The rationale of the present work is to formulate and evaluate metoprolol tartrate (MT), which is a beta-1 selective adrenergic blocking agent in a new ocular gel delivery system; this is our way and method to increase its contact to the cornea, giving a longer time of drug contact to the eye and slow possible release from the preparation. Metoprolol tartrate is chosen as a candidate for gel formulation because although it has been available for a few years as ophthalmic solutions, it has not been marketed as an ocular gel yet. Two polymers; Carbopol 934 and Pluronic F127 (PF127) were used in two different concentrations in this study. Metoprolol tartrate was used in two concentrations, 0.5% and 1% (w/w). All formulations were exposed to visual examinations, pH measurement, in vitro release, rheological study and differential scanning calorimetry (DSC). Results showed that all formulations were clear, showed pH within the acceptable range suitable to be administered in the eye, and exhibited pseudoplastic flow behavior. DSC results concluded that, MT was compatible with different polymers used. In vitro release results showed that the release rate of metoprolol tartrate from gel preparations decreased as an inverse function of polymer concentration, and the release rate of the drug increased as the initial concentration increased. Intra-ocular pressure (IOP) measurements of rabbit’s eye treated with 1% (w/w) metoprolol tartrate in gel formulations with different concentrations of the polymer were determined. Carbopol 934 gel formulations showed that this polymer extended the duration of pressure reducing effect of MT to more than 5hr when compared with Pluronic F127 gel formulations. The area above the curve (AAC), maximum response, time of maximum response (tmax), and the duration of the drug action were also calculated.

Because of their ability to translocate different cargos into cells, arginine-rich cell penetrating peptides (CPPs) are promising vehicles for drug and gene delivery. The use of CPP-based carriers, however, is hampered by the lack of specificity and by interactions with negative serum components. Polyethylene glycol (PEG) is used to decrease such non-specific interactions, albeit its use is associated with reduced transfection efficiency. In this study, we describe the development of PEGylated CPP-based gene carrier with an improved targeting and a high transfection activity. The system was prepared by condensing DNA with a polycation followed by coating with a lipid envelope containing the octaarginine (R8) peptide as a model CPP. R8-modified nanoparticles produced high transfection activities, but the efficiency was reduced by PEG shielding. The reduced activity could be fully restored by the addition of a targeting ligand and a pH-sensitive fusogenic peptide. The efficiency of the proposed system is quite high, even in the presence of serum, and shows improved targeting and selectivity. Surprisingly, the effect of the fusogenic peptide was dramatically reduced in the absence of R8. Although shielded, R8 augmented the activity of the fusogenic peptide, suggesting a synergistic effect between the two peptides at the intracellular level.

We report on the development of a highly efficient gene delivery system based on synergism between octaarginine (R8), a representative cell penetrating peptide, and YSK05, a recently developed pH-sensitive cationic lipid. Attaching a high density of R8 on the surface of YSK05 nanoparticles (NPs) that contained encapsulated plasmid DNA resulted in the formation of positively charged NPs with improved transfection efficiency. To avoid the development of a net positive charge, we controlled the density and topology of the R8 peptide through the use of a two-step coating methodology, in which the inner lipid coat was modified with a low density of R8 which was then covered with an outer neutral YSK05 lipid layer. Although used in low amounts, the R8 peptide improved cellular uptake and endosomal escape of the DNA encapsulated in YSK05 NPs, which resulted in a high transfection efficiency. The two-step coating design was essential for achieving a high degree of transfection, as evidenced by the low activity of NPs modified with the same amount of R8 in a regular single-coated design. In addition, a high transfection efficiency was not observed when R8 or YSK05 were used alone, which confirms the existence of a synergistic effect between both components. The results of this study indicate that cationic cell penetrating peptides have the ability to improve transfection activities without imparting a net positive charge when used in the proper amount and in conjunction with the appropriate design. This is expected to significantly increase the potential applications of these peptides as tools for augmenting the activity of lipid nanoparticles used in gene delivery.

Background: Bacterial vaginosis (BV) is one of the most common infections in childbearing age. Aim: To compare the efficacy of metronidazole (once-daily 0.8% MTZ in situ gel) versus twice-daily conventional MTZ vaginal gel in the treatment of bacterial vaginosis (BV). Material and methods: All patients who presented to Assiut Women Health Hospital- Egypt with symptoms suggestive of BV were counseled to participate in the study. One hundred-four eligible participants were randomly assigned to either MTZ in situ gel or a conventional vaginal gel. All participants were followed-up twice after one and 4 weeks of the beginning of treatment to ensure cure of infection and any side-effects. Results: Demographic criteria of the participants were matched in both groups. The cure rate after one week from the treatment was 74.5% in the in situ gel group and 63.8% in the conventional vaginal gel group (P=0.252), while after 4 weeks, the cure rate showed significant difference in the in situ gel group as compared to the conventional vaginal gel group (66.7%) and (40.4%), respectively (P=0.009). Conclusion: Once daily in situ MTZ gel (0.8%) is more effective than twice-daily conventional gel after four weeks of treatment with nearly same side effects. These findings confirm the use of this novel and efficient modality of long-term treatment of BV.

Background: Bacterial vaginosis (BV) is one of the most common infections in childbearing age. Aim: To compare the efficacy of metronidazole (once-daily 0.8% MTZ in situ gel) versus twice-daily conventional MTZ vaginal gel in the treatment of bacterial vaginosis (BV). Material and methods: All patients who presented to Assiut Women Health Hospital- Egypt with symptoms suggestive of BV were counseled to participate in the study. One hundred-four eligible participants were randomly assigned to either MTZ in situ gel or a conventional vaginal gel. All participants were followed-up twice after one and 4 weeks of the beginning of treatment to ensure cure of infection and any side-effects. Results: Demographic criteria of the participants were matched in both groups. The cure rate after one week from the treatment was 74.5% in the in situ gel group and 63.8% in the conventional vaginal gel group (P=0.252), while after 4 weeks, the cure rate showed significant difference in the in situ gel group as compared to the conventional vaginal gel group (66.7%) and (40.4%), respectively (P=0.009). Conclusion: Once daily in situ MTZ gel (0.8%) is more effective than twice-daily conventional gel after four weeks of treatment with nearly same side effects. These findings confirm the use of this novel and efficient modality of long-term treatment of BV.

Background: Bacterial vaginosis (BV) is one of the most common infections in childbearing age. Aim: To compare the efficacy of metronidazole (once-daily 0.8% MTZ in situ gel) versus twice-daily conventional MTZ vaginal gel in the treatment of bacterial vaginosis (BV). Material and methods: All patients who presented to Assiut Women Health Hospital- Egypt with symptoms suggestive of BV were counseled to participate in the study. One hundred-four eligible participants were randomly assigned to either MTZ in situ gel or a conventional vaginal gel. All participants were followed-up twice after one and 4 weeks of the beginning of treatment to ensure cure of infection and any side-effects. Results: Demographic criteria of the participants were matched in both groups. The cure rate after one week from the treatment was 74.5% in the in situ gel group and 63.8% in the conventional vaginal gel group (P=0.252), while after 4 weeks, the cure rate showed significant difference in the in situ gel group as compared to the conventional vaginal gel group (66.7%) and (40.4%), respectively (P=0.009). Conclusion: Once daily in situ MTZ gel (0.8%) is more effective than twice-daily conventional gel after four weeks of treatment with nearly same side effects. These findings confirm the use of this novel and efficient modality of long-term treatment of BV.

Background: Bacterial vaginosis (BV) is one of the most common infections in childbearing age. Aim: To compare the efficacy of metronidazole (once-daily 0.8% MTZ in situ gel) versus twice-daily conventional MTZ vaginal gel in the treatment of bacterial vaginosis (BV). Material and methods: All patients who presented to Assiut Women Health Hospital- Egypt with symptoms suggestive of BV were counseled to participate in the study. One hundred-four eligible participants were randomly assigned to either MTZ in situ gel or a conventional vaginal gel. All participants were followed-up twice after one and 4 weeks of the beginning of treatment to ensure cure of infection and any side-effects. Results: Demographic criteria of the participants were matched in both groups. The cure rate after one week from the treatment was 74.5% in the in situ gel group and 63.8% in the conventional vaginal gel group (P=0.252), while after 4 weeks, the cure rate showed significant difference in the in situ gel group as compared to the conventional vaginal gel group (66.7%) and (40.4%), respectively (P=0.009). Conclusion: Once daily in situ MTZ gel (0.8%) is more effective than twice-daily conventional gel after four weeks of treatment with nearly same side effects. These findings confirm the use of this novel and efficient modality of long-term treatment of BV.

We aimed to investigate the effect of adding sildenafil vaginal gel to clomiphene citrate (CC) in infertile women with prior CC failure. METHODS: This is a self- controlled clinical trial. Women with CC failure (in prior 5 cycles) and thin endometrium were recruited (N = 42). In their 6th (CC only) cycle, women continued on CC 100 mg/ day for 5 days, and had measurement of endometrial thickness and Doppler assessment of uterine arteries on day of HCG administration. In the 7th cycle, women (N = 36) were given usual dose of CC supplemented with sildenafil vaginal gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 to day of HCG administration. Endometrial thickness and uterine artery Doppler were measured on the day of HCG injection. RESULTS: In the 7th (CC + sildenafil vaginal gel) cycle, endometrial thickness was significantly higher than in the 6th (CC only) cycle (9.3 mm +/- 3.1mm versus 6.6 mm +/- 1.4 mm, respectively, P = 0.001). Uterine artery pulsatility index dropped from 2.4 +/- 0.8 in 6th cycle to 1.6 +/- 1.3 in 7th cycle (P = 0.002). Clinical pregnancy rate increased but numbers were too small (only 3 pregnancies). CONCLUSION: Sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow, and may improve pregnancy rate in patients with CC failure due to thin endometrium. Mucoadhesive vaginal gel formulation allowed shorter duration of sildenafil application, and less frequent daily dosing.

We aimed to investigate the effect of adding sildenafil vaginal gel to clomiphene citrate (CC) in infertile women with prior CC failure. METHODS: This is a self- controlled clinical trial. Women with CC failure (in prior 5 cycles) and thin endometrium were recruited (N = 42). In their 6th (CC only) cycle, women continued on CC 100 mg/ day for 5 days, and had measurement of endometrial thickness and Doppler assessment of uterine arteries on day of HCG administration. In the 7th cycle, women (N = 36) were given usual dose of CC supplemented with sildenafil vaginal gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 to day of HCG administration. Endometrial thickness and uterine artery Doppler were measured on the day of HCG injection. RESULTS: In the 7th (CC + sildenafil vaginal gel) cycle, endometrial thickness was significantly higher than in the 6th (CC only) cycle (9.3 mm +/- 3.1mm versus 6.6 mm +/- 1.4 mm, respectively, P = 0.001). Uterine artery pulsatility index dropped from 2.4 +/- 0.8 in 6th cycle to 1.6 +/- 1.3 in 7th cycle (P = 0.002). Clinical pregnancy rate increased but numbers were too small (only 3 pregnancies). CONCLUSION: Sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow, and may improve pregnancy rate in patients with CC failure due to thin endometrium. Mucoadhesive vaginal gel formulation allowed shorter duration of sildenafil application, and less frequent daily dosing.

We aimed to investigate the effect of adding sildenafil vaginal gel to clomiphene citrate (CC) in infertile women with prior CC failure. METHODS: This is a self- controlled clinical trial. Women with CC failure (in prior 5 cycles) and thin endometrium were recruited (N = 42). In their 6th (CC only) cycle, women continued on CC 100 mg/ day for 5 days, and had measurement of endometrial thickness and Doppler assessment of uterine arteries on day of HCG administration. In the 7th cycle, women (N = 36) were given usual dose of CC supplemented with sildenafil vaginal gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 to day of HCG administration. Endometrial thickness and uterine artery Doppler were measured on the day of HCG injection. RESULTS: In the 7th (CC + sildenafil vaginal gel) cycle, endometrial thickness was significantly higher than in the 6th (CC only) cycle (9.3 mm +/- 3.1mm versus 6.6 mm +/- 1.4 mm, respectively, P = 0.001). Uterine artery pulsatility index dropped from 2.4 +/- 0.8 in 6th cycle to 1.6 +/- 1.3 in 7th cycle (P = 0.002). Clinical pregnancy rate increased but numbers were too small (only 3 pregnancies). CONCLUSION: Sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow, and may improve pregnancy rate in patients with CC failure due to thin endometrium. Mucoadhesive vaginal gel formulation allowed shorter duration of sildenafil application, and less frequent daily dosing.