Development of Transdermal Oleogel Containing Olmesartan Medoxomil: Statistical Optimization and Pharmacological Evaluation.

Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM side effects and boost its therapeutic efficacy and bioavailability. OLM oleogel formulations were composed of Tween 20, Aerosil 200, and lavender oil. A central composite response surface design chose the optimized formulation, containing Oil/Surfactant (SAA) ratio of 1:1 and Aerosil % of 10.55%, after showing the lowest firmness and compressibility, and the highest viscosity, adhesiveness, and bioadhesive properties (Fmax and Wad). The optimized oleogel increased OLM release by 4.21 and 4.97 folds than the drug suspension and gel, respectively. The optimized oleogel formulation increased OLM permeation by 5.62 and 7.23 folds than the drug suspension and gel, respectively. The pharmacodynamic study revealed the superiority of the optimized formulation in maintaining normal blood pressure and heart rate for 24 h. The biochemical analysis revealed that the optimized oleogel achieved the best serum electrolyte balance profile, preventing OLM-induced tachycardia. The pharmacokinetic study showed that the optimized oleogel increased OLM's bioavailability by more than 4.5- and 2.5-folds compared to the standard gel and the oral market tablet, respectively. These results confirmed the success of oleogel formulations in the transdermal delivery of OLM.

Corrigendum to "Biochemical and pharmacological prospects of citrus sinensis peel" [Heliyon 8, (8), (August 2022), e09979].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09979.].

Curcumin nanoemulsion counteracts hepatic and cardiac complications associated with high-fat/high-fructose diet in rats.

The relationship between the incidence of cardiovascular abnormalities and non-alcoholic fatty liver disease (NAFLD) has long been postulated. Curcumin (CUR) is a potential anti-atherosclerotic agent but its poor water solubility hinders its pharmacological use. Therefore, the present study aimed to investigate the effect of formulation of CUR nanoemulsion prepared using the spontaneous emulsification technique on high fat high fructose (HFHF)-induced hepatic and cardiac complications. Fifty Wistar rats were divided into five groups. CUR nanoemulsion at doses of 5 and 10 mg/kg and conventional powdered CUR at a dose of 50 mg/kg were orally administered daily to rats for two weeks, and compared with normal control and HFHF control. Results revealed that the high dose level of CUR nanoemulsion was superior to conventional CUR in ameliorating the HFHF-induced insulin resistance status and hyperlipidemia, with beneficial impact on rats' recorded electrocardiogram (ECG), serum aspartate aminotransferase (ALT) and alanine aminotransferase (AST) levels, leptin, adiponectin, creatine phosphokinase, lactate dehydrogenase and cardiac troponin-I. In addition, hepatic and cardiac oxidative and nitrosative stresses, oxidative DNA damage and disrupted cellular energy statuses were counteracted. Results were also confirmed by histopathological examination. PRACTICAL APPLICATIONS: The use of curcumin nanoemulsion could be beneficial in combating hepatic and cardiac complications resulting from HFHF diets.

Biochemical and pharmacological prospects of Citrus sinensis peel.

Gastric ulcer and hepatotoxicity due to irrational drug overuse are two of the most serious conditions associated with inflammation and oxidative stress that affect the digestive system. This study aimed to experimentally evaluate the hepatoprotective/gastroprotective effects of aqueous and butanol citrus peel extracts and hesperidin in rat models of ulcer and hepatotoxicity. Acute toxicity study was performed for determining the safe dose of citrus extracts to analyze efficacy. In the experiments on hepatoprotective and gastroprotective effects, rats were classified into nine groups in each experiment: (1) negative control, (2) positive control hepatotoxic model with paracetamol (640 mg/kg)/gastric ulcer model:ethanol 70% (1 ml), (3)reference hepatoprotective:silymarin (25 mg/kg)/gastroprotective:ranitidine (50 mg/kg), and (4-9) groups treated for 2 weeks before induction of each disease with either citrus aqueous or butanol extracts or hesperidin (125-250 mg/kg). Drugs, ethanol, or tested compounds were administered orally. The levels of biochemical parameters, such as AST, ALT, NO, MDA, CRP, and ILß6, were significantly reduced, but CAT level was increased. Postmortem examination of liver and stomach tissues of treated animals revealed marked improvement compared with positive control animals. Hesperidin exerted the best hepatoprotective, antioxidant, anti-inflammatory, and gastroprotective effects, followed by butanol and then aqueous citrus peel extracts.

Pharmacological and metabolomic profiles of Musa acuminata wastes as a new potential source of anti-ulcerative colitis agents.

Musa acuminata (MA) is a popular fruit peels in the world. Non-food parts of the plant have been investigated for their antioxidant and anti-ulcerative colitis activity. Metabolomic approaches were found to be informative as a screening tool. It discovered different metabolites depending on statistical analysis. The antioxidant activity content was measured by colorimetric method. Seventy six investigated metabolites were observed. The identities of some of these markers were confirmed based on their MS2 fragmentation and NMR spectroscopy. These include: cinnamic acid and its dimer 2-hydroxy-4-(4-methoxyphenyl)-1H-phenalen-1-one beside; gallic acid and flavonoids; quercetin, quercetin-3-O-ß-D-glucoside, luteolin-7-O-ß-D-glucopyranoside. GC/MS analysis of MA peels essential oil led to identification of 37 compounds. The leaves, pseudostem and fruit peels extracts were tested for their safety and their anti-ulcerative colitis efficacy in rats. Rats were classified into: normal, positive, prednisolone reference group, MA extracts pretreated groups (250-500 mg/kg) for 2 weeks followed by induction of ulcerative colitis by per-rectal infusion of 8% acetic acid. Macroscopic and microscopic examinations were done. Inflammatory markers (ANCA, CRP and Ilß6) were measured in sera. The butanol extracts showed good antioxidant and anti-inflammatory activities as they ameliorated macroscopic and microscopic signs of ulcerative colitis and lowered the inflammatory markers compared to untreated group. MA wastes can be a potential source of bioactive metabolites for industrial use and future employment as promising anti-ulcerative colitis food supplements.

The Potential Synergistic Activity of Zolmitriptan Combined in New Self-Nanoemulsifying Drug Delivery Systems: ATR-FTIR Real-Time Fast Dissolution Monitoring and Pharmacodynamic Assessment.

PURPOSE: The current work aimed to overcome the poor permeability and undesirable adverse effects of Zolmitriptan (ZMT) and to increase its efficacy in the treatment of acute migraine by exploiting the synergistic effect of the essential oil, lavender, to fabricate ZMT self-nanoemulsifying drug delivery systems (ZMT-SNEDDS). METHODS: ZMT-SNEDDS were fabricated based on full factorial design (32) to statistically assess the impact of oil and surfactant concentrations on the nanoemulsion globule size, zeta potential and percentage drug dissolution efficiency. An ATR-FTIR method was developed and validated for continuous real-time monitoring of ZMT dissolution and permeation. The dose of the optimized ZMT-SNEDDS used in the efficacy study was selected according to the acute toxicity study. The efficacy study was performed on migraineous rats induced by nitroglycerin and was evaluated by the activity cage and thermal tests, electroencephalogram, electroconvulsive stimulation, and biochemical analysis of brain tissue. Finally, histopathological and immunohistochemical examinations of the cerebra were carried out. RESULTS: Upon dilution, the optimized ZMT-SNEDDS (F5) exhibited nanosized spherical droplets of 19.59±0.17 nm with narrow size distribution, zeta potential (-23.5±1.17mV) and rapid emulsification characteristics. ATR-FTIR spectra elucidated the complete time course of dissolution and permeation, confirming F5 superior performance. Moreover, ZMT-SNEDDS (F5) showed safety in an acute toxicity study. ZMT concentration in rat brain tissues derived from F5 was lower compared to that of ZMT solution, yet its effect was better on the psychological state, algesia, as well as maintaining normal brain electrical activity and delayed convulsions. It counteracted the cerebral biochemical alternations induced by nitroglycerin, which was confirmed by histopathological examination. CONCLUSION: In a nutshell, these findings corroborated the remarkable synergistic efficacy and the high potency of lavender oil-based ZMT-SNEDDS in migraine management compared to the traditional zolmitriptan solution.

Nicotinamide and ascorbic acid nanoparticles against the hepatic insult induced in rats by high fat high fructose diet: A comparative study.

AIMS: Non-alcoholic fatty liver disease (NAFLD) caused by consumption of high levels of fat and sugars (HFHS) in diet is considered one of the most dangerous medical complications among children and adolescents. Nicotinamide is among the promising candidates in ameliorating HFHS diet-induced NAFLD, but its use is limited by the possibility of prompting hepatotoxicity in high doses. Ascorbic acid is another promising candidate, however its use as a hepatoprotective agent is limited by its chemical instability. Therefore, the aim of the study was to overcome their delivery limitations and enhance their hepatoprotective activity by loading into nanoparticles. KEY FINDINGS: In the present study, upon incorporating nicotinamide or ascorbic acid in chitosan nanoparticles, they ameliorated the insulin-resistant status induced in rats by a high-fat-high-fructose (HFHF) diet. Both formulae decreased serum level of ALT and AST, as well as liver tissue total cholesterol, triglycerides and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. They also decreased oxidative and nitrosative stresses along with a significant increase in the hepatocellular energy. The biochemical findings were further confirmed by histopathological examination. Finally from the obtained data it could be concluded that chitosan nicotinamide nanoparticles at a dose level (10 mg/kg, p.o.) demonstrated beneficial pharmacological effect with safer toxicity profile than chitosan ascorbic acid nanoparticles. SIGNIFICANCE: Nicotinamide chitosan nanoparticles could be recommended as daily supplement in the recovery from NAFLD.

Synthesis and Evaluation of New Coumarin Derivatives as Antioxidant, Antimicrobial, and Anti-Inflammatory Agents.

New pyranocoumarin and coumarin-sulfonamide derivatives were prepared and evaluated for their antioxidant, antimicrobial, and/or anti-inflammatory activities. Coumarin-sulfonamide compounds 8a-d demonstrated significant antioxidant activity, while 7c,d, 8c,d, and 9c,d exhibited antimicrobial activity equal to or higher than the standard antimicrobials against at least one tested microorganism. Regarding the anti-inflammatory testing, pyranocoumarins 2b, 3a,b and 5c and coumarin-sulfonamide compound 9a showed more potent antiproteinase activity than aspirin in vitro; however, five compounds were as potent as aspirin. The anti-inflammatory activity of the promising compounds was further assessed pharmacologically on formaldehyde-induced rat paw oedema and showed significant inhibition of oedema. For in vitro COX-inhibitory activity of coumarin derivatives, pyranocoumarin derivative 5a was the most selective (SI = 152) and coumarin-sulfonamide derivative 8d was most active toward COX-2 isozyme. The most active derivatives met the in silico criteria for orally active drugs; thus, they may serve as promising candidates to develop more potent and highly efficient antioxidant, antimicrobial, and/or anti-inflammatory agents.

Exploiting Citrus aurantium seeds and their secondary metabolites in the management of Alzheimer disease.

Fruit by-products are considered nature's golden gift for human health and a good starting point to discover new drugs depending on the fact that they contain millions of bio-active compounds that are responsible for therapeutic activities. In this context, the main goal of this study is to recycle Citrus aurantium (C. aurantium) seeds to produce pharmaceutical molecules to be used in the prevention of the progressive neurological damage associated with Alzheimer disease (AD). Donepezil (0.75 mg/kg), hesperidin (125 and 250 mg/kg) and limonoids (50 and 100 mg/kg) were used for treatment of rats for 2 weeks prior to concomitant administration of AlCl3 for three successive weeks. Protection against cognitive deterioration was observed among study group with insignificant difference from normal control group and significant difference from positive control group in the Y-Maze test. On the other hand, treatment with both doses of hesperidin (125 and 250 mg/kg) and high dose of limonoids only (100 mg/kg) produced improvement in psychological state, observed by significant increase in ambulation frequency in comparison to positive control group, however it was not as frequent as normal group, as it was significantly less than normal group in the open field test. Regarding acetylcholine esterase (AChE) and beta-amyloid (ß amyloid) levels, the effect of limonoids low dose was the best as it didn't have a significant effect when compared to normal control, also hesperidin in both doses showed insignificant effects on ß amyloid levels when compared to normal control group. Our results encourage the use of C. aurantium seeds which are wasted in huge amounts, as Alzheimer prophylactic food additives.

The Carcinogenic Agent Diethylnitrosamine Induces Early Oxidative Stress, Inflammation and Proliferation in Rat Liver, Stomach and Colon: Protective Effect of Ginger Extract.

Background: Diethylnitrosamine (DENA), a well-known dietary carcinogen, related to cancer initiation of various organs. The present study investigated the deleterious mechanisms involved in the early destructive changes of DENA in different organs namely, liver, stomach and colon and the potential protective effect of GE against these mechanisms. Methods: Adult male albino rats were assigned into four groups. A normal control group received the vehicle, another group was injected with a single necrogenic dose of DENA (200 mg/kg, i.p) on day 21. Two groups received oral GE (108 or 216 mg/kg) daily for 28 days. Sera, liver, stomach and colon were obtained 7 days after DENA injection. Serum aspartate transaminase and alanine transaminase were detected as well as reduced glutathione (GSH), malondialdehyde, nitric oxide metabolites, interleukin 1ß, tumor necrosis factor (TNF-α), alpha-fetoprotein (AFP) and nuclear factorerythroid 2-related factor2 (Nrf2) in liver, stomach and colon. Histopathological studies and immunohistochemical examination of cyclooxygenase-2 (COX2) were conducted. Results: DENA induced elevation in liver function enzymes with significant increase in oxidation and inflammation biomarkers and AFP while decreased levels of Nrf2 in liver, stomach and colon were detected. Histologically, DENA showed degenerative changes in hepatocytes and inflammatory foci. Inflammatory foci displayed increased expression of COX2 in immunohistochemical staining. GE-pretreatment improved liver function and restored normal GSH with significant mitigation of oxidative stress and inflammatory biomarkers compared to DENA-treated group. AFP was reduced by GE in both doses, while Nrf2 increased significantly. Histology and immunostaining of hepatic COX-2 were remarkably improved in GE-treated groups in a dose dependent manner. Conclusion: GE exerted a potential anti-proliferative activity against DENA in liver, stomach and colon via Nrf2 activation, whilst suppression of oxidation and inflammation.

Effects of genistein on pentylenetetrazole-induced behavioral and neurochemical deficits in ovariectomized rats.

Estrogenic compounds have been documented in literature to exert neuroprotective effects. This study investigated the potential neuroprotective effect of genistein; a phytoestrogen at doses of 5, 10, 20, and 40 mg/kg p.o. in ovariectomized rats challenged with pentylenetetrazole (PTZ) 90 mg/kg i.p. Systemic acute administration of PTZ induced seizures, increased oxidative stress, and caused apoptosis and histological abnormalities. Pretreatment with genistein delayed seizure onset, reduced the seizure duration, improved oxidative stress profile, decreased estrogen receptor expression, reduced apoptosis, and improved the histopathological pattern. Overall, the genistein doses (10 and 20 mg/kg) showed the strongest protective effects. In conclusion, the current study suggests that genistein exhibits neuroprotective effects against PTZ-induced seizures. Such effects might be attributed to its estrogenic, antioxidant, and/or anti-apoptotic properties.

Antihypercholesterolaemic effect of ginger rhizome (Zingiber officinale) in rats.

INTRODUCTION: Many herbal medicinal products have potential hypocholesterolaemic activity and encouraging safety profiles. However, only a limited amount of clinical research exists to support their efficacy. AIM OF THE WORK: The present study was designed to evaluate the antihypercholesterolaemic effects of aqueous ginger (Zingiber officinale) infusion in hypercholesterolaemic rat models. METHODS: 48 rats were used throughout the experiment, which were divided into six groups, eight animals each as follows: normal control group (normal rats which fed with standard diet). After induction of hypercholesterolaemia by feeding rats with high cholesterol diet, the remaining rats were divided into five groups: group 1, hypercholesterolaemic control group (hypercholesterolaemic rats group); groups 2, 3 and 4, rats were given aqueous infusion of ginger (100, 200 and 400 mg/kg, respectively) orally; and group 5, rats were given atorvastatin (0.18 mg/kg) orally as a reference antihypercholesterolaemic drug. The blood was obtained from all groups of rats after being lightly anaesthetized with ether and the following lipid profile [serum total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-C and triglyceride levels] was measured at zero time and 2 and 4 weeks after ginger and atorvastatin treatment, and the risk ratio (TC/HDL-cholesterol) was assessed. RESULTS: The results revealed that the hypercholesterolaemic rats treated with aqueous ginger infusion in the three doses used after 2 and 4 weeks of treatment induce significant decrease in all lipid profile parameters which were measured and improved the risk ratio.