A Modified Ridge-Splitting Technique to Restore a Completely Edentulous Maxillary Arch With a Cement-Retained Implant Prosthesis.

The present report describes a technique in which the maxillary bone was molded to the desired location using a series of instruments for ridge-splitting procedures. This technique aims to improve bone quality all around the implants at both the crest and apex locations. In some clinical scenarios, insufficient horizontal bone with less than 3 mm prevents implant placement. Thus, ridge splitting is a treatment of choice, and this technique creates bone expansion to form a better receptor site for endosteal implants. A case report is presented involving a completely edentulous 52-year-old male patient presented to the clinic with a horizontal bone defect. The patient complained of having difficulty eating and wants to improve his smile. In this clinical case, a modified ridge-splitting technique was employed, differing from the conventional procedure that uses mallets, chisels, or osteotomes. A lancet and spatula were used for precise ridge splitting, followed by the placement of four endosseous tapered implants-two on each side (Dentis USA, La Palma, USA). Each implant had a diameter of 3.7 mm and a length of 10 mm. These implants were clinically placed in a single visit, with a torque of 30 N/cm² applied to ensure secure fixation. To accommodate the patient's unique maxillary bone anatomy, 25-degree angulated abutments were chosen for the four implants, ensuring a common path of insertion, and optimal angulation for long-term stability and aesthetics. Subsequently, a cemented provisional dental prosthesis restoration was fitted, and the patient reported satisfaction with both function and aesthetics. After a period of five months of osseointegration, the stability of the implants was assessed using a resonance frequency analyzer, yielding positive results. The average resonance frequency values for the maxillary left (canine and premolar) were ISQ 68 and ISQ 71, respectively, while for the maxillary right (lateral incisor and premolar), the values were ISQ 69 and ISQ 73. These readings indicate satisfactory implant stability following the osseointegration process. The postoperative cone-beam computed tomography (CBCT) showed gain to the bone width besides better function and good results concerning the esthetics. This report describes a modified ridge-splitting technique with a predictable and satisfactory outcome that fulfilled the patient's demands. The presented approach overcomes the disadvantages of two-staged implant placement bone grafting procedures and is also a more affordable option for the patient. CBCT evaluation confirmed bone gain with minimal morbidity after the procedure.

AI & experimental-based discovery and preclinical IND-enabling studies of selective BMX inhibitors for development of cancer therapeutics.

The current work aims to design and provide a preliminary IND-enabling study of selective BMX inhibitors for cancer therapeutics development. BMX is an emerging target, more notably in oncological and immunological diseases. In this work, we have employed a predictive AI-based platform to design the selective inhibitors considering the novelty, IP prior protection, and drug-likeness properties. Furthermore, selected top candidates from the initial iteration of the design were synthesized and chemically characterized utilizing 1H NMR and LC-MS. Employing a panel of biochemical (enzymatic) and cancer cell lines, the selected molecules were tested against these assays. In addition, we used artificial intelligence to predict and evaluate several critical IND-focused physicochemical and pharmacokinetics values of the selected molecules. A secondary objective of the current work was also to validate the sole role of BMX in animal models known to be mediated by BMX. More than 50 molecules were designed in the present study employing five novel discovered scaffolds. Two molecules were nominated for further IND-focused studies. Compound II showed promising in-vitro activity against BMX in both enzymatic assays compared to other kinases and in cancer cell lines with known BMX overexpression. Interestingly, compound II showed very favorable physicochemical and pharmacokinetics properties as predicted by the used platforms. The animal study further confirmed the sole role of BMX in the disease model. The current work provides promising data on a selective BMX inhibitor as a potential lead for therapeutics development, and the asset is currently in the optimization stage. Notably, the current study shows a framework for a combined approach employing both AI and experimentation that can be used by academic labs in their research programs to more streamline programs into IND-focused to be bridged easily for further clinical development with industrial partners.

Preparation and characterization of aqueous vitamin E/Soluplus® dispersions for film coating applications.

OBJECTIVE: The goals of this study were to (1) delineate a technique to prepare stable aqueous vitamin E/Soluplus® dispersions; (2) characterize films cast from the aqueous dispersions; and (3) demonstrate the utility of the aqueous dispersions in fluid bed coating applications. This study demonstrated the feasibility of using vitamin E in the preparation of amphiphilic film withs potential use in delayed-release coating applications. METHODS: Low viscosity aqueous vitamin E/Soluplus® dispersions were prepared by first spray drying ethanolic vitamin E/Soluplus® solutions followed by high-shear homogenization of the solid dispersions in water. Concentrated (10%) aqueous dispersions containing 0%, 10%, 20%, and 30% of vitamin E in the binary blend with Soluplus® were then cast into films and characterized for contact angle and mechanical strength by texture analysis. RESULTS: All films were hydrophilic and homogenous, which confirmed the utility of vitamin E as a plasticizer for the Soluplus® polymer. The 0% and 10% films were brittle whereas the 30% were tacky. The 20% dispersion was subsequently used to coat acetaminophen granules by a fluidized bed process to a dry weight gain of 10-30%. When tested by a dissolution study, a delay in acetaminophen release was observed as a function of weight gain. CONCLUSION: The results from this study demonstrated that it is feasible to produce stable vitamin E/Soluplus® aqueous dispersions to be used as solvent-free functional film coating materials.

Correlation of Implant Stability Between Two Noninvasive Methods Using Submerged and Nonsubmerged Healing Protocols: A Randomized Clinical Trial.

Various invasive and noninvasive methods have been used for measuring primary implant stability. Periotest damping device and resonance frequency analysis with the Osstell device have been classified as noninvasive methods. Primary and secondary implant stability measurements using both devices have given reproducible quantitative values. In this clinical randomized trial, a general correlation was evaluated between the implant stability recorded using both Osstell and Periotest devices on the day of implant installation and 3 months after healing for the submerged and nonsubmerged loading protocols. The present study also investigated whether the difference in gender of the included patients would have an effect on the correlation between the two devices. Eighty completely edentulous patients were recruited, and all patients ranged from 50 to 69 years of age. Overall, 56 men and 24 women were included, with a mean age of 62.5 years for men and 59.6 years for women. A single implant was installed in the midline of the completely edentulous mandible to improve retention of the patient's lower denture. After implant installation, one implant stability quotient (ISQ) value at the buccal surface was recorded, and then the Periotest M device was used to measure the damping effect (Periotest value [PTV]) of the installed implant using the smart peg screwed to the implant. Patients were then randomized into 2 groups using sealed envelopes: the submerged and nonsubmerged groups. For both groups, all ISQ and Periotest readings were recorded in the patient's case report file on the day of implant installation and 3 months after healing. When the ISQ of the buccal surface was correlated to the PTV, there was a moderate negative statistically significant correlation between the 2 readings (correlation coefficient = -.466, P = .000). There tended to be a weak negative correlation between the 2 devices in the male group (correlation coefficient = .395, P = .046) during implant installation, although there tended to be no correlation between the 2 devices in the female group (correlation coefficient = -.367, P = .342). After 3 months of healing, when correlating the readings of the buccal surface of the Osstell with that of the Periotest within each group (submerged and nonsubmerged), there was no statistically significant correlation between the readings within each group (correlation coefficient = -.014, -.430, P = .942, P = .052, respectively). However, there was a strong negative statistically significant correlation between the 2 devices for the female group for both the nonsubmerged group (correlation coefficient = -.823, P = .003) and submerged group (correlation coefficient = -.857, P = .014), whereas there was no statistically significant correlation within the male group for both the nonsubmerged group (correlation coefficient = -.377, P = .123) and submerged group (correlation coefficient = -.022, P = .940). The correlation between the Osstel and Periotest device remains controversial. The present study concluded that there is a significant negative correlation between the 2 devices when recording primary implant stability, although this significance is lost after 3 months of loading when recording secondary implant stability. Gender also affects the implant stability recording, which is mainly due to the difference in bone density between men and women.

Development and evaluation of paclitaxel nanoemulsion for cancer therapy.

Tocosol™ is a tocopherol-based paclitaxel (PTX) nanoemulsion consisting of α-tocopherol (α-T) isomer of vitamin E as a solubilizer and vitamin E TPGS as the primary emulsifier. Despite its positive attributes in early clinical studies, it failed the pivotal phase III clinical trials. The long-term goal of this work was to reformulate Tocosol™. In this study, Tocosol™ formulation was optimized by replacing the α-T isomer with the more pharmacological active isomer γ-tocotrienol (γ-T3), and the surfactant vitamin E TPGS was replaced with in-house designed PEGylated γ-T3 surfactant. The reformulated paclitaxel γ-T3/PEGylated γ-T3 -based nanoemulsion was significantly more active against pancreatic tumor cell lines than α-T/Vitamin E TPGS based formulation (IC50 = 0.5 µM and 1.1 µM, respectively). Furthermore, the reformulated product showed an average size of 220 ± 6 nm with surface charge equal to -42 ± 2 mV. The optimized product was physically and chemically stable over 6 months per ICH storage condition guidelines.

Novel liquid-liquid extraction and self-emulsion methods for simplified isolation of extra-virgin olive oil phenolics with emphasis on (-)-oleocanthal and its oral anti-breast cancer activity.

Epidemiological and clinical studies compellingly documented the ability of Mediterranean diet rich in extra-virgin olive oil (EVOO) to reduce breast and colon cancers incidence, cardiovascular diseases, and aging cognitive functions decline. (-)-Oleocanthal (OC) and other EVOO phenolics gain progressive research attention due to their documented biological effects against cancer, inflammations, and Alzheimer's disease. There is no simple, reliable, and cost-effective isolation protocol for EVOO phenolics, which hinder their therapeutic applications. This study develops novel methods to isolate OC and other EVOO phenolics. This includes the use of ultra-freezing to eliminate most EVOO fats and the successful water capacity to efficiently extract OC and EVOO phenolics as self-emulsified nano-emulsion. Subsequent resin entrapment and size exclusion chromatography afforded individual EVOO phenolics in high purity. OC in vitro and in vivo oral anti-breast cancer (BC) activities validated its lead candidacy. Effective isolation of EVOO phenolics provided in this study will facilitate future preclinical and clinical investigations and stimulate the therapeutic development of these important bioactive natural products.

Oral Health-Related Quality of Life in Single Implant Mandibular Overdenture Retained by CM LOC versus Ball Attachment: A Randomized Controlled Trial.

AIM: This randomised clinical study aimed to detect whether CMLOC attachment could improve Oral Health-Related Quality of Life (OHRQOL) when compared to ball attachment. METHODS: Eighty edentulous patients were recruited to receive a single symphyseal implant for mandibular overdenture, after three months, randomisation was done to divide them into two groups; Dalbo ball (control group) and Cendres and Metaux locator (CM-LOC) (intervention) attachments respectively, oral health impact profile for edentulous patients (OHIP-EDENT)questionnaire was recorded before implant placement, two weeks after pick up, at 3, 6, 9, and 12 months. RESULTS: Results revealed a lack of statistical significance between the two groups except for psychological discomfort at 2 weeks after pick-up (p-value = 0.029). CONCLUSION: Single implant overdenture is a simple, reliable treatment modality for treating edentulous mandible and both CM LOC and Ball attachments are good alternatives for such treatment modality.

Development and in-vitro characterization of nanoemulsions loaded with paclitaxel/γ-tocotrienol lipid conjugates.

Vitamin E TPGS is a tocopherol (α-T) based nonionic surfactant that was used in the formulation of the Tocosol™ paclitaxel nanoemulsion, which was withdrawn from phase III clinical trials. Unlike tocopherols, however, the tocotrienol (T3) isomers of vitamin E were found to have innate anticancer activity and were shown to potentiate the antitumor activity of paclitaxel. The primary objective of the present study was therefore to develop a paclitaxel nanoemulsions by substituting α-T oil core of Tocosol™ with γ-T3 in, and vitamin E TPGS with PEGylated γ-T3 as the shell, and test the nanoemulsions against Bx-PC-3 and PANC-1 pancreatic tumor cells. A secondary objective was to test the activity of paclitaxel when directly conjugated with the γ-T3 isomer of vitamin E. The synthesis of the conjugates was confirmed by NMR and mass spectroscopy. Developed nanoemulsions were loaded with free or lipid conjugated paclitaxel. Nanoemulsions droplets were <300 nm with fastest release observed with formulations loaded with free paclitaxel when γ-T3 was used as the core. Substituting α-T with γ-T3 was also found to potentiate the anticancer activity of the nanoemulsions. Although marginal increase in activity was observed when nanoemulsions were loaded with free paclitaxel, a significant increase in activity was observed when lipid conjugates were used. The results from this study suggest that the developed paclitaxel nanoemulsions with either γ-T3, PEGylated γ-T3, or paclitaxel lipid conjugates may represent a more promising option for paclitaxel delivery in cancer chemotherapy.

Bar versus ball attachments for implant-supported overdentures in complete edentulism: A systematic review.

BACKGROUND: Implant-supported overdenture is one of the most predictable treatment options used in complete edentulism. However, differences have been reported between bar and ball attachments used to retain overdentures in terms of patient satisfaction and prosthesis retention. PURPOSE: The purpose of this study is to compare the effectiveness of bar and ball attachments for conventionally loaded implant-supported overdentures in completely edentulous patients to improve patient satisfaction and prosthesis retention. MATERIALS AND METHODS: We conducted the review according to the Cochrane methods and following MECIR standards. We searched Cochrane Oral Health Group Trial register, Cochrane Central Register of Controlled Trials, MEDLINE, and the WHO ICTRP (March 31, 2017). Two review authors assessed trials for inclusion and risk of bias, extracted data, and checked for accuracy. We have expressed results as risk ratio or mean differences, together with their 95% confidence intervals. RESULTS: We included 10 trials (465 participants). After 5 y, one trial reported higher patient satisfaction when bar attachment was used (MD 1.30, 95% CI 0.20-2.40), and reported no difference between both systems in prosthesis retention (MD -0.90, 95% CI -1.90 to 0.10). Two trials reported no implant failures after 1 and 5 y in both attachments. Downgrading of evidence was based on the unclear risk of bias of included studies and the wide CI crossing the line of no effect. CONCLUSIONS: There is insufficient evidence to support bar or ball attachment to be used with implant-supported overdentures in completely edentulous patients to improve patient satisfaction and prosthesis retention (PROSPERO 2014:CRD42014014594).

Synthesis, physiochemical characterization, and in vitro antitumor activity of the amide and pH cleavable hydrazone conjugates of γ-tocotrienol isomer of vitamin E with methoxy-poly(ethylene) glycol.

The anticancer activity of water soluble methoxy polyethylene glycol (mPEG) derivatives of tocotrienol (T3) isomers of vitamin E was previously found to be reduced when compared to the parent free isomers. This could be due to the ester bond formation between the mPEG and the 6-OH group on the chroman moiety of the T3 isomer. To further investigate, the objectives of the current study were to (1) synthesize and characterize stable amide and cleavable hydrazone conjugates between mPEG and carbon-5 on the chroman moiety of T3, and (2) examine the cytotoxicity of the newly synthesized mPEG conjugates against breast (MCF-7 and MDA-MB-231) and pancreatic (BxPC-3 and PANC-1) cancer cells. Conjugates were synthesized by direct conjugation of succinyl chloride derivatives of mPEG to the α-tocopherol and γ-tocotrienol isomers of vitamin E, and were characterized by 1H NMR, FT-IR, and mass spectrometry. The micelles of the amide and hydrazone self-assembled conjugates were characterized for size, zeta, CMC, and stability at different pH media. The hydrolysis of the hydrazone conjugate was pH dependent with highest release at acidic (pH 5.5) conditions, whereas the amide conjugate was stable in all tested media. The amide conjugate nonetheless showed greater cytotoxicity than the hydrazone conjugate, which suggested that maintaining solubility and the presence of free 6-OH group are important for γ-T3 to exert anticancer activity in vitro. The results from the current study demonstrated the importance of considering the nature of the chemical bond between T3 and mPEG when designing functional ingredients for use in drug delivery.

Gemcitabine-vitamin E conjugates: Synthesis, characterization, entrapment into nanoemulsions, and in-vitro deamination and antitumor activity.

Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the γ-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienol isomers of vitamin E can potentiate the anticancer activity of gemcitabine. To accomplish this objective, a full synthesis scheme for gemcitabine conjugation to fatty acids (stearic and linoleic) and the tocopherol and tocotrienol isomers of vitamin E (α-T and γ-T3) was presented. The conjugates were characterized by 1H NMR and mass spectrometry analysis and tested for their susceptibility to deamination. Also discussed is the impact of entrapping the conjugates into nanoemulsions on the physiochemical properties of the delivery system and the in vitro anticancer activity of gemcitabine against Bx-PC-3 and PNAC-1 pancreatic cancer cells. In-vitro enzymatic deamination study showed that the γ-T3 conjugate of gemcitabine was least affected by deamination deactivation reaction when compared with the free and conjugated gemcitabine in solution. Furthermore, in-vitro cytotoxicity study demonstrated that entrapment of gemcitabine-lipid conjugates into nanoemulsions significantly enhanced their anticancer activity when compared to the free drug. It was concluded that conjugation to the γ-T3 isomer is a viable option for gemcitabine delivery and is worthy of further investigation.

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E.

Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T3) isomers. PEGylated α-tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T3. Yield and the identity of the synthesized products were confirmed by 1H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T3 isomers were significantly more active as inhibitors for P-glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, γ-T3PGS 1000 and δ-T3PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for γ-T3PGS 1000 and δ-T3PGS 1000 conjugate.

Extraction of Vitamin E Isomers from Palm Oil: Methodology, Characterization, and in Vitro Anti-Tumor Activity.

Vitamin E refers to a family of eight tocopherols (T) and tocotrienol (T3) isomers. Due to the unique pharmacological and anticancer activity of the individual isomers, there is a need to extract and separate the individual T3 isomers from T/T3 rich fractions of palm oil. The objective of the present study was to present a detailed protocol for the extraction of gram quantities of vitamin E isomers from a T3 rich fraction (Tocotrol™) that was obtained from palm oil, by column chromatography using a binary hexane:EtOAc (1-12%) phase system. The chemical integrity and identity of the extracted isomers was confirmed by TLC, HPLC, 1H-NMR, and Raman analysis. To evaluate their anticancer activity, vitamin E isomers were first entrapped into nanoemulsions and then tested against a panel of breast and pancreatic cancer cell lines. Nanoemulsions were prepared by the solvent evaporation technique. They had an average droplet size between 156-200 nm. In confirmation to what has been reported in the literature, γ-T3 and δ-T3 isomers were found to be significantly more active against tumor cells than the α-T and α-T3 isomers. The current study has demonstrated the feasibility of extracting the individual vitamin E isomers at high yields from natural sources while maintaining their chemical integrity and pharmacological activity.

PEGylated γ-tocotrienol isomer of vitamin E: Synthesis, characterization, in vitro cytotoxicity, and oral bioavailability.

Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T3). The PEGylated α-tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated γ-T3 variants with mPEG molecular weights of 350 (γ-T3PGS 350) and 1000 (γ-T3PGS 1000) were synthesized by a two-step reaction procedure and characterized by (1)H NMR, HPLC, and mass spectroscopy. The physical properties of their self-assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T3 and vitamin E TPGS. PEGylated T3 were also found to retain the in vitro cytotoxic activity of the free T3 against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated γ-T3 also increased the oral bioavailability of γ-T3 by threefolds when compared to the bioavailability of γ-T3 formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of γ-T3 represents a viable platform for the oral and parenteral delivery of γ-T3 for potential use in the prevention of breast cancer.

Effect of lipid viscosity and high-pressure homogenization on the physical stability of "Vitamin E" enriched emulsion.

Recently there has been a growing interest in vitamin E for its potential use in cancer therapy. The objective of this work was therefore to formulate a physically stable parenteral lipid emulsion to deliver higher doses of vitamin E than commonly used in commercial products. Specifically, the objectives were to study the effects of homogenization pressure, number of homogenizing cycles, viscosity of the oil phase, and oil content on the physical stability of emulsions fortified with high doses of vitamin E (up to 20% by weight). This was done by the use of a 27-run, 4-factor, 3-level Box-Behnken statistical design. Viscosity, homogenization pressure, and number of cycles were found to have a significant effect on particle size, which ranged from 213 to 633 nm, and on the percentage of vitamin E remaining emulsified after storage, which ranged from 17 to 100%. Increasing oil content from 10 to 20% had insignificant effect on the responses. Based on the results it was concluded that stable vitamin E rich emulsions could be prepared by repeated homogenization at higher pressures and by lowering the viscosity of the oil phase, which could be adjusted by blending the viscous vitamin E with medium-chain triglycerides (MCT).