Choc-Tadalafil Fusion: Unlocking Solubility and Taste Harmony with ß-CD-Infused Medicated Chocolate.

OBJECTIVE: The primary limitations of tadalafil in treating erectile dysfunction are its low solubility and unpleasant bitter taste, which ultimately result in inadequate patient adherence. The present study aimed to develop and characterize a medicated chocolate formulation containing Tadalafil and ß-CD (solubility enhancer) employing the concept of Design of Experiment (DoE) using chocolate as a user-friendly excipient. METHODS: An inclusion complex was formulated by incorporating the drug into ß-CD using the kneading method for solubility improvement and also as a taste masker for Tadalafil. The ratio of drug: ß-CD inclusion complex was selected based on a phase solubility study. The inclusion complex was molded into a chocolate base and optimized using the DoE approach. Further, drug excipient interaction was evaluated by DSC and FTIR study. RESULT: Phase solubility study suggested a 1:1 ratio of Tadalafil: ß-CD for better solubility. DSC spectra suggested the conversion of crystalline structure into an amorphous state which indicates improvement of the drug solubility. DSC and FTIR studies revealed that there was no significant interaction between drug and excipients. Next, %CDR (cumulative drug release) at 30 min revealed the immediate effect of Tadalafil from chocolate formulation and free drug analysis (an unbound drug with ß-CD) proved reduced bitterness of the drug in the complex. Additionally, the medicated chocolate was found to be stable at room temperature as per stability study. CONCLUSION: ß-CD was found to be a promising multifunctional excipient as a solubility enhancement carrier and taste masker for bitter-tasting drugs.

Envisioning the Future: Nanomicelles Revolutionizing Ocular Drug Delivery.

Due to the complexities of the eye's anatomy and physiology, achieving targeted drug delivery with minimal harm to healthy eye tissues has proven to be difficult. The focus of the review is on the potential of lipid and polymer micelle-based drug delivery systems, specifically nanomicelles, to overcome these challenges and improve the absorption of insoluble drugs. Nanomicelles offer several advantages, such as enhanced drug release kinetics, increased drug incorporation, and improved formulation of hydrophobic medicines. The review provides insights into various excipients, preparation methods, and evaluation techniques used in nanomicellar-based drug delivery systems. Furthermore, the review highlights current research and patents related to nanomicelles in ocular drug delivery, suggesting growing interest and potential for future developments in this field. Nanomicelles present a promising approach that may revolutionize ocular drug delivery and open new possibilities for treating various ocular diseases while minimizing adverse effects on healthy eye tissues.

In-Vitro and Ex-Vivo Evaluation of Transfersomal Gel of Methotrexate

Abstract Methotrexate on its oral and intravenous administration results in unwanted adverse effects. This drawback can be overcome by transdermal delivery because of its painless objective for systemic drug administration. Transfersomes are ultra-deformable vesicles with the flexibility to reach deeper tissues of the skin. The objective of this research work was to develop methotrexate transfersomal gel by thin film hydration technique, evaluated for entrapment efficiency, deformability, mean vesicle size, and stability, and incorporated into carbopol gel for ease of handling and skin applicability for a longer period of retention on skin. MTX-TFS gel & conventional gel were characterized for consistency, transparency, viscosity, and pH. Ex-vivo skin permeation studies were performed using abdominal goat skin and drug release kinetic parameters and transdermal flux were calculated using mathematical models. The results indicate that MTX was successfully entrapped (84.77 ± 2.35 %w/w) in transfersomes having 240±1.6 nm vesicle sizes and 27.13±0.7 deformability index. The gel was permeated through the skin at a rate of 28.12±2.58 µg/cm2/hr as compared to the conventional gel (10.35±2.14 µg/cm2/ hr). From the study, it was concluded that the MTX-TFS gel can be used as a possible substitute for the conventional formulation for transdermal drug delivery due to 3 times improvement in transdermal flux.

Effect of components (polymer, plasticizer and solvent) as a variable in fabrication of diclofenac transdermal patch.

Transdermal drug delivery influence consumer acceptance and marked increase in bioavailability of some drugs which undergoes hepatic first-pass metabolism. Fabrication of transdermal patch requires lots of attention regarding the amount of components used for it. Because of varied nature of polymer and plasticizer, transdermal patches have different properties and different drug release. This study is on the basis to evaluate the amount to be needed for fabrication of diclofenac transdermal patch. Study shows that Hydroxy Propyl Methyl Cellulose has great influence on transdermal patch, if it is used alone in combination with glycerin or PEG-4000 plasticizer.

Interrelationship of the Risser sign, knee epiphysis, and bone age in determining skeletal maturity: a case-control study.

The purpose of our study was to correlate the chronological age with Risser staging, knee epiphyseal closure, and bone age by the Tanner and Whitehouse (TW3) or Greulich and Pyle (GP) method simultaneously, to find out the most correlated methods used to calculate the age in a Korean population. A case-control study was carried out in 293 children between the age of 9 and 18 years. Skeletal age was estimated by using the atlas of the GP and TW3 methods; knee epiphysis closure and the Risser staging were also noted. Spearman's correlation coefficient test showed that in both the sexes the GP method is more correlated (r=0.58 for female patients, range: 0.55-0.61; and 0.58 for male patients, range: 0.54-0.61) with the Risser staging and physeal stages of the knee joint than the TW3 method (r=0.52 for female patients, range: 0.44-0.61; and 0.55 for male patients, range: 0.48-0.61) in Korean children. Our results suggested that by using the combination of Risser sign, knee epiphyseal closure, and GP bone age, one can calculate a person's chronological age most accurately.

Correlation and comparison of Risser sign versus bone age determination (TW3) between children with and without scoliosis in Korean population.

BACKGROUND: Most studies comparing the Risser staging for skeletal maturity are representing the American or European standards which are not always applicable to Asian population who have relatively less height and body mass. There is no article available that compares the Risser sign and bone age correlation between patients with idiopathic scoliosis and patients without scoliosis. MATERIALS AND METHODS: To analyze and compare the skeletal age with the Risser sign between scoliosis and non-scoliosis group, a cross-sectional study was done in 418 scoliosis (untreated, bracing or surgically) and 256 non-scoliosis children of Korean origin. Relationship was found in both groups using Pearson correlation test. RESULTS: In scoliosis group, Pearson correlation exhibited significant correlation (p < 0.01) between Risser sign and chronological age (r2 = 0.791 for girls, 0.787 for boys) and Risser sign and TW3 age (r2 = 0.718 for girls, 0.785 for boys). Non-scoliosis group also showed significant relationship (p < 0.01) between Risser sign and chronological age (r2 = 0.893 for girls, 0.879 for boys) and Risser sign and TW3 age (r2 = 0.913 for girls, 0.895 for boys). Similarly, comparing Cobb angles of each patient according to their Risser staging, exhibited that if scoliosis remains untreated Cobb angle will increase with the increase in their Risser staging (r2 = 0.363 for girls, 0.443 for boys; p < 0.01). CONCLUSION: Our results showed that chronological age is equally as reliable as skeletal age method to compare with Risser sign, and therefore, we do not mean to imply that only the Risser sign compared with skeletal age should be considered in the decision making in idiopathic as well as non-scoliosis patients of Korean ethnicity. Concomitant indicators such as menarchal period, secondary sex characteristics, and recent growth pattern will likely reinforce our data comparing Risser sign with skeletal age in decision making.

Deceleration in maturation of bone during adolescent age in achondroplasia--a retrospective study using RUS scoring system.

OBJECTIVES: Knowledge of bone age in achondroplasia is required for the prediction of adult height, timings of limb lengthening, and epiphysiodesis procedures. The purpose of this investigation was to determine the differences in skeletal age in achondroplasia and a control population with the Tanner-Whitehouse 3 method using the RUS score and to determine the right age for the interventional procedure for limb lengthening procedure or deformity correction in these patients. MATERIALS AND METHODS: Left hand radiographs of 34 patients (age range, 5-18 years) with achondroplasia were evaluated for skeletal age using the RUS scoring system, which were compared with the left hand radiographs of 41 patients (age range, 5-18 years) without achondroplasia measuring skeletal age. The difference in chronological age and RUS bone age were evaluated statistically according to gender and age group. RESULTS: In the achondroplasia group, chronological age were 10.5 +/- 4.3 years for males and 10.1 +/- 3.6 years for females and RUS bone age were 9.2 +/- 4.0 years for males and 8.9 +/- 3.4 years for females, which showed statistically significantly difference (males p = 0.0003 and females p < 0.0001), while in the control group, chronological age were 11.1 +/- 2.9 years for males and 10.7 +/- 3.4 years for females and RUS bone age were 11.2 +/- 3.4 years for males and 10.7 +/- 3.3 years for females, which did not show statistically significantly difference (males p = 0.54 and females p = 0.76). Our finding suggested a delay of 1.4 years for males and 1.2 years for females in the maturation of bone in achondroplasia patients. Difference between chronological age and RUS bone age was 0.9 +/- 1.1 for <10 years and 1.6 +/- 0.9 for >10 years in the study group, while 0.1 +/- 1.1 for <10 years and -0.2 +/- 0.6 for >10 years in the control group, which also showed >statistically significant difference (<10 years p = 0.04 and >10 years p < 0.0001). These differences indicate that there was a delay in the maturation of bones by 1 year in the group <10 years and 1.8 years in the group >10 years in achondroplasia patients compared to nonachondroplasia patients. CONCLUSION: We recommend the use of the Tanner-Whitehouse 3 method especially the radius, ulna, short bone score to measure the skeletal age and to wait for a longer time before interventional procedures in achondroplasia patients.

Differential wedging of vertebral body and intervertebral disc in thoracic and lumbar spine in adolescent idiopathic scoliosis - A cross sectional study in 150 patients.

BACKGROUND: Hueter-Volkmann's law regarding growth modulation suggests that increased pressure on the end plate of bone retards the growth (Hueter) and conversely, reduced pressure accelerates the growth (Volkmann). Literature described the same principle in Rat-tail model. Human spine and its deformity i.e. scoliosis has also same kind of pattern during the growth period which causes wedging in disc or vertebral body. METHODS: This cross sectional study in 150 patients of adolescent idiopathic scoliosis was done to evaluate vertebral body and disc wedging in scoliosis and to compare the extent of differential wedging of body and disc, in thoracic and lumbar area. We measured wedging of vertebral bodies and discs, along with two adjacent vertebrae and disc, above and below the apex and evaluated them according to severity of curve (curve < 30 degrees and curve > 30 degrees ) to find the relationship of vertebral body or disc wedging with scoliosis in thoracic and lumbar spine. We also compared the wedging and rotations of vertebrae. RESULTS: In both thoracic and lumbar curves, we found that greater the degree of scoliosis, greater the wedging in both disc and body and the degree of wedging was more at apex supporting the theory of growth retardation in stress concentration area. However, the degree of wedging in vertebral body is more than the disc in thoracic spine while the wedging was more in disc than body in lumbar spine. On comparing the wedging with the rotation, we did not find any significant relationship suggesting that it has no relation with rotation. CONCLUSION: From our study, we can conclude that wedging in disc and body are increasing with progression on scoliosis and maximum at apex; however there is differential wedging of body and disc, in thoracic and lumbar area, that is vertebral body wedging is more profound in thoracic area while disc wedging is more profound in lumbar area which possibly form 'vicious cycle' by asymmetric loading to spine for the progression of curve.

Antitumor polycyclic acridines. 20. Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: telomere-targeted agents.

The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.

Antitumor polycyclic acridines. Part 16. Triplex DNA as a target for DNA-binding polycyclic acridine derivatives.

Triple-stranded DNA structures have been implicated in a number of major biological processes, including the transcription and translation of a number of genes, as well as in the interaction of DNA with a number of proteins. Furthermore, antigene therapies under development are based on the recognition and binding of a single oligonucleotide strand to a double-stranded sequence, thus forming a triple helix. Triplex DNA formation is a relatively weak and temporary phenomenon; therefore, molecules that selectively bind to and stabilize triple helices may show a variety of novel biological effects. The biophysical and biological characterization of a series of antitumor polycyclic acridines that bind to triplex DNA is reported. These compounds, whose synthesis has been previously reported, have been tested for their interaction with both purine and pyrimidine type triple helices and compared with the relevant double-stranded DNA. As a pyrimidine triplex model we have used the T*AT sequence, which we have compared with the AT duplex, whereas the purine triplex oligonucleotide d[G3A4G3]*d[G3A4G3].d[C3T4C3] has been compared with the duplex d[G3A4G3].d[C3T4C3]. The compounds demonstrate various degrees of preferential binding to triplex DNA over normal duplex DNA, as measured by UV, fluorescence, circular dichroism, and thermal denaturation. Tri-substituted acridine derivatives demonstrated the highest affinity and ability to stabilize triplex DNA structures. Furthermore, structure/affinity analysis gives insights into the structural features that optimize affinity and selectivity for triplex DNA, and may play a role in their profile of antitumor activity.

Antitumor polycyclic acridines. 8.(1) Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts.

Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 microM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, NSC 714186) and a low overall growth-inhibitory activity in the NCI 60 cell panel (mean GI(50) 13.18 microM); in addition, the activity profile of 12d does not COMPARE with agents of the topoisomerase II class. Compound 12d is soluble in water, stable in the pH range of 5-9, efficiently transported into tumor cells, and is currently the lead structure for further elaboration in this new class of telomerase inhibitor.

Antitumor polycyclic acridines. Part 12. Physical and biological properties of 8,13-diethyl-6-methylquino[4,3,2-kl]acridinium iodide: a lead compound in anticancer drug design.

The biophysical and biological characterization of 8,13-diethyl-6-methylquino[4,3,2-k]lacridinium iodide (6) is reported. The compound binds to DNA, as measured by UV, fluorescence, and circular dichroism studies, and stabilizes the double helix and higher order DNA structures (DNA triplexes and quadruplexes) against thermal denaturation. Unlike many DNA ligands, (6) shows no specificity for binding to specific base pair combinations and does not inhibit topoisomerase I (topo I) or topo II activity. Furthermore, the biological fingerprint elicited by (6) in in vitro evaluations does not compare with clinical agents of the topo II inhibition class. The compound provokes cell cycle arrest in response to DNA damage and the biological sequelae are dependent on the p53 status of the cell line. DNA damage by (6) upregulates p53 and p21(CIP/WAF1) proteins. The unusual structure of (6) and its ease of synthesis in a "one-pot" reaction are features that are being exploited in the design and development of a new series of G-quadruplex stabilizing telomerase inhibitors. However, although the second-generation compounds that resulted from (6) present strong telomerase inhibition, (6) in itself presents yet a different mode of action, with a strong preference for triplex DNA, sequences often found in a number of genes.