Assembly of In-Situ Gel Containing Nano-Spanlastics of an Angiotensin II Inhibitor as a Novel Epitome for Hypertension Management: Factorial Design Optimization, In-vitro Gauging, Pharmacokinetics, and Pharmacodynamics Appraisal.

More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.

Anti-Alzheimer's Activity of Polyphenolic Stilbene-Rich Acetone Fraction of the Oil-Removed Seeds of Passiflora edulis: in Vivo and in Silico Studies.

The stilbene-rich acetone fraction in high yield (6.6 %, PEAS) of Passiflora edulis Sims was prepared and evaluated for neuroprotective activity in murine Alzheimer's disease model induced by aluminum chloride and D-galactose. The phytochemical and HPLC-DAD-MS analysis of the polyphenolic stilbene-rich acetone fraction showed that it contained different stilbenes including trans-piceatannol, scirpusins A-B and cassigarol E. The total phenolic content (TPC) of PEAS was 413.87±1.71 mg GAE eqv/g. The neuroprotective activity of PEAS is typically presented in the Morris water maze-reference Spatial Memory test, where the Alzheimer's mice treated at 100 mg/kg (Alz-ED1) and 200 mg/kg (Alz-ED2) spent less than 47 % and 66 % of the time, respectively, than the Alzheimer's model mice (Alz). Two simple stilbenes, trans-piceatannol and trans-resveratrol, showed selectively inhibitory activity in silico against acetylcholinesterase (AChE). Two stilbene dimers, cassigarol E and scirpusin A, exhibited low nanomolar inhibitory potential against AChE and butyrylcholinesterase (BChE), significantly lower than those of the positive control, donepezil and tacrine. These findings suggest that the stilbenes from P. edulis seeds, particularly the stilbene dimers, warrant further investigation as potential neuroprotective candidates in the prevention of cognitive deficits associated with Alzheimer's disease.

CagA+ Helicobacter pylori infection and N-nitrosodimethylamine administration induce cholangiocarcinoma development in hamsters.

BACKGROUND: Helicobacter pylori (HP) has been detected in the hepatobiliary tract of cholangiocarcinoma (CCA) patients in regions both endemic and non-endemic for Opisthorchis viverrini (OV) infection. However, whether H. pylori infection promotes CCA development remains unknown. We investigated CCA development in hamsters induced by a combination of infection with H. pylori and administration of N-nitrosodimethylamine (NDMA) and compared findings with those in an OV plus NDMA group. MATERIALS AND METHODS: Eighty-five hamsters were divided into four groups: (1) normal, (2) administered NDMA, (3) infected with cagA+ H. pylori and administered NDMA (HN group), and (4) infected with OV and administered NDMA (ON group). Animals were euthanized at 3 and 6 months post-infection. Histopathological changes of liver and the expression of markers associated with carcinogenesis were studied. RESULTS: At 3 months post-infection (p.i.), cholangitis and lymphoid follicles without tumor appearance were noted in the HN group, whereas extensive fibrosis was seen in members of the ON group, 10% of which had developed tumors. At 6 months p.i., 10% of hamsters administered NDMA alone had developed CCA, whereas in the HN and ON groups, 20% and 60% of hamsters, respectively, had developed CCA. Cytokeratin-19 (CK19) expression was observed in the CCA tissues of both the HN and the ON groups, confirming the bile duct origin of the CCA cells. CCA development in the HN group might be inflammation-mediated, as suggested by overexpression of HMGB1, PCNA, IL-8, and 8-OxodG in CCA tissues. CONCLUSION: cagA+ H. pylori infection and carcinogen intake can induce CCA development with slow progression.

Promising Antidiabetic and Antimicrobial Agents Based on Fused Pyrimidine Derivatives: Molecular Modeling and Biological Evaluation with Histopathological Effect.

Diabetes is the most common metabolic disorder in both developing and non-developing countries, and a well-recognized global health problem. The WHO anticipates an increase in cases from 171 million in 2000 to 366 million by 2030. In the present study, we focus on the preparation of pyrimidine derivatives as potential antidiabetic and antimicrobial agents. Thein vivoeffect on total serum glucose concentration, cholesterol and antioxidant activity was assessed in adult male albino Wister rats and compared to the reference drug glimperide. Promising results were observed for compound 5. The histopathological study confirms that compound 5 results in significant activity with liver maintenance. The antimicrobial activities were evaluated against several bacterial strains such as Salmonella typhimurium ATCC 25566, Bacillus cereus, Escherichia coli NRRN 3008, Pseudomonas aeruginosa ATCC 10145, Staphylococcus aureus ATCC 6538and fungi such as Rhizopus oligosporus, Mucor miehei and Asperillus niger. Compounds 4 and 5 showed a good inhibition of the bacterial zone compared to the reference drug cephradine. Finally, we suggest protein targets for these drugs based on computational analysis, and infer their activities from their predicted modes of binding using molecular modeling. The molecular modeling for compounds 4 and 5 resulted in improved docking scores and hydrogen bonding. The docking studies are in good agreement with the in vitro and in vivo studies.

The Unexplored Wound Healing Activity of Urtica dioica L. Extract: An In Vitro and In Vivo Study.

Wound healing is a great challenge in many health conditions, especially in non-healing conditions. The search for new wound healing agents continues unabated, as the use of growth factors is accompanied by several limitations. Medicinal plants have been used for a long time in would healing, despite the lack of scientific evidence veryfying their efficacy. Up to now, the number of reports about medicinal plants with wound healing properties is limited. Urtica dioica L. is a well-known plant, widely used in many applications. Reports regarding its wound healing potential are scant and sparse. In this study, the effect of an Urtica dioica L. extract (containing fewer antioxidant compounds compared to methanolic or hydroalcoholic extracts) on cell proliferation, the cell cycle, and migration were examined. Additionally, antioxidant and anti-inflammatory properties were examined. Finally, in vivo experiments were carried out on full-thickness wounds on Wistar rats. It was found that the extract increases the proliferation rate of HEK-293 and HaCaT cells up to 39% and 30% after 24 h, respectively, compared to control cells. The extract was found to increase the population of cells in the G2/M phase by almost 10%. Additionally, the extract caused a two-fold increase in the cell migration rate of both cell lines compared to control cells. Moreover, the extract was found to have anti-inflammatory properties and moderate antioxidant properties that augment its overall wound healing potential. Results from the in vivo experiments showed that wounds treated with an ointment of the extract healed in 9 days, while wounds not treated with the extract healed in 13 days. Histopathological examination of the wound tissue revealed, among other findings, that inflammation was significantly reduced compared to the control. Urtica dioica L. extract application results in faster wound healing, making the extract ideal for wound healing applications and a novel drug candidate for wound healing.

Development and optimization of nanoemulsion based gel for enhanced transdermal delivery of nitrendipine using box-behnken statistical design.

Objective: The purpose of present research was to develop and statistically optimize nitrendipine nanoemulsion gel for transdermal delivery using box-behnken statistical design.Method: The nanoemulsion formulations bearing nitrendipine were prepared by application of ternary phase diagram and spontaneous emulsification method. Box-behnken design was employed for the optimization of nitrendipine loaded nanoemulsion. The independent variables were oil, surfactant and co-surfactant while globule size, drug content and zeta potential were dependent variables. The optimized nanoemulsion formulation was incorporated into gel and evaluated for in-vitro release, ex-vivo permeation studies, confocal laser scanning microscopy, skin irritation and histopathological studies.Results: The optimized formulation through box-behnken statistical design showed globule size of 20.43 ± 1.50 nm, drug content of 97.05 ± 1.77% and zeta potential of -15.45 ± 0.35 mV. The ex-vivo study confirmed the enhanced delivery of nitrendipine from nanoemulsion gel than compare to drug solution by virtue of better permeation and solubility. Nanoemulsion gel was proved significantly superior by confocal laser scanning microscopy for satisfactory permeation and distribution of gel, deep into the rat skin. The optimized gel was found with no allergic dermal effects and was proved safe by histopathological studies for transdermal application.Conclusions: Results reveals that developed nitrendipine nanoemulsion gel overcomes the limitation of low penetration and accentuate permeation through albino Wistar rat skin. It was concluded that nanoemulsion gel could be utilized as a potential carrier for transdermal delivery of nitrendipine.

Comparative lyophilized platelet-rich plasma wafer and powder for wound-healing enhancement: formulation, in vitro and in vivo studies.

Platelet-rich plasma (PRP) accelerates wound healing, as it is an excellent source of growth factors. PRP was separated from whole human blood by centrifugation. PRP powder and wafers were prepared by lyophilization, with the wafers prepared using sodium carboxymethylcellulose (Na CMC). The PRP wafers showed porous structures, as indicated by scanning electron microscopy (SEM) images, and the ability of the wafer to absorb exudates and thus promote wound healing was tested with the hydration capacity test. The platelet count was tested and indicated that the presence of PRP in the wafers had no effect on the platelet count. An antimicrobial activity test was carried out, showing that PRP had antibacterial activity against Gram-negative bacteria. Compared with lyophilized PRP powder and PRP-free wafers, PRP wafers showed the highest percent of wound size reduction on induced wounds in rats. Histopathological examination of rat skin showed that the PRP wafers achieved the shortest healing time, followed by the lyophilized PRP powder and finally the PRP-free wafers. The present study revealed that PRP can be formulated as a wafer, which is a promising pharmaceutical delivery system that can be used for enhanced wound-healing activity and improved the ease of application compared to lyophilized PRP powder.

The histopathological comparison on the destruction of the periodontal tissue between normal junctional epithelium and long junctional epithelium.

BACKGROUND AND OBJECTIVE: The barrier function of long junctional epithelium is thought to be important after periodontal initial therapy and periodontal surgery. Although the difference between long junctional epithelium and normal junctional epithelium regarding their resistance to destruction of periodontal tissue has been investigated, the mechanism still remains unclear. Using our rat experimental periodontitis model in which loss of attachment and resorption of alveolar bone is induced by the formation of immune complexes, we investigated the resistance of periodontal tissue containing long junctional epithelium and normal junctional epithelium to destruction. MATERIAL AND METHODS: Rats were divided into four groups. In the immunized long junctional epithelium (I-LJE) group, rats were immunized with lipopolysaccharide (LPS), and curettage and root planing procedures were performed on the palatal gingiva of the maxillary first molars to obtain reattachment by long junctional epithelium. In the immunized normal junctional epithelium (I-JE) group, rats were immunized without curettage and root planing procedures. In the nonimmunized long junctional epithelium (nI-LJE) group, rats were not immunized but curettage and root-planing procedures were performed. In the control group, neither immunization nor curettage and root-planing was performed. In all rats, periodontal inflammation was induced by topical application of LPS into the palatal gingival sulcus of maxillary first molars. The rats were killed at baseline and after the third and fifth applications of LPS. Attachment loss and the number of inflammatory cells and osteoclasts in the four groups were compared histopathologically and histometrically. RESULTS: After the third application of LPS in the I-LJE group, attachment loss showed a greater increase than in control and nI-LJE groups, and inflammatory cell infiltration and osteoclasts were increased more than in the other groups. After the fifth application of LPS, attachment loss was greater and there was a higher degree of inflammatory cell infiltration in nI-LJE and I-LJE groups than in control and I-JE groups. CONCLUSION: Our findings suggest that the destruction of periodontal tissue is increased in tissue containing long junctional epithelium compared with normal junctional epithelium and that the immunized condition accelerates the destruction by forming immune complexes.

A new species of philometrid parasite (Nematoda, Philometridae) and histopathological lesions in juvenile whitemouth croakers, Micropogonias furnieri (Desmarest).

A new species of nematode parasite, Philometroides tahieli sp. nov. is described. The juvenile whitemouth croaker, Micropogonias furnieri Desmarest, was collected during the spring and summer of the years 2008-2010 from estuarial environments of Argentina. During investigations of the parasite fauna a nematode encapsulated in the musculature of the operculum was found. The nematodes were removed from the host's muscle tissue and slide-mounted in lactophenol solution to clarify the specimens. Opercular muscle with the parasite was processed for histopathological examination. Philometroides tahieli sp. nov. can be identified by the location of gravid females in the host, presence of anterior oesophageal bulb, bosses on the surface of the body, presence of transversal mounds and 14 cephalic papillae in two circular rows. The pathogenicity of the parasite is low in the natural environment, but lesions are consistent with a chronic process. The appearance of caseous necrosis suggests the presence of a locally acting substance. Philometroides tahieli sp. nov. is the second species of this genera described from brackish waters, and since the discovery of Philometroides maplestoni in 1928, is the first species of this genus recorded for South America.

A hemodynamic, metabolic and histopathological study of a heterotopic auxiliary swine liver graft with portal vein arterialization.

BACKGROUND: Auxiliary heterotopic liver transplantation with portal vein arterialization (AHLT-PVA) is a model that has been hardly studied, despite its therapeutic potential. METHODS: Hemodynamic and biochemical characterization was carried out during graft implantation, in a pig-to-pig model (n=15 AHLT-PVA). Furthermore a histopathological study was performed to establish microscopic alterations due to PVA. RESULTS: Reperfusion of the arterialized graft produced an increase in heart rate (HR) vs. baseline (P=.004) and vs. inferior vena cava clamping phase (P=.004); and a decrease in systemic vascular resistance vs. cava clamping phase (P=.021). At the end of implantation, cardiac output remained elevated (P=.001), likewise HR remained increased vs. baseline phase (P=.002). Mean arterial pressure decreased with cava clamping, but was not affected by the reperfusion of the graft, nor the skin closure. The histopathological study at 3, 10, and 21 days post-PVA revealed that functional liver structure was maintained although it is common to find foci of perilobular necrosis on day 3 (P=.049), and perilobular connective tissue proliferation at day 10 (P=.007), vs. native liver. CONCLUSIONS: The described arterialized liver graft model minimizes the number of vascular anastomoses vs. previously described models. It is hemodynamically and metabolically well tolerated and the double arterial vascularization of the graft does not cause significant changes in liver histology.

Occlusal trauma accelerates attachment loss at the onset of experimental periodontitis in rats.

BACKGROUND AND OBJECTIVE: Occlusal trauma is an important factor that influences the progression of periodontitis, but it is unclear whether occlusal trauma influences periodontal destruction at the onset of periodontitis. We established an experimental periodontitis model with both site-specific loss of attachment and alveolar bone resorption. The purpose of the present study was to investigate the effects of occlusal trauma on periodontal destruction, particularly loss of attachment, at the onset of experimental periodontitis. MATERIAL AND METHODS: Sixty rats were used in the present study. Forty-eight rats immunized with lipopolysaccharide (LPS) intraperitoneally were divided into four groups. In the trauma (T) group, occlusal trauma was induced by placing an excessively high metal wire in the occlusal surface of the mandibular right first molar. In the inflammation (I) group, periodontal inflammation was induced by topical application of LPS into the palatal gingival sulcus of maxillary right first molars. In the trauma + inflammation (T+I) group, both trauma and periodontal inflammation were simultaneously induced. The PBS group was administered phosphate-buffered saline only. Another 12 nonimmunized rats (the n-(T+I) group) were treated as described for the T+I group. All rats were killed after 5 or 10 d, and their maxillary first molars with surrounding tissues were observed histopathologically. Loss of attachment and osteoclasts on the alveolar bone crest were investigated histopathologically. To detect immune complexes, immunohistological staining for C1qB was performed. Collagen fibers were also observed using the picrosirius red-polarization method. RESULTS: There were significant increases in loss of attachment and in the number of osteoclasts in the T+I group compared with the other groups. Moreover, widespread distribution of immune complexes was observed in the T + I group, and collagen fibers oriented from the root surface to the alveolar bone crest had partially disappeared in the T, T+I and n-(T+I) groups. CONCLUSION: When inflammation was combined with occlusal trauma, immune complexes were confirmed in more expanding areas than in the area of the I group without occlusal trauma, and loss of attachment at the onset of experimental periodontitis was increased. Damage of collagen fibers by occlusal trauma may elevate the permeability of the antigen through the tissue and result in expansion of the area of immune-complex formation and accelerating inflammatory reaction. The periodontal tissue destruction was thus greater in the T+I group than in the I group.

Histologic and ultrastructural study of intracranial Gaucheroma causing deafness in a patient with Gaucher disease type 3: Effects of substrate reduction therapy.

Hearing loss is frequently associated with Gaucher disease (GD). Gaucher cells are enlarged reticuloendothelial cells containing glucocerebroside in the lysosomes due to deficiency of the glucocerebrosidase. Gaucheromas consist of accumulated Gaucher cells. Gaucher cells accumulate in variable tissues including the liver, spleen, bone marrow, and the middle ear and the mastoid causing conductive hearing loss. Neurons and astrocytes in the central nervous system are affected in neuronopathic GD leading to sensorineural hearing loss. Gaucheromas can develop even in patients treated with enzyme replacement therapy (ERT). We report a 19-year-old female patient with GD type 3 who developed profound bilateral hearing loss associated with intracranial Gaucheroma. Combination therapy of ERT with imiglucerase and substrate reduction therapy (SRT) with eliglustat significantly decreased the size of Gaucher cells and cleared the characteristic microtubular structures in the lysosomes in Gaucher cells. Early implementation of SRT may prevent at least conductive hearing impairment in GD although it may not prevent sensorineural hearing loss due to inner hair cell dysfunction which is also known to be associated with neuronopathic GD.

In vivo effect of single oral dose of artemether against early juvenile stages of Schistosoma mansoni Egyptian strain.

The current treatment and control of schistosomiasis, rely on a single drug, praziquantel, although, it has minor activity against juvenile stages of the parasite. Studies have shown that artemether (ART) exhibits effects against juveniles of Schistosoma mansoni Liberian and Puerto Rican strains, Schistosoma japonicum and Schistosoma haematobium. Aiming to assess the in vivo activity of single oral dose of ART against early juvenile stages of S. mansoni Egyptian strain, this study was established. Mice were treated with ART (400 mg/kg) at two time points evenly spaced over the period of larval development (7 and 21 days post-infection; pi), and a third treatment point (day 49 pi) was included to elucidate when susceptibility decreases. Administration of ART on day 7 pi reduced the total worm burden by 85.94%. The greatest reductions were seen when treatment was given on day 21 pi, with total and female worm burden reductions of 91.52% and 90.57%, respectively, and cessation of oviposition. Similar dose given on day 49 pi reduced total worm burden by 55.17% and female worm burden by 66.51%. Moreover, it induced significant reduction in the tissue egg load and significant alterations in the oogram pattern with decreased immature eggs and increased dead eggs. Antipathological activities were evident in significant reductions in granulomata count and diameter. In conclusion, ART exhibits major in vivo schistosomicidal effects against the early larval migratory stages of S. mansoni Egyptian strain, mainly the 21-day old schistosomula, hence preventing disease progression and morbidity.

Evaluation of acute oral toxicity, anti-diabetic and antioxidant effects of Aloe vera flowers extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera (L.) Burm.f. is widely used in various traditional systems of medicine worldwide. Since over 5000 years ago, several cultures have used A. vera extract medicinally for conditions ranging from diabetes to eczema. It has been shown to reduce the symptoms of diabetes by enhancing insulin secretion and protecting pancreatic islets. AIM OF THE WORK: This research study aimed to investigate the in-vitro antioxidant effect, the acute oral toxicity, and the possible pharmacological in-vivo anti-diabetic activity with histological examination of the pancreas of the standardized deep red A. vera flowers methanolic extracts (AVFME). MATERIALS AND METHODS: The liquid-liquid extraction procedure and TLC technique were used to investigate chemical composition. Total phenolics and flavonoids in AVFME were quantified by Folin-Ciocalteu and AlCl3 colorimetric methods, respectively. The present study involved evaluating the in-vitro antioxidant effect of AVFME using ascorbic acid as the reference standard, an acute oral toxicity study by using thirty-six albino rats and different concentrations of AVFME (200 mg/kg, 2, 4, 8 and 10 g/kg b.w.). Furthermore, the in-vivo anti-diabetic study was performed on alloxan-induced diabetes in rats (120 mg/kg, I.P.) and two doses of AVFME (200 and 500 mg/kg b.w., orally) were used as compared to glibenclamide (5 mg/kg, orally) as a standard hypoglycemic sulfonylurea medication. A histological examination of the pancreas was performed. RESULTS: AVFME resulted in the highest phenolic content of 150.44 ± 4.62 mg gallic acid equivalent per gram (GAE/g) along with flavonoid content of 70.38 ± 0.97 mg of quercetin equivalent per gram (QE/g). An in-vitro study revealed that the antioxidant effect of AVFME was strong as ascorbic acid. The results of the in-vivo studies showed that the AVFME didn't cause any apparent toxicity signs or death in all groups at different doses which proves the safety of this extract with a wide therapeutic index. The antidiabetic activity of AVFME demonstrated a considerable drop in blood glucose levels as glibenclamide, without severe hypoglycemia or significant weight gain which is considered an advantage of AVFME over glibenclamide use. The histopathological study of pancreatic tissues confirmed the protective effect of AVFME on the pancreatic beta-cells. The extract is proposed to have antidiabetic activity through inhibition of α-amylase, α-glucosidase, and dipeptidyl peptidase IV (DPP-IV). Molecular docking studies were conducted to understand possible molecular interactions with these enzymes. CONCLUSION: AVFME represents a promising alternative source of active constituents against diabetes mellitus (DM) based on its oral safety, antioxidant, anti-hyperglycemic activities, and pancreatic protective effects. These data revealed the antihyperglycemic activity of AVFME is mediated by pancreatic protective effects while significantly enhancing insulin secretion through increasing functioning beta cells. This suggests that AVFME has the potential as a novel antidiabetic therapy or a dietary supplement for the treatment of type 2 diabetes (T2DM).

GC-MS profiling and evaluation of acute oral toxicity, anti-tumour, antimicrobial and antioxidant activities of Croton socotranus Balf.f. aerial parts: in-vitro, in-vivo and in-silico studies.

Croton socotranus Balf.f. shrub is widely used traditionally in Asia as an anti-infective. The study was conducted for metabolite profiling, oral acute toxicity and antioxidant studies, antimicrobial activity and anticancer effect against human hepatoma (HepG2), breast cancer (MCF-7) and rhabdomyosarcoma (RD) cells. Gas chromatography-mass spectrometry analysis revealed the presence of 39 compounds, predominantly comprising fatty acids (57.76%), sesquiterpenes (24.56%) and triterpenes (9.54%). The n-hexane fraction exhibited promising antimicrobial activity and displayed a potent anti-tumour effect against HepG2, MCF-7 and RD cells with IC50 values of 3.4, 6.5 and 7.1 µg/mL, respectively. Histological examination revealed significant morphological changes consistent with the changes observed in the apoptotic mechanism of action. The molecular docking study provided insights into the rational binding modes of the identified compounds with phosphoinositide 3-kinase and poly(ADP-ribose)polymerase-1 enzymes. Our findings suggest the potential of C. socotranus as a valuable source of antimicrobial and anticancer agents.

Agaricus Subrufescens ameliorates ovarian dysfunction and regulates altered biochemical parameters in rats with Letrozole induced polycystic ovarian syndrome.

OBJECTIVE: The objective of this study is to investigate the effects of an ethanolic extract derived from Agaricus subrufescens on rat models exhibiting Polycystic Ovarian Syndrome (PCOS) induced by Letrozole. METHODS: A total of thirty female Wistar rats were divided into five groups, each consisting of six rats. The negative control group was administered a volume of 1 mL of a 0.5% solution of carboxy methylcellulose (CMC). Letrozole (1 mg/kg) was administered to additional groups for a duration of 21 days in order to induce polycystic ovary syndrome (PCOS). Animals designated as positive controls were euthanized on the 22nd day. Both the test group and the standard group were subjected to treatment from the 22nd day to the 36th day. The experimental group was administered ethanolic extract of Agaricus subrufescens at doses of 200 mg/kg and 400 mg/kg p.o, while the control group received clomiphene citrate at a dose of 1 mg/kg. The study observed various physiological markers in individuals with polycystic ovarian disease, including estimated blood glucose levels, total cholesterol levels, triglyceride levels, and hormonal fluctuations such as increased testosterone and estrogen levels, as well as decreased progesterone levels. The presence of menstrual irregularities was confirmed through the examination of vaginal smears and histopathological changes in the ovaries. RESULTS: The consumption of Agaricus subrufescens was found to have a significant impact on various physiological parameters, including blood glucose levels, testosterone levels, anovulation, and menstrual irregularity. All therapeutic interventions significantly normalized the levels of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT). The rats with polycystic ovary syndrome (PCOS) that were induced by Letrozole exhibited increased levels of urea and creatinine. The findings of this study indicate that the administration of Agaricus subrufescens therapy has a protective effect on renal function, as evidenced by a reduction in serum levels of urea and creatinine. In rats with polycystic ovary syndrome (PCOS) induced by Letrozole, the inhibition of hepatic synthesis, promotion of ovarian follicle immaturity, and elevation of androgen secretions result in an increase in the weight of the liver and ovaries. The weight of endocrine organs exhibited a decrease across all treatment groups. The histopathological examination of PCOS specimens revealed an increased presence of cysts and theca lutein cells. The group of rats with polycystic ovary syndrome (PCOS) that did not receive treatment exhibited a higher number of cysts compared to the groups that received treatment. CONCLUSION: This study demonstrated that the administration of Letrozole orally resulted in the development of polycystic ovarian disease. The results indicated heightened levels of blood glucose, total cholesterol, and triglycerides, as well as alterations in hormone levels such as increased testosterone and estrogen, and decreased progesterone. These hormonal changes were accompanied by menstrual irregularities, which were confirmed through the examination of vaginal smears and histopathological analysis of the ovaries in the control group with polycystic ovarian disease. The treatment groups that received Agaricus subrufescens exhibited a decrease in blood glucose, total cholesterol, and testosterone levels.

Utilization of propranolol hydrochloride mucoadhesive invasomes as a locally acting contraceptive: in-vitro, ex-vivo, and in-vivo evaluation.

It was found that propranolol hydrochloride (PNL), which is a beta-blocker used for hypertension treatment, has a potent spermicidal activity through local anesthetic activity or beta-blocking effect on sperm cells subsequently it could be used as a contraceptive remedy. This study aimed to entrap PNL into invasomes (INVs) and then formulate it as a locally acting contraceptive gel. PNL-loaded mucoadhesive INVs were prepared via the thin-film hydration technique. The D-optimal design was utilized to fabricate INVs employing lipid concentration (X1), terpenes concentration (X2), terpenes type (X3), and chitosan concentration (X4) as independent variables, while their impact was observed for entrapment efficiency percent (Y1; EE%), particle size (Y2; PS), zeta potential (Y3; ZP), and amount of drug released after 6 h (Y4; Q6h). Design Expert® was bestowed to nominate the desired formula. The selected INV was subjected to further studies and formulated into a mucoadhesive gel for ex-vivo and in-vivo investigations. The optimum INV showed a spherical shape with EE% of 65.01 ± 1.24%, PS of 243.75 ± 8.13 nm, PDI of 0.203 ± 0.01, ZP of 49.80 ± 0.42 mV, and Q6h of 53.16 ± 0.73%. Differential scanning calorimetry study asserted the capability of INVs to entrap PNL. Permeation studies confirmed the desired sustained effect of PNL-loaded INVs-gel compared to PNL-gel, INVs, and PNL solution. Sperm motility assay proved the potency of INVs-gel to inhibit sperm motility. Besides, the histopathological investigation verified the tolerability of the prepared INVs-gel. Taken together, the gained data justified the efficacy of PNL-loaded INVs-gel as a potential locally acting contraceptive.

Development and Optimization of Terpene-Enriched Vesicles (Terpesomes) for Effective Ocular Delivery of Fenticonazole Nitrate: In vitro Characterization and in vivo Assessment.

OBJECTIVE: The aim of the current study was to load fenticonazole nitrate, a slightly water-soluble antifungal agent, into terpene-enriched phospholipid vesicles (terpesomes) as a potential delivery system for the management of ocular fungal infection. METHODS: Thin film hydration method was used to prepare terpesomes according to a 32 full factorial design to inspect the effect of several variables on vesicles' features. The investigated factors were terpenes type (X1) and terpenes amount (X2) while the dependent responses were encapsulation efficiency percent (Y1), particle size (Y2) and polydispersity index (Y3). Design Expert® program was used to chose the best achieved formula. The selected terpesomes were further optimized via incorporation of a positive charge inducer (stearylamine) to enhance adhesion to the negatively charged mucus covering the eye surface. The in vivo performance of the optimized fenticonazole nitrate-loaded terpesomes relative to drug suspension was evaluated by measuring the antifungal activity (against Candida albicans) retained in the tear's fluid at different time intervals after ocular application in albino rabbits. RESULTS: The optimized terpesomes showed spherical vesicles with entrapment efficiency of 79.02±2.35%, particle size of 287.25±9.55 nm, polydispersity index of 0.46±0.01 and zeta potential of 36.15±1.06 mV. The in vivo study demonstrated significantly higher ocular retention of the optimized fenticonazole nitrate-loaded terpesomes relative to the drug suspension. Moreover, the histopathological studies proved the safety and biocompatibility of the prepared terpesomes. CONCLUSION: The obtained results verified the potential of the terpesomes for safe and effective ocular delivery of fenticonazole nitrate.

Utilization of PEGylated cerosomes for effective topical delivery of fenticonazole nitrate: in-vitro characterization, statistical optimization, and in-vivo assessment.

In this investigation, we focused on ceramide IIIB, a skin component whose depletion tends to augment multiple skin disorders and fungal infections. Ceramide IIIB was included into PEGylated surfactant-based vesicular phospholipid system to formulate 'PEGylated cerosomes' (PCs) loaded with fenticonazole nitrate (FTN). FTN is a potent antifungal agent adopted in the treatment of mixed mycotic and bacterial infections. The ceramide content of the vesicles may provide protective and regenerative skin activity whereas Brij®; the PEGylated surfactant, can enhance drug deposition and skin hydration. Both components are expected to augment the topical effect of FTN. PCs were prepared by thin-film hydration technique. A 23 full-factorial design was applied to study the effect of ceramide amount (X1), Brij type (X2) and Brij amount (X3) on the physicochemical properties of the formulated PCs namely; entrapment efficiency (EE%;Y1), particle size (PS;Y2), polydispersity index (PDI;Y3) and zeta potential (ZP;Y4). The optimal formula was selected for further in-vivo dermatokinetic and histopathological study. The optimal FTN-loaded PC (PC6) showed nanosized cerosomes (551.60 nm) with high EE% (83.00%w/w), and an acceptable ZP value of 20.90 mV. Transmission electron micrographs of the optimal formula illustrated intertwined tubulation form deviated from the conventional spherical vesicles. Finally, the dermatokinetic study of PC6 showed higher drug concentration and localization of FTN in skin layers when compared with FTN suspension and the histopathological study confirmed its safety for topical application. The overall findings of our study verified the effectiveness of utilizing PEGylated cerosomes to augment the activity of FTN as a topical antifungal agent.

Cubosomes as a Potential Oral Drug Delivery System for Enhancing the Hepatoprotective Effect of Coenzyme Q10.

Coenzyme Q10 (CoQ10) acts as an antioxidant that protects the cells by preventing lipid peroxidation. Owing to its low solubility, CoQ10 has shown poor delivery properties and poor bioavailability. The aim of this study is to develop CoQ10 loaded cubosomes in order to enhance its oral delivery and hepatoprotective activity. Cubosomes are cubic nanostructured systems resulting from the colloidal dispersion of cubic liquid crystalline structure in water. CoQ10 loaded cubosomes were prepared using poloxamer 407 and glyceryl monooleate at three weight ratios (1:2.5, 1:5 and 1:7.5) and were further characterized. They were investigated for their hepatoprotective effect in thioacetamide (TAA) induced hepatotoxicity in Wistar rats. The developed CoQ10 cubosomes exhibited moderate to high entrapment efficiency percentages (44.69-75.96%), nanometric dimensions (132.4-223.2 nm), and negatively charged zeta potential values (<-21.3). In-vitro release profiles showed a sustained release of CoQ10 from the developed cubosomes up to 48 h. In-vivo study revealed an improved hepatoprotective effect of CoQ10 cubosomes via reducing liver enzymes, nitric oxide and malondialdehyde as well as elevating phosphoinositide 3-kinase, catalase and glutathione peroxidase, compared to plain drug. These results were in good agreement with histopathological investigations. Consequently, the developed cubosomes showed a potential effect in enhancing the hepatoprotective activity of CoQ10.