of GFAP immunoexpression has been reduced to moderate with fluoxetine (40) and pioglitazone, and to mild with metformin and the combination groups. The CCI-induced changes in sciatic nerve were less in fluoxetine (40), pioglitazone, and metformin groups, and least in the combination groups. In the second set, the immobility duration was significantly reduced by F20, F40, P, F20+P, and F20+M compared to the CCI group. The F20+P group showed the highest decrease, however still significantly lower than that of the sham group. The treatments didn't affect locomotor activity in the open field test. Limitations: Measuring the cytokines levels only in blood and not in the spinal cord and sciatic nerve and measuring the outcome measures in the first set of experiments at only one time-point. Conclusions: Co-administration of pioglitazone or metformin with low-dose fluoxetine improved mechanical allodynia, thermal hyperalgesia, and neurohistopathological changes while coadministration of pioglitazone, but not metformin, improved the depressive-like behavior in the peripheral nerve injury model of neuropathic pain in rats. Extrapolation of the current results to clinical reality could be beneficial for pain patients with diabetes and/or depression, however this needs further confirmatory studies.
Could Plasma CXCL12 Predict Ventricular Dysfunction in Patients with Severe Myocardial Infarction?
International Journal of Angiology, Sep 23, 2022
Plasma level of chemokine CXCL12 can predict adverse cardiovascular outcomes in patients with cor... more Plasma level of chemokine CXCL12 can predict adverse cardiovascular outcomes in patients with coronary artery disease, but data on its relationship with severity of coronary stenosis in cases of severe myocardial infarction (MI) are scarce and conflicting. The objective of this study was to investigate link between plasma CXCL12 levels and different grades of left ventricular ejection fraction (LVEF) in statin-treated and -untreated patients with severe MI. A total of 198 consecutive patients with first-time severe MI (ST-elevated myocardial infarction [STEMI], n = 121 and non-ST-elevated myocardial infarction [NSTEMI], n = 77) were recruited from Coronary Care Unit, King Abdulaziz University Hospital. They have one to two coronary arteries blocked ≥50%, or three arteries blocked 30 to 49%. Demographic and clinical criteria were collected and plasma CXCL12 level was measured. No correlations were detected between demographic and clinical criteria and CXCL12 level. While troponin peaks and LVEF significantly differed between STEMI and NSTEMI patients, CXCL12 level showed nonsignificant changes. Plasma CXCL12 levels decreased significantly in statin-treated patients compared with those untreated. From receiver operating characteristic (ROC) analysis, high CXCL12 levels were associated with no statin therapy. For STEMI and NSTEMI patients, area under the receiver operating characteristic curve for CXCL12 test were 0.685 and 0.820, while sensitivity and specificity values were 75.9 and 54.8%, and 73.1 and 84%, respectively. Plasma CXCL12 levels showed nonsignificant changes with different ranges of LVEF and troponin peaks. In patients with severe MI, irrespective of statin therapy, plasma CXCL12 showed no correlation with different ranges of LVEF suggesting that it cannot predict left ventricular dysfunction in these cases. However, cross-sectional design of this study is a limitation.
Brazilian Journal of Medical and Biological Research, 2022
Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and... more Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via offlabel routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mgÁkg-1 Áday-1), oral roflumilast (5 mgÁkg-1 Á day-1), or rectal roflumilast (5 mgÁkg-1 Áday-1) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-a, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-a. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-a, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.
Egyptian Journal of Basic and Clinical Pharmacology (Print), 2011
In this study, we examined the renoprotective effects of curative and prophylactic doses of epler... more In this study, we examined the renoprotective effects of curative and prophylactic doses of eplerenone and captopril in L-NAME-treated rats. Rats were divided into seven groups: The first and second (normal control and hypertensive control) groups received distilled water and L-NAME (L-nitro arginine methyl ester, 50 mg/kg per day), respectively, for eight weeks. The third and fourth groups received L-NAME (50 mg/kg per day) plus a prophylactic dose of eplerenone (50 mg/kg per day) or captopril (25 mg/kg per day), respectively, for eight weeks. The fifth, sixth and seventh groups received L-NAME (50 mg/kg per day) for eight weeks, followed by curative doses of eplerenone (100 mg/kg per day), captopril (50 mg/kg per day) or eplerenone plus captopril (50 + 25 mg/kg per day), respectively, for five weeks. The drugs were administered by gastric gavage. During prophylactic therapy, eplerenone and captopril decreased the L-NAME-induced rise in systolic blood pressure (SBP) and serum creatinine levels. Furthermore, both drugs improved microalbuminuria and renal histopathological changes and increased serum nitric oxide (sNO) levels. During curative therapy, eplerenone improved microalbuminuria and renal histopathological changes. Captopril or the combination of captopril and eplerenone improved all L-NAME-induced changes. The combination improved renal histopathological changes more significantly than each individual drug did. In conclusion, eplerenone and captopril have prophylactic and curative renoprotective effects in L-NAMEtreated rats, indicating the promising role of eplerenone as an add-on therapy to captopril in antihypertensive drug regimens.
Background: This study was designed to examine effects of telmisartan; an angiotensin receptor bl... more Background: This study was designed to examine effects of telmisartan; an angiotensin receptor blocker; self-nanoemulsifying drug delivery system (SNEDDS) in reversing already-established hepatic fibrosis. Method: Forty rats were given thioacetamide (200 mg/kg, intraperitoneally) twice/week for 8 weeks then divided into 5 groups (n ¼ 8), PC and 4 treated groups. Treatments were given orally for another 2 months as follows: telmisartan low and high doses (TL and TH: 1.8 and 3.6 mg/kg/day) and telmisartan SNEDDS at the same doses (TLS and THS). At end of treatment, blood was obtained and liver was isolated. Results: Rats showed significant elevations of plasma ALT and AST and hepatic IL-6, TNF-a, and MDA, significant reductions of plasma albumin, hepatic GSH, and body weight, and hepatic histopathological damage. All treatments except for TL significantly reversed these thioacetamide-induced changes. THS group showed significant differences from all groups. Regarding ratio of free telmisartan concentration in hepatic homogenate to that of plasma, TH and TLS groups showed non-significant variation between each other while THS group showed significant differences from them. No significant changes were detected in blood pressure, hemoglobin, white blood cells, and platelets. Conclusion: Telmisartan SNEDDS, compared with telmisartan, more effectively reversed chronic hepatic fibrosis with good safety profile.
Effect of eucalyptol on matrix metalloproteinase-9 and its tissue inhibitor in hypertensive rats
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Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP... more Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1), compared with lisinopril, were investigated in a model of hypertension induced by chronic intraperitoneal (IP) injection of low dose nicotine in rats. The hypertensive rats were randomly allocated to 4 groups (n=8): Positive control (PC, untreated), eucalyptol-treated group (1.0 mg/kg, IP), lisinopril-treated group (10 mg/kg, IP), and eucalyptol+lisinopril-treated group. Systolic blood pressure and plasma levels of MMP-9 and TIMP-1 were measured. All treatments decreased the elevated blood pressure and plasma levels of MMP-9 and TIMP-1 most significantly with the combination group which showed non-significant differences from the normal control group. Lisinopril reduced plasma levels of MMP-9 and TIMP-1 more significantly than eucalyptol. In conclusion, eucalyptol significantly decreased the increased plasma levels of MMP-9 and TIMP-1 in nicotine-in...
Background: T-box family members are transcription factors characterized by highly conserved resi... more Background: T-box family members are transcription factors characterized by highly conserved residues corresponding to the DNA-binding domain known as the T-box. TBX2 has been implicated in several developmental processes, such as coordinating cell fate, patterning, and morphogenesis of a wide range of tissues and organs, including lungs, limbs, heart, kidneys, craniofacial structures, and mammary glands.Methods: In the present study, we have clinically and genetically characterized a proband showing a severe form of chondrodysplasia with developmental delay. Whole-exome sequencing (WES), Sanger sequencing, and 3D protein modeling were performed in the present investigation.Results: Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2. 3D-TBX2 protein modeling revealed a substantial reduction of the mutated protein, which might lead to a loss of function (LOF) or nonsense-mediated decay (NMD).Conclusion: This study has not only expan...
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