Modified one third tubular plate (spring plate) augmented with reconstruction plates for treatment of comminuted posterior wall acetabular fractures, Short to midterm outcomes of 24 patients.

The most common form of acetabular fracture is believed to be the posterior wall; its incidence ranges from 25% to 47%. Managing such fractures has been difficult in the past and until recently. To obtain a favorable functional outcome, an accurate diagnosis and a well-executed treatment strategy are essential. Objective: To evaluate the clinical and functional outcomes of employing a spring plate augmented by a traditional 3.5 mm reconstruction plate for the treatment of comminuted posterior wall acetabular fractures. Patients and Methods: A prospective case series was performed on 24 patients with comminuted fractures of the posterior wall. After an average of 6 days, the patients underwent surgery. Eighteen patients were fixed with one spring plate, six patients were fixed with two spring plates, and all were reinforced with a 3.5-mm reconstruction plate. Each case was followed once every three months until the fracture healed and then regularly every six months thereafter. Results: There were 21 men and 3 women. The average follow-up period was 14 months, and the median age was 34.5 years. The main reason for injuries was motor vehicle collisions. The mean operation time was 107.5 min. The clinical results were evaluated by the MAP and m HHS, and the means were 10.2 (5-12) and 86 (64-96), respectively. Only two patients developed avascular necrosis and were treated by total hip replacement, another three (12.5%) had mild arthritis. Conclusion: Comminuted acetabulum posterior wall fractures can be stabilized with spring plates. It could be used in conjunction with the primary reconstruction plate as a viable alternative for stable and anatomical reduction. High patient satisfaction and good functional results make this approach effective.

Genetic potential and inheritance pattern of agronomic traits in faba bean under free and infested Orobanche soil conditions.

BACKGROUND: Orobanche is an obligate parasite on faba bean in the Mediterranean region, causes considerable yield losses. Breeding tolerant faba bean genotypes to Orobanche is pivotal to sustain production and ensuring global food security, particularly considering the challenges posed by population growth. In the present study, seven faba bean lines and four testers were used in a line×tester mating design during 2020-2021 and 2021-2022 growing seasons. The eleven parents and their 28 F1 crosses were evaluated under Orobanche free and naturally infested soils. RESULTS: The results demonstrated considerable variations among the evaluated genotypes, wide diversity among the parental materials, and heterotic effects for all studied agronomic traits under Orobanche-free and infested soils. Orbanche infestation displayed a significant adverse impact on all the studied agronomic traits. The genotypes Line1, Line2, Line3, and Line5 displayed superior performance under Orobanche-infested conditions and recorded the highest values of all studied agronomic traits. Additionally, Line1, Line2, Line3, Line5, and Line7 exhibited desirable significant GCA for most evaluated traits under the two infestation conditions. The obtained crosses displayed significant negative or positive heterosis for studied agronomic characters such as plant height, number of branches per plant, number of pods per plant, number of seeds per plant, and seed weight per plant were observed. Furthermore, specific cross combinations such as Line2×Sakha3, Line3×Nubaria5, Line7 × Nubaria5, Line6×Nubaria1, Line5×Sakha3, Line1×Sakha3, and Line1 × Nubaria5 exhibited superior performance in seed yield and contributing traits under Orobanche-infested conditions. Moreover, these specific crosses showed superior efficacy in reducing dry weight of Orobanche spikes. The results obtained from GGE biplot analysis closely aligned with those from the line×tester procedure, affirming the significance of GGE biplot as a valuable statistical tool for assessing genotype combining ability in line× tester data. Both additive and non-additive gene actions were reported to be predominantly involved in the inheritance of the studied agronomic traits in faba bean. CONCLUSIONS: The detected genetic diversity within the evaluated faba bean genotypes and their developed crosses exhibits substantial potential for improving faba bean productivity under Orobanche-infested conditions. The parental genotypes, Line1, Line2, Line3, Line5, and Line7, were identified as effective and promising combiners. Moreover, the developed crosses Line2×Sakha3, Line3×Nubaria5, Line7×Nubaria5, Line6×Nubaria1, Line5×Sakha3, Line1×Sakha3, and Line1×Nubaria5 could be considered valuable candidates for developing high-yielding and tolerant faba bean genotypes to Orobanche.

Ilizarov-Assisted Healing for a Neglected Non-united Fracture Calcaneus: A Case Report and Literature Review.

Although calcaneal fracture is not a rare injury and nonunion is rare, proper management of a calcaneal fracture is mandatory because it can be a prerequisite for long-term functional disabilities of the foot, including posttraumatic osteoarthritis of the hindfoot joint, chronic pain, and persistent swelling syndromes. Restoration of axial alignment and joint congruence with careful caution toward soft tissues is the basic principle of treatment; however, few literature reviews to date have addressed the characteristics of a calcaneal nonunion fracture. We discuss a case of a 30-year-old male, manual worker, and diabetic type 1 with a calcaneal fracture reaching the articular surface of the subtalar joint who underwent a simple fracture to a painful nonunion fracture after conservative treatment for seven months before presenting to our hospital being unable to walk with heel deformity. The Ilizarov frame was used to correct deformities in the hindfoot, enhance healing by compressing the fracture site, and allow early weight bearing with the maintenance of subtalar joint function. Our result demonstrates increased calcaneal healing when the Ilizarov foot frame is used, and when the calcaneal fracture site is compressed, this is a good option for maintaining foot and ankle function, even in diabetic patients.

Modified gastro-soleus turn-down flap for chronic or neglected achilles tendon ruptures.

BACKGROUND: Achilles' tendon chronic rupture is a common entity that is usually misdiagnosed or mistreated. Hence, she was presented to us later or with complications affecting her gait. Surgical resection is needed to either bridge the gap or reinforce the strength of the tendon repair. OBJECTIVES: Our study's goal was to assess the clinical results of repairing chronic Achilles' tendon lesions employing the middle segment of the proximal portion of the tendon (gastro-soleus), as a turn-down flap. METHODS: Our prospective interventional single arm study included 18 patients with chronic Achilles' tendon rupture attending at Al-Azhar university hospitals in Cairo, Egypt from May 2020 to April 2023. Diagnosis of the patients was confirmed by radiographic and clinical investigations. They were all treated with the same open reconstruction procedure using a modified GSF. The average follow-up was 12 months. The results of this study were assessed by the Achilles tendon rupture score (ATRS), American Orthopedic Foot and Ankle Society (AOFAS) score, and capacity to perform repeated heel raises on the affected side. RESULTS: The mean operative time was 72.77 min. The median (IQR) time of reconstruction was 10 (8-12) after the injury. The median (IQR) length of flab was 4.5 (4.3-5) 9 (Table 2). No intraoperative complications occurred. The typical follow-up period was 12 months (6-18 months). In terms of the ATRS, we found a significant reduction from 82.8 ± 3 preoperatively to 20.8 ± 6.7 at 12 months postoperatively (P value = 0.001). As regards the AOFAS score, it was increased from 49.5 ± 10 preoperatively to 83.8 ± 8.5 12 months postoperatively (P = 0.001). In terms of the post operative complications, there was no re-rupture. Two patients experienced superficial wound infection which improved with daily dressing and antibiotics. Additionally, two patients had slight ankle stiffness four months after the operation, which improved after programmed rehabilitation at the sixth month. CONCLUSION: The modified GSTF is a simple, safe, well-tolerated and effective method of treatment with excellent functional results and greater patient content.

Broken Heart: A Clear Case of Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a recognized clinical syndrome characterized by reversible cardiomyopathy with a distinctive left ventricular apical ballooning appearance. TC is associated with risk factors such as estrogen deficiency, emotional and physical stress, and genetic factors. The clinical presentation of TC can be like that of a myocardial infarction. While catecholamine-induced myocardial stunning is suggested by current evidence, the exact pathophysiological mechanisms remain uncertain. Diagnostic criteria, including the InterTAK Diagnostic Criteria, have been established by the Takotsubo International Registry. Supportive and symptomatic medication constitutes the mainstay of treatment, with a focus on improving left ventricle (LV) function over several days, leading to full recovery within three to four weeks. Given its resemblance to myocardial infarction, cautious diagnosis and management are essential for optimal outcomes. We present the case of a previously healthy 35-year-old female who presented with chest pain and dyspnea after discovering her father's death. On examination, she exhibited hypotension, bradycardia, and a new-onset left bundle branch block (LBBB) in her electrocardiogram. Her left ventricular ejection fraction (LVEF) on presentation was 22%, and troponin T (TnT) levels were notably elevated at 430 (normal ranges < 14). After two days of treatment and monitoring at the cardiac intensive care unit (CICU), she improved clinically, and her LVEF improved to 52%.

Regioselective Claisen-Schmidt Adduct of 2-Undecanone from Houttuynia cordata Thunb as Insecticide/Repellent against Solenopsis invicta and Repositioning Plant Fungicides against Colletotrichum fragariae.

The U.S. Department of Agriculture (USDA) has established research programs to fight the phytopathogen Colletotrichum fragariae and the invasive red imported fire ant, Solenopsis invicta. C. fragariae is known to cause anthracnose disease in fruits and vegetables, while S. invicta is known for its aggressive behavior and painful stings and for being the cause of significant damage to crops, as well as harm to humans and animals. Many plants have been studied for potential activity against C. fragariae and S. invicta. Among the studied plants, Houttuynia cordata Thunb has been shown to contain 2-undecanone, which h is known for its antifungal activity against Colletotrichum gloesporioides. Based on the mean amount of sand removed, 2-undecanone showed significant repellency at 62.5 µg/g, similar to DEET (N,N-diethyl-meta-toluamide), against S. invicta. The 2-Undecanone with an LC50 of 44.59 µg/g showed toxicity against S. invicta workers. However, neither H. cordata extract nor 2-undecanone had shown activity against C. fragariae despite their known activity against C. gloesporioides, which in turn motivates us in repositioning 2-undecanone as a selected candidate for a Claisen-Schmidt condensation that enables access to several analogs (2a-f). Among the prepared analogs, (E)-1-(3-methylbenzo[b]thiophen-2-yl)dodec-1-en-3-one (2b) and (E)-1-(5-bromothiophen-2-yl)dodec-1-en-3-one (2f) showed promising activity against C. fragariae, revealing a distinctive structural activity relationship (SAR). The generated analogs revealed a clear regioselectivity pattern through forming the C=C alkene bond at position C-1. These data open the window for further lead optimization and product development in the context of managing C. fragariae and S. invicta.

Novel Natrosol/Pectin-co-poly (acrylate) based pH-responsive polymeric carrier system for controlled delivery of Tapentadol Hydrochloride.

Background & Objectives: This study aimed to create a controlled delivery system for Tapentadol Hydrochloride by developing interpenetrating networks (IPNs) of Natrosol-Pectin copolymerized with Acrylic Acid and Methylene bisacrylamide, and to analyze the effects of various ingredients on the physical and chemical characteristics of the IPNs. Methods: Novel Tapentadol Hydrochloride-loaded Natrosol-Pectin based IPNs were formulated by using the free radical polymerization technique. Co-polymerization of Acrylic Acid (AA) with Natrosol and Pectin was performed by using Methylene bisacrylamide (MBA). Ammonium persulfate (APS) was used as the initiator of crosslinking process. The impact of ingredients i.e. Natrosol, Pectin, MBA, and Acrylic Acid on the gel fraction, porosity, swelling (%), drug loading, and drug release was investigated. FTIR, DSC, TGA, SEM and EDX studies were conducted to confirm the grafting of polymers and to evaluate the thermal stability and surface morphology of the developed IPNs. Results: Swelling studies exhibited an increase in swelling percentage from 84.27 to 91.17% upon increasing polymer (Natrosol and Pectin) contents. An increase in MBA contents resulted in a decrease in swelling from 85 to 67.63%. Moreover, the swelling was also observed to increase with higher AA contents. Significant drug release was noted at higher pH instead of gastric pH value. Oral toxicological studies revealed the nontoxic and biocompatible nature of Natrosol-Pectin IPNs. Interpretation & Conclusion: The developed IPNs were found to be an excellent system for the controlled delivery of Tapentadol Hydrochloride.

The Oligostilbene Gnetin H Is a Novel Glycolysis Inhibitor That Regulates Thioredoxin Interacting Protein Expression and Synergizes with OXPHOS Inhibitor in Cancer Cells.

Since aerobic glycolysis was first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism has sparked the interest of scientists around the world as it might offer new avenues of treatment for malignant cells. Our current study claims the discovery of gnetin H (GH) as a novel glycolysis inhibitor that can decrease metabolic activity and lactic acid synthesis and displays a strong cytostatic effect in melanoma and glioblastoma cells. Compared to most of the other glycolysis inhibitors used in combination with the complex-1 mitochondrial inhibitor phenformin (Phen), GH more potently inhibited cell growth. RNA-Seq with the T98G glioblastoma cell line treated with GH showed more than an 80-fold reduction in thioredoxin interacting protein (TXNIP) expression, indicating that GH has a direct effect on regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with phenformin also substantially enhances the levels of p-AMPK, a marker of metabolic catastrophe. These findings suggest that the concurrent use of the glycolytic inhibitor GH with a complex-1 mitochondrial inhibitor could be used as a powerful tool for inducing metabolic catastrophe in cancer cells and reducing their growth.

Fabrication and Assessment of Orodispersible Tablets Loaded with Cubosomes for the Improved Anticancer Activity of Simvastatin against the MDA-MB-231 Breast Cancer Cell Line.

Various factors limit the use of simvastatin as an anticancer drug. Therefore, this study aimed to analyse simvastatin (SIM)-loaded cubosome efficacy against breast cancer. SIM-loaded cubosomes were prepared using the emulsification method using different glyceryl monooleate, Pluronic F127 (PF-127), and polyvinyl alcohol (PVA) ratios. The best cubosomal formula was subjected to an in vitro cytotoxicity analysis using the human breast cancer cell line, MDA-MB-231 (MDA) (ATCC, HTB-26), and formulated as oral disintegrating tablets through direct compression. PF-127 and PVA positively affected drug loading, and the entrapment efficiency percentage of different SIM-cubosomal formulations ranged from 33.52% to 80.80%. Vesicle size ranged from 181.9 ± 0.50 to 316.6 ± 1.25 nm. PF-127 enhanced in vitro SIM release from cubosome formulations due to its solubilising action on SIM. The in vitro dissolution analysis indicated that SIM exhibited an initial dissolution of 10.4 ± 0.25% within the first 5 min, and 63.5 ± 0.29% of the loaded drug was released after 1 h. Moreover, cubosome formula F3 at 25 and 50 µg/mL doses significantly decreased MDA cell viability compared to the 12.5 µg/mL dose. The untreated SIM suspension and drug-free cubosomes at all doses had no significant influence on MDA cell viability compared to the control.

Role of EGF/ERK1/2/HO-1 axis in mediating methotrexate induced testicular damage in rats and the ameliorative effect of xanthine oxidase inhibitors.

Objectives: Methotrexate (MTX) is commonly used in the management of several malignancies and autoimmune disorders; however, testicular damage is one of the most detrimental effects of MTX administration. The current the protective effect of xanthine oxidase inhibitors either purine analogue; allopurinol (ALL) or non-purine analogue; febuxostat (FEB) in testicular injury induced by MTX in rats.Materials and methods: Thirty-two rats were randomly allocated to four groups; control (received vehicles), MTX (received single dose, 20 mg/kg, i.p.), MTX + ALL (received MTX plus ALL) and MTX + FEB (received MTX plus ALL). ALL and FEB were administered orally at 100- and 10 mg/kg, respectively for 15 days. Total and free testosterone were measured in serum. In addition, total antioxidant capacity (TAC), epidermal growth factor (EGF), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), extracellular signal-regulating kinase1/2 (ERK1/2), and total nitrite/nitrate (NOx) end products were measured in testicular tissues. At the same time, immunoexpression of HO-1in testicular tissue was measured. Histopathological examination was done.Results: ALL and FEB increased total and free serum testosterone. Both drugs showed a significant reduction in testicular MDA, NOx, TNF-α levels with an increase in TAC, EGF, and ERK1/2 levels in testicular tissue. Furthermore, both drugs enhanced HO-1 immunoexpression in testicular tissue. All these findings were parallel to the preservation of normal testicular architecture in rats treated with ALL and FEB.Conclusion: All and FEB were equally protective against testicular damage induced by MTX through anti-inflammatory, anti-apoptotic, and antioxidant actions. Their effects might be through activation of the EGF/ERK1/2/HO-1 pathway.

In Vitro and In Silico Studies of Neolignans from Magnolia grandiflora L. Seeds against Human Cannabinoids and Opioid Receptors.

Magnolia grandiflora L. (Magnoliaceae) is a plant of considerable medicinal significance; its flowers and seeds have been used in various traditional remedies. Radioligand binding assays of n-hexane seeds extract showed displacement of radioligand for cannabinoid (CB1 and CB2) and opioid δ (delta), κ (kappa), and µ (mu) receptors. Bioactivity-guided fractionation afforded 4-O-methylhonokiol (1), magnolol (2), and honokiol (3), which showed higher binding to cannabinoid rather than opioid receptors in radioligand binding assays. Compounds 1-3, together with the dihydro analog of 2 (4), displayed selective affinity towards CB2R (Ki values of 0.29, 1.4, 1.94, and 0.99 µM, respectively), compared to CB1R (Ki 3.85, 17.82, 14.55, and 19.08 µM, respectively). An equal mixture of 2 and 3 (1:1 ratio) showed additive displacement activity towards the tested receptors compared to either 2 or 3 alone, which in turn provides an explanation for the strong displacement activity of the n-hexane extract. Due to the unavailability of an NMR or X-ray crystal structure of bound neolignans with the CB1 and CB2 receptors, a docking study was performed to predict ligand-protein interactions at a molecular level and to delineate structure-activity relationships (SAR) of the neolignan analogs with the CB1 and CB2 receptors. The putative binding modes of neolignans 1-3 and previously reported related analogs (4, 4a, 5, 5a, 6, 6a, and 6b) into the active site of the CB1 and CB2 receptors were assessed for the first time via molecular docking and binding free-energy (∆G) calculations. The docking and ∆G results revealed the importance of a hydroxyl moiety in the molecules that forms strong H-bonding with Ser383 and Ser285 within CB1R and CB2R, respectively. The impact of a shift from a hydroxyl to the methoxy group on experimental binding affinity to CB1R versus CB2R was explained through ∆G data and the orientation of the alkyl chain within the CB1R. This comprehensive SAR, influenced by the computational study and the observed in vitro displacement binding affinities, has indicated the potential of magnolia neolignans for developing new CB agonists for potential use as analgesics, anti-inflammatory agents, or anxiolytics.

Protective effect of eicosapentaenoic acid against estradiol valerate-induced endometrial hyperplasia via modulation of NF-κB/HIF-1α/VEGF signaling pathway in rats.

BACKGROUND: Early diagnosis and treatment of endometrial hyperplasia (EH) remains mandatory for endometrial cancer (EC) prevention. OBJECTIVE: To study the possible protective effect of eicosapentaenoic acid (EPA) in EH - induced by estradiol valerate (EV) in rats. METHODS/MATERIALS: Adult female Wistar rats were given EV with or without EPA for 10 days. The uterine changes were evaluated by both physical (weight index) and histopathological methods. The markers of oxidative stress (Uterine malondialdehyde (MDA) and serum total antioxidant capacity (TAC) as well as serum estradiol and progesterone levels, and apoptosis (uterine caspase-3) were determined. Immunohistochemical estimations of nuclear factor kappa B (NF-κB) and vascular endothelial growth factor (VEGF) in addition to hypoxia-inducible factor 1 alpha (HIF-1α) immunoblotting were measured in uterine tissue. KEY FINDINGS: EV showed significant increase in uterine weight index that is accompanied with histopatholigical evidences of EH. Such changes were associated with significant alterations in oxidative stress markers, modulation of estradiol and progesterone serum levels, an increase in HIF-1α, NF-κB and VEGF immuno-expressions and a significant decrease in caspase-3. EPA, in either dose, showed significant amelioration in uterine weight index as well as in histopathological changes. Such effect was accompanied with significant improvement in the measured hormonal levels, oxidative stress, apoptosis, and inflammatory parameters. CONCLUSIONS: EPA in the used doses provided biochemical and histopathological improvement in EV-induced EH via modulation of NF-κB/HIF-1α/VEGF signaling pathway.

Development and Evaluation of Sodium Alginate/Carbopol 934P-Co-Poly (Methacrylate) Hydrogels for Localized Drug Delivery.

This research was carried out to create a pH-responsive polymeric system for the targeted drug delivery of Diloxanide furoate. It relied on sodium alginate (Na-Alg) and Carbopol 934P as building blocks. Using an aqueous free radical polymerization method, SCH1-SCH12 was created with varying polymer, MAA, and MBA input ratios. Positive outcomes were seen in the swelling and release profiles at higher pH levels. Hydrogel formation, as well as component compatibility, thermal stability, and Diloxanide furoate loading, were all validated by instrumental characterization. A drug loading percentage of 83.56% was determined, with the swelling reaching 743.19%. For the formulation with MBA, the gel fraction was 94.58%. The release of diloxanide furoate increased to 91.77% at neutral pH. The formulation containing Carbopol 934P provided the highest mucoadhesion force (3993.42 dynes/cm2). The created hydrogel has been shown to be biocompatible by toxicological testing of the network. Based on the findings, the created polymeric nexus proved promising for pH-dependent localized and regulated delivery of Diloxanide furoate.

p53, Pirh2, and L1CAM as Promising Prognostic Biomarkers of Endometrial Carcinoma: An Immunohistochemical and Genetic Study.

Endometrial cancer (EC) is the most common gynecologic cancer and the current methods for the prediction of its prognosis and treatment response are unfortunately suboptimal. In this study, we evaluated the prognostic value of p53, Pirh2, and L1CAM in 60 cases of EC using immunohistochemistry (IHC) and polymerase chain reaction. TP53 missense mutations result in nuclear accumulation of p53 protein that can be detected as overexpression by IHC. This is in the form of diffuse strong nuclear positivity involving at least at least >50% of the tumor cells as a whole or if >50% of the tumor cells of a discrete geographical areas. Abnormal p53 IHC expression was expressed in 33.3% of the cases and significantly associated with the tumor grade, myometrial invasion (MI), lymphovascular invasion (LVSI), nodal metastasis, and FIGO stage, and the advanced European Society for Medical Oncology (ESMO) risk groups ( P <0.001 for each). High IHC Pirh2 expression was noted in 58.3% of the cases, and significantly associated with MI, LVSI, nodal metastasis, FIGO stage, and high-risk group ( P <0.001, P =0.011, P =0.010, P =0.024, P =0.005, respectively). There was a significant upregulation of Pirh2 mRNA expression in EC specimens as compared with the control adjacent tissues ( P =0.001). Upregulated Pirh2 mRNA expression had a significant association with Pirh2 immunostaining, tumor grade, tumor stage, MI, lymph node involvement, LVSI, and relapse ( P <0.001 for each). Positive L1CAM immunoexpression was noted in 26.7% and was significantly associated with grade, MI, LVSI, nodal metastasis, FIGO stage, and high-risk group ( P =0.003, P =0.023, P =0.003, P <0.001, P <0.001, P =0.002, respectively). Analysis of follow-up period revealed that EC with abnormal p53 IHC expression, high pirh2 and positive L1CAM expression exhibited a potent relation with tumor relapse, shorter overall survival and disease-specific survival ( P <0.001 for each). Mutant p53, high Pirh2, and L1CAM-positive EC are highly aggressive tumors with a shortened survival rate, dismal outcome, and high risk of relapse after the standard protocol of therapy.

The role of sodium lauryl sulfate on formulation of directly compressed tablets containing simvastatin and aspirin: Effect on drugs dissolution and gastric mucosa.

According to the American College of Cardiology/American Heart Association (ACC/AHA), both aspirin and statin are used in the primary prevention of cardiovascular diseases. Aspirin (ASA) is contraindicated if there is gastrointestinal bleeding because it will exaggerate the condition. In this study, the effect of surfactant; sodium lauryl sulfate (SLS), in enhancing the in vitro dissolution of simvastatin (SIM) and ASA, as well as gastric irritation and upset, was studied. Oral tablets containing both ASA and SIM with and without the SLS were manufactured using the direct compression technique. The prepared tablets were characterized with respect to hardness, friability, uniformity of dosage units, in vitro disintegration, and dissolution. The effect of the addition of SLS in reducing the in vivo irritation and protection of gastric mucosa were also investigated. The results showed that the compressed tablets possessed sufficient hardness, acceptable friability, and are uniform with respect to disintegration, drugs contents, and tablet weight. The results showed that SIM alone exhibited a gastroprotective effect on the induced irritation. In addition, the incorporation of the SLS in the tablets containing SIM and ASA significantly enhanced the dissolution rates of both drugs and significantly decreased the gastric irritation and the ulcer index. The ulcer index of aspirin was decreased from 2.3 for tablets manufactured without SLS to 0.8 for tablets containing SLS. In a conclusion, the addition of pH modifier surfactant; SLS could enhance the dissolution rate of poorly soluble acidic drugs, reduce gastric upset and irritation without any effect on the main characters of the tablets. Moreover, the addition of SLS is very useful in improving the therapeutic activities and reducing the side effects of ASA and SIM for patients who require long-term administration of these drugs.

Formulation and Evaluation of Transdermal Gel Containing Tacrolimus-Loaded Spanlastics: In Vitro, Ex Vivo and In Vivo Studies.

Our goal was to prepare Span 60-based elastic nanovesicles (spanlastics (SPLs)) of tacrolimus (TCR) using the adapted ethanol injection method, characterize them, and evaluate their ability to improve the transdermal permeation of the active substance. The impact of two different concentrations of penetration enhancers, namely, propylene glycol and oleic acid, on the entrapment efficiency, vesicle size, and zeta potential was assessed. Moreover, in vitro release through a semipermeable membrane and ex vivo penetration through hairless rat skin were performed. Morphological examination and pharmacokinetics were performed for one selected formulation (F3OA1). TCR-loaded SPLs were effectively formulated with two different concentrations of permeation enhancers, and the effect of these enhancers on their physicochemical properties differed in accordance with the concentration and kind of enhancer used. The results of in vitro release displayed a considerable (p < 0.05) enhancement compared to the suspension of the pure drug, and there was a correlation between the in vitro and ex vivo results. The selected TCR-loaded nanovesicles incorporated into a gel base showed appreciable advantages over the oral drug suspension and the TCR-loaded gel. Additionally, the pharmacokinetic parameters were significantly (p < 0.05) improved based on our findings. Moreover, the AUC0−7 ng·h/mL form F3 OA1 was 3.36-fold higher than that after the administration of the TCR oral suspension.

Aceclofenac-Loaded Microspheres Prepared by Vesicular Ionotropic Gelation to Minimize Drug-induced Gastric Ulcers in Rats.

BACKGROUND: Aceclofenac is a non-steroidal anti-inflammatory drug and a potent analgesic. However, its oral ingestion may cause gastrointestinal problems, including dyspepsia, abnormal pain, nausea, diarrhea, and ulcerative colitis. OBJECTIVE: This study aimed to prepare vesicular-based enteric microspheres containing aceclofenac by ionotropic gelation technique to minimize gastric irritation in rats. METHODS: The micron-size vesicles were prepared by the ionic-orifice gelation method. Three types of vesicularbased microcapsules containing aceclofenac were prepared by employing sodium alginate as the coating material in combination with Eudragit L100, Eudragit S100, and polyvinylpyrrolidone PVP K90. The drug to sodium alginate to polymer ratios were 1:0.5:0.5, 1:1:1, and 1:1.5:1.5, respectively. Gelation of sodium alginate was induced by the dropwise addition of calcium chloride solution (10 % w/v). Aceclofenac-loaded microspheres were evaluated in terms of aceclofenac content and in vitro drug release, and FTIR, DSC, and XRD were used for physicochemical evaluation of some selected formulae. The effects of microencapsulation on aceclofenac-induced ulcerative activity in male Wistar rats were also investigated. RESULTS: The results indicated no interaction between aceclofenac and microcapsules forming polymers. In addition, microcapsules formulations M1, M4, and M7 gave maximal protection in acidic pH and optimal release in alkaline pH. The histopathological studies revealed that the reduction of ulceration is evident from the macroscopic and microscopic studies, which showed complete protection of the tissue morphology with no ulcers, indicating the effectiveness of the microcapsules system against aceclofenac-induced gastric ulceration in rats again. CONCLUSION: Ionotropic gelation seems to be a simple, efficient technique to prepare aceclofenac-loaded microspheres with a reduced risk of gastric ulceration. It is possible to overcome the problem of gastric damage while utilizing aceclofenac by avoiding the exposure of the drug to the ulcer-prone area of the gastrointestinal tract.

Rupatadine ameliorated ulcerative colitis in rats via modulation of platelet-activatiweng factor/interleukin-6/vascular endothelial growth factor signalling pathway.

OBJECTIVES: This study aimed to analyse the potential effect of rupatadine (RUP) on ulcerative colitis (UC) induced by acetic acid (AA). METHODS: Forty male adult Wistar rats were divided into five groups: Control group: received vehicles for 14 days; AA model group: received AA at the 13th day; Sulfasalazine (SLZ) + AA group: received SLZ (250 mg/kg) for 14 days and AA at the 13th day; RUP-3 + AA group: received RUP (3 mg/kg/day) for 14 days and AA at the 13th day; and RUP-6 + AA group: received RUP (6 mg/kg/day) for 14 days and AA at the 13th day. Evidence of UC was assessed both macroscopically and microscopically. Oxidative stress markers (total antioxidant capacity and malondialdehyde), antioxidant enzyme (superoxide dismutase), histamine and platelet-activating factor (PAF) were determined. Immunohistochemical estimations of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were done. KEY FINDINGS: The AA group showed evidence of UC that was associated with a significant increase in oxidative stress, histamine and PAF levels with significant elevation in colonic VEGF and IL-6 immuno-expressions. RUP, in a dose-dependent manner, significantly ameliorated UC. CONCLUSION: RUP protects against UC by reducing oxidative stress and by regulating the PAF/IL-6/VEGF pathway.

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection.

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460-1047 nm) and entrapment efficiency ranging from 36.4-44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan®). Observed bacterial suppression was detected in rabbit's eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.

Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor.

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 µM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.