Kv7 Channel Activators Flupirtine and ML213 Alleviate Neuropathic Pain Behavior in the Streptozotocin Rat Model of Diabetic Neuropathy.

Background & Objective: Chronic peripheral neuropathic pain (PNP) is a debilitating condition that is associated with many types of injury/diseases, including diabetes mellitus. Patients with longstanding diabetes develop diabetic PNP (DPNP), which is resilient to currently available drugs. The underlying molecular mechanisms of DPNP are still illusive, but Kv7 channels that have been implicated in the pathogenesis of various types of chronic pain are likely to be involved. Indeed, using the streptozotocin (STZ) rat model of DPNP, we have previously shown that Kv7 activation with their non-selective activator retigabine attenuated neuropathic pain behavior suggesting that these channels are implicated in DPNP pathogenesis. Here, we evaluated, in the same STZ model, whether the more potent and more selective Kv7 channel openers flupirtine and ML213 attenuate STZ-induced pain hypersensitivity. Methods: Male Sprague Dawley rats (250-300 g) were used. The STZ model involved a single injection of STZ (60 mg/kg, i.p.). Behavioral testing for mechanical and heat pain sensitivity was performed using a dynamic plantar aesthesiometer and Hargreaves analgesiometer, respectively. Results: STZ rats exhibited behavioral signs of mechanical and heat hypersensitivity as indicated by significant decreases in the mean paw withdrawal threshold (PWT) and mean paw withdrawal latency (PWL), respectively, at 35 days post-STZ treatment. Single injections of flupirtine (10 mg/kg, i.p.) and ML213 (5 mg/kg, i.p.) to STZ rats (35-days after STZ treatment) caused significant increases in the mean PWT, but not PWL, indicating attenuation of mechanical, but not heat hypersensitivity. Both flupirtine and ML213 were as effective as the positive control gabapentin (10/kg, i.p.), and their anti-allodynic effects were prevented by the Kv7 channel-specific blocker XE991 (3 mg/kg, i.p.). Conclusion: The findings suggest that Kv7 channels are involved in the mechanisms of mechanical but not heat hypersensitivity associated with DPNP, and that their activation may prove to be effective in alleviating DPNP symptoms.

In Vitro Assessment of the Cytotoxic Effect of 5-Fluorouracil, Thymoquinone and their Combination on Tongue Squamous Cell Carcinoma Cell Line.

BACKGROUND: Tongue cancer is the most prevalent type of oral cancer. Recently, natural compounds have been considered important resources for several anticancer drugs. Thymoquinone (TQ) exhibits a potent anti-cancer effect. 5-Fluorouracil (5-FU) is a chemotherapeutic drug that has been utilized in the treatment of cancer. Recently, combination therapy has gained popularity as a treatment option for patients with cancer. OBJECTIVES: The present study was carried out to assess the cytotoxic effect of 5-Fluorouracil (5-FU), Thymoquinone (TQ), and their combination on tongue squamous cell carcinoma cell line (HNO-97). METHODS: Tongue carcinoma cell line (HNO-97) was maintained in cultured flasks and the cells were divided into four groups; group Ι: control untreated group, group ΙΙ: HNO-97-treated cells with different concentrations of 5-FU from 0.5 µM/ml to 3µM/ml, group ΙIΙ: HNO-97-treated cells with different concentrations of TQ from 7.25µM/ml to 23.05µM/ml, and group ΙV: HNO-97-treated cells with both 5-FU and TQ in serial concentrations  till (IC50) in a dose of 27.44 µM/ml. Determination of the cytotoxic effect of the tested agents on the HNO-97 cell line was done using methyl thiazole tetrazolium assay, nuclear morphometric analysis, microscopic examination, and annexin-v/ propidium iodide staining assay. RESULT: The findings revealed that the cytotoxic effect of 5-FU, TQ, and their combination on tongue squamous cell carcinoma cell line (HNO-97) was dose-dependent. The microscopic examination revealed that 5-FU, TQ alone, or their combination induced apoptotic cell death. P-value < 0.05 was statistically significant. CONCLUSION: The combination of 5-FU and TQ produced a marked cytotoxic effect on HNO-97 cells.

Microleakage of Lithium Disilicate Veneers Bonded to Different Substrates with Light-cure and Dual-cure Resin Cements.

Background: This study aimed to evaluate the microleakage of lithium disilicate veneers with finish lines placed cervically in different substrates (enamel, dentin, and resin composite) and bonded with light-cure (LC) and amine-free dual-cure (DC) resin cements. Material and Methods: Forty-eight human maxillary central incisors were randomly assigned into three groups according to finish line substrate (n=16/group). Each group was subdivided randomly into two subgroups (n=8/subgroup) according to resin cement type: LC resin cement (Variolink Esthetic LC, Ivoclar Vivadent) and DC resin cement (Variolink Esthetic DC, Ivoclar Vivadent). All the specimens received lithium disilicate veneers (IPS e.max Press, Ivoclar Vivadent). After 5000 cycles of thermocycling, the microleakage was measured using the dye penetrating technique. Data were analyzed statistically using Scheirer Ray Hare test, Kruskal-Wallis H-test, and Mann-Whitney U-test. The level of significance was set at p ≤ .05. Results: There was a statistically significant difference between different substrates in microleakage (p=.001), but there was no statistically significant difference between resin cements (p=.907), and there was no interaction between substrates and resin cements (p=.983). Microleakage was lesser when the finish line was placed at enamel and resin composite than at dentin. Similar leakage scores were observed with LC and DC resin cements. Conclusions: The finish line of ceramic veneer is suggested to be placed in enamel or good-quality resin composite restoration. Regarding microleakage and durability, LC and amine-free DC resin cements are suggested for ceramic veneer cementation. Key words:Different substrates, Dual-cure resin cement, Light-cure resin cement, Lithium disilicate veneers, Microleakage.

Effect of different storage media on elemental analysis and microhardness of cervical cavity margins restored with a bioactive material.

Objectives: This study aimed to investigate the elemental analysis and microhardness of a bioactive material (Activa) and marginal tooth structure after storage in different media. Materials and Methods: Fifteen teeth received cervical restorations with occlusal enamel and gingival dentin margins using the tested material bonded with a universal adhesive, 5 of them on the 4 axial surfaces and the other 10 on only the 2 proximal surfaces. The first 5 teeth were sectioned into 4 restorations each, then stored in 4 different media; deionized water, Dulbecco's phosphate buffered saline (DPBS), Tris buffer, and saliva. The storage period for deionized water was 24 hours while it was 3 months for the other media. Each part was analyzed by scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) analysis for different substrates/distances and the wt% of calcium, phosphorus, silica, and fluoride were calculated. The other 10 teeth were sectioned across the restoration, stored in either Tris buffer or saliva for 24 hours or 3 months, and were evaluated for microhardness of different substrates/areas. Data were analyzed using analysis of variance and Tukey's post hoc test. Results: Enamel and dentin interfaces in the DPBS group exhibited a significant increase in calcium and phosphorus wt%. Both silica and fluoride significantly increased in tooth structure up to a distance of 75 µm in the 3-month-media groups than the immediate group. Storage media did not affect the microhardness values. Conclusions: SEM-EDS analysis suggests an ion movement between Activa and tooth structure through a universal adhesive while stored in DPBS.

Enhancing Pharmacokinetics and Pharmacodynamics of Rosuvastatin Calcium through the Development and Optimization of Fast-Dissolving Films.

Rosuvastatin (RSV) is a widely used cholesterol-lowering medication, but its limited bioavailability due to its susceptibility to stomach pH and extensive first-pass metabolism poses a significant challenge. A fast-dissolving film (FDF) formulation of RSV was developed, characterized, and compared to the conventional marketed tablet to address this issue. The formulation process involved optimizing the thickness, disintegration time, and folding durability. All formulations were assessed for in vitro disintegration, thickness, folding endurance, in vitro dissolution, weight, and content uniformity. The study's results revealed that the optimized RSV-FDF displayed a significantly faster time to maximum plasma concentration (tmax) of 2 h, compared to 4 h for the marketed tablet. The maximum plasma concentration (Cmax) for the RSV-FDF (1.540 µg/mL ± 0.044) was notably higher than that of the marketed tablet (0.940 µg/mL ± 0.017). Additionally, the pharmacodynamic assessment in male Wistar rats demonstrated that the optimized RSV-FDF exhibited an improved lipid profile, including reduced levels of low-density lipoproteins (LDLs), elevated high-density lipoproteins (HDLs), decreased triglycerides (TGs), and lower very-low-density lipoproteins (VLDLs) compared to the conventional tablet. These findings underscore the potential of RSV-FDFs as a promising alternative to enhance the bioavailability and therapeutic efficacy of rosuvastatin in treating dyslipidemia. The faster onset of action and improved lipid-lowering effects make RSV-FDFs an attractive option for patients requiring efficient cholesterol management.

Retention strength of zirconia occlusal veneer restoration.

AIM: The present study aimed to evaluate the retention strength of nonretentive zirconia occlusal veneers bonded to different bonding surfaces (enamel, enamel and dentin, and enamel with composite filling) using two adhesive resin cement systems that use either organophosphate carboxylic acid or organophosphate monomers as a ceramic primer. MATERIALS AND METHODS: Sixty extracted mandibular molars were prepared to receive occlusal veneers as follows (n = 20): 1-mm reduction within enamel; 2-mm reduction within enamel and dentin; 1-mm reduction within enamel with composite filling. Each occlusal veneer was designed with an occlusal bar to aid in the retention test, then milled from a zirconia block, and sintered. Within each group, the zirconia occlusal veneers were bonded using either Duo-Link Universal or Panavia V5 (10 specimens each). All specimens were thermocycled for 5000 cycles. After the pull-off test, the retention strength was calculated for each specimen. Each specimen was examined under magnification to determine its mode of failure. Representative specimens were examined using a scanning electron microscope. Data were analyzed using the two-way analysis of variance (ANOVA) and Tukey HSD tests (P = 0.05). RESULTS: Both bonding substrate and cement type had a significant influence on retention strength values (P < 0.05). The two-way ANOVA showed a significant interaction between bonding substrate and cement type (P = 0.003). There were significant differences in the retention strength between the cements in both the enamel and enamel and dentin substrates (P < 0.05), but no significant difference between the cements in the enamel with composite filling substrate (P > 0.05). The predominant mode of failure was cement remaining principally in the restoration surface (adhesive failure), followed by cement adhesion to both the tooth and the restoration surface (mixed failure). CONCLUSIONS: Among the studied substrates, enamel was the optimal dental bonding surface. However, bonding to dentin was not a limiting factor for the retention of zirconia occlusal veneers. The resin cement using an organophosphate (Panavia V5) provided superior retention strength compared with the cement using organophosphate carboxylic acid monomer (Duo-Link Universal).

Efficacy of Sofosbuvir plus Ledipasvir in Egyptian patients with COVID-19 compared to standard treatment: a randomized controlled trial.

COVID-19 is a pandemic disease caused by SARS-CoV-2, which is an RNA virus similar to the hepatitis C virus (HCV) in the replication process. Sofosbuvir/ledipasvir is an approved drug to treat HCV infection. This study investigates the efficacy of Sofosbuvir/ledipasvir as a treatment for patients with moderate COVID-19 infection. This is a single-blinded parallel-randomized controlled trial. The participants were randomized equally into the intervention group that received Sofosbuvir/ledipasvir (S.L. group), and the control group received Oseltamivir, Hydroxychloroquine, and Azithromycin (OCH group). The primary outcomes were the cure rate over time and the incidence of serious adverse events. The secondary outcomes included the laboratory findings. 250 patients were divided equally into each group. Both groups were similar regarding gender, but age was higher in the S.L. group (p=0.001). In the S.L. group, 89 (71.2%) patients were cured, while only 51 (40.8%) patients were cured in the OCH group. The cure rate was significantly higher in the S.L. group (RR=1.75, p<0.001). Kaplan-Meir plot showed a considerably higher cure over time in the S.L. group (Log-rank test, p=0.032). There were no deaths in the S.L. group, but there were six deaths (4.8%) in the OCH group (RR=0.08, p=0.013). Seven patients (5.6%) in the S.L. group and six patients (4.8%) in the OCH group were admitted to the intensive care unit (ICU) (RR=1.17, P=0.776). There were no significant differences between treatment groups regarding total leukocyte and neutrophils count, lymph, and urea. Sofosbuvir/ledipasvir is suggestive of being effective in treating patients with moderate COVID-19 infection. Further studies are needed to compare Sofosbuvir/ledipasvir with new treatment protocols.

Low level laser therapy versus benzydamin in prevention and treatment of oral mucositis induced by anticancer treatments (clinical and biochemical study) / Terapia a laser de baixa intensidade versus benzidamina na prevenção e tratamento da mucosite oral induzida por terapia oncológica

Objective: In this study, patients undergoing neck and head radiotherapy (RT) with or with no chemotherapy were contrasted to the low-level laser therapy (LLLT) efficacy against benzydamine hydrochloride in treating and preventing oral mucositis (OM) (CHT). Material and Methods: This study included 90 individuals with neck and head cancer who were undergoing radiotherapy (RT) individually or in mixture with chemotherapy (CHT), varying in age from 18 to 80 years. Three equal groups were randomly formulated: Group, I patients were using oral care only, Group II patients were using benzydamine hydrochloride mouth rinse, and Group III patients were medicated by using low-level laser therapy. The National Institute of Cancer-Common Toxicity Criteria (NIC-CTC) and the World Health Organization (WHO) were used to rate the severity of OM, and the pain was validated utilizing a visual analog scale (VAS). The salivary level of tumor necrotic factor-α (TNF- α) was assayed. Results: As per WHO and NIC, the grade of oral mucositis at the end of cancer treatment was less in the LLLT group than in the other two groups. The alteration in TNF- α level was not significant. The laser group is more liable to have less salivary levels of the pro-inflammatory cytokines TNF- α . Conclusion: The incidence of oral mucositis severity has seemed to be reduced due to the prophylactic use of benzydamine hydrochloride and laser therapy protocols. However, laser therapy was more efficient in controlling the shape and progression of OM (AU)

Objetivo: Neste estudo, pacientes submetidos à radioterapia (RT) da cabeça e pescoço com ou sem quimioterapia foram avaliados quanto à eficácia da terapia com laser de baixa potência (LLLT) versus o cloridrato de benzidamina no tratamento e prevenção da mucosite oral (MO) (CHT). Material e Métodos: Este estudo incluiu 90 indivíduos com câncer de cabeça e pescoço submetidos à radioterapia (RT) individualmente ou em combinação com quimioterapia (QT), com idade variando de 18 a 80 anos. Três grupos iguais foram aleatoriamente formulados: os pacientes do Grupo I usaram apenas higiene bucal, os pacientes do Grupo II usaram bochechos com cloridrato de benzidamina e os pacientes do Grupo III foram medicados com terapia a laser de baixa intensidade. Foram utilizados os critérios do National Institute of Cancer-Common Toxicity Criteria (NIC-CTC) e da Organização Mundial da Saúde (OMS) para classificar a gravidade da OM, e a dor foi validada utilizando uma escala visual analógica (VAS). O nível salivar de fator necrótico tumoral-α (TNF-α) foi ensaiado. Resultados: De acordo com a OMS e NIC, o grau de mucosite oral ao final do tratamento do câncer foi menor no grupo LLLT do que nos outros dois grupos. A alteração no nível de TNF-α não foi significativa. O grupo com tratamento a laser apresentou menores níveis de citocinas pró-inflamatórias TNF-α na saliva. Conclusão: A gravidade da mucosite oral parece ser reduzida devido ao uso profilático de cloridrato de benzidamina e protocolos de laserterapia. No entanto, a laserterapia foi mais eficiente em controlar a forma e a progressão da MO. (AU)

Efficacy of Sofosbuvir plus Ledipasvir in Egyptian patients with COVID-19 compared to standard treatment: Randomized controlled trial

BackgroundCOVID-19 is a pandemic disease caused by SARS-CoV-2, which is an RNA virus similar to HCV in the replication process. Sofosbuvir/ledipasvir is an approved drug by the FDA to treat HCV infection. This study investigates the efficacy of Sofosbuvir/ledipasvir as a treatment for patients with moderate COVID-19 infection.. MethodsThis is a single-blinded parallel-randomized controlled trial. The participants were randomized equally into the intervention group received Sofosbuvir/ledipasvir (S.L. group), and the control group received Oseltamivir, Hydroxychloroquine, and Azithromycin (OCH group). The primary outcomes were the cure rate over time and the incidence of serious adverse events. The secondary outcomes included the laboratory findings. ResultsTwo hundred and fifty patients were divided equally into each group. Both groups were similar regarding gender, but age was higher in the S.L. group (p=0.001). In the S.L. group, 89 (71.2%) patients were cured, while only 51 (40.8%) patients were cured in the OCH group. The cure rate was significantly higher in the S.L. group (RR=1.75, p<0.001). Kaplan-Meir plot showed a considerably higher cure over time in the S.L. group (Log-rank test, p=0.032). There were no deaths in the S.L. group, but there were six deaths (4.8%) in the OCH group (RR=0.08, p=0.013). Seven patients (5.6%) in the S.L. group and six patients (4.8%) in the OCH group were admitted to ICU (RR=1.17, P=0.776). There was no significant difference between treatment groups regarding Total Leukocyte Count, Neutrophils count, Lymph and Urea. ConclusionSofosbuvir/ledipasvir is suggestive of being effective in treating patients with moderate COVID-19 infection. Further studies are needed to compare Sofosbuvir/ledipasvir with the new treatment protocols.

Polymorphisms in sequence of permanent tooth emergence: a cross-sectional study on Jordanian children and adolescents.

OBJECTIVE: This study aimed at providing the norms of polymorphic gender- variation in the sequence of permanent tooth emergence in Jordanian children and adolescents. MATERIALS AND METHODS: A total of 2650 Jordanian children and adolescents (1232 males and 1418 females) aged 4-16 years were examined for permanent tooth emergence. By counting the cases of present-absent and absent-present across all possible intra-arch tooth pairs, the frequencies of sequence polymorphisms were calculated and expressed as percentages in and arch-specific matrices. RESULTS: Sequence polymorphisms were more common in tooth pairs in phase II than in phase I of permanent tooth emergence and only rarely did teeth in phase I reverse sequence with teeth in phase II. In addition, maxillary and mandibular polymorphisms were most common in the sequences of canine-second premolar and first premolar-canine, respectively. Furthermore, central incisor-first molar and second molar-second premolar sequences were much more common in the mandible than in the maxilla. It was noticed that males and females had more similar frequencies of polymorphic sequences in the maxillary than in the mandibular tooth pairs. CONCLUSIONS: This study presented the norms of pairwise sequence polymorphisms in permanent tooth emergence in the Jordanians. Such norms are adequately useful for the evaluation and prediction of tooth emergence sequence in individual children and valuable in the assessment of emergence sequence problems in pediatric dentistry and in planning and following-up orthodontic treatment.