Clinical safety and pharmacokinetic evaluation of aqueous extract of Cocculus hirsutus, an anti-viral phytopharmacetical drug as a potential for the treatment of dengue and COVID-19.

Background and aim: Dengue a worldwide concern for public health has no effective vaccine or drug available for its prevention or treatment. There are billions of people who are at risk of contracting the dengue virus (DENV) infections with only anti-mosquito strategies to combat this disease. Based on the reports, particularly in vitro studies and small animal studies showing anti-viral activity of aqueous extract of Cocculus hirsutus (AQCH), studies were conducted on AQCH tablets as a potential for the treatment of dengue and COVID-19 infections. The current study was part of the research on AQCH tablet formulation and was aimed to evaluate safety and pharmacokinetics in healthy human subjects. Materials and methods: Sixty healthy adult human subjects were divided into 5 groups (cohorts: I to V; n = 12 per cohort) and randomized in the ratio of 3:1 to receive active treatment or placebo in a blinded manner. Five doses 100 mg, 200 mg, 400 mg, 600 mg and 800 mg tablets were administered three times daily at an interval of 8 h for days 01-09 under fasting conditions and a single dose in morning on day 10. Safety assessment was based on monitoring the occurrence, pattern, intensity, and severity of adverse events during study period. Blood samples were collected for measurement of the bio-active marker Sinococuline concentrations by a validated LC-MS/MS method followed by pharmacokinetic evaluation. Results and conclusion: The test formulation was well tolerated in all cohorts. Sinococuline peak plasma concentration (Cmax) and total exposure of plasma concentration (AUC) demonstrated linearity up to 600 mg and saturation kinetics at 800 mg dose. There was no difference observed in elimination half-life for all the cohorts, suggesting absence of saturation in rate of elimination. Dose accumulation was observed and steady state was achieved within 3 days. The information on human pharmacokinetics of AQCH tablets would assist in further dose optimization with defined pharmacokinetic-pharmacodynamic relationship.

Cocculus hirsutus-Derived Phytopharmaceutical Drug Has Potent Anti-dengue Activity.

Dengue is a serious public health concern worldwide, with ∼3 billion people at risk of contracting dengue virus (DENV) infections, with some suffering severe consequences of disease and leading to death. Currently, there is no broad use vaccine or drug available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat the dengue menace. The present study is an extension of our earlier study aimed at determining the in vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue. In our previous report, we had identified a methanolic extract of aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. The dried aerial parts of C. pareira supplied by local vendors were often found to be mixed with aerial parts of another plant of the same Menispermaceae family, Cocculus hirsutus, which shares common homology with C. pareira. In the current study, we have found C. hirsutus to have more potent anti-dengue activity as compared with C. pareira. The stem part of C. hirsutus was found to be more potent (∼25 times) than the aerial part (stem and leaf) irrespective of the extraction solvent used, viz., denatured spirit, hydro-alcohol (50:50), and aqueous. Moreover, the anti-dengue activity of stem extract in all the solvents was comparable. Hence, an aqueous extract of the stem of C. hirsutus (AQCH) was selected due to greater regulatory compliance. Five chemical markers, viz., Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine, and Coniferyl alcohol, were identified in fingerprinting analysis. In a test of primary dengue infection in the AG129 mice model, AQCH extract at 25 mg/kg body weight exhibited protection when administered four and three times a day. The AQCH was also protective in the secondary DENV-infected AG129 mice model at 25 mg/kg/dose when administered four and three times a day. Additionally, the AQCH extract reduced serum viremia and small intestinal pathologies, viz., viral load, pro-inflammatory cytokines, and vascular leakage. Based on these findings, we have undertaken the potential preclinical development of C. hirsutus-based phytopharmaceutical, which could be studied further for its clinical development for treating dengue.

Comparative Evaluation of Effectiveness of 2% Lignocaine Hydrochloride with Clonidine Hydrochloride versus 2% Lignocaine Hydrochloride with Adrenaline Bitartrate as Local Anesthetic for Adult Patients Undergoing Surgical Extraction of Impacted Mandibular Third Molars: A Randomized Controlled Clinical Study.

BACKGROUND AND OBJECTIVES: Clonidine is a common additive to local anesthetics for various regional and local nerve blocks. However, its effectiveness in dentistry has not yet been fully explored. Thus, this study was performed to evaluate the quality of anesthesia, vasoconstrictive effects, hemodynamic response, and pain control using a solution of 2% lignocaine hydrochloride with clonidine hydrochloride in comparison with the standard solution of 2% lignocaine hydrochloride and adrenaline bitartrate for pterygomandibular nerve blocks. MATERIALS AND METHODS: A parallel arm, triple-blind randomized controlled study was conducted on 152 patients belonging to ASA-I (American Society of Anesthesiologists) category in the age group of 18-45 years, requiring surgical extraction of impacted mandibular third molars. The patients were divided equally into two groups randomly by computer-generated sequence; Group 1: 2% lignocaine hydrochloride with 1 ml of clonidine hydrochloride (150 µg/ml) and Group 2: 2% lignocaine hydrochloride with adrenaline bitartrate 1: 80,000 (12.5 µg/ml). The variables evaluated were systolic, diastolic, and mean arterial blood pressures, heart rate (HR), blood loss, onset, depth (pain), and duration of anesthesia. RESULTS: There was a statistically nonsignificant difference seen between the two groups (P > 0.05) for the onset of anesthesia, pain assessed, and blood loss, whereas a statistically highly significant difference was seen for cardiovascular variables (systolic, diastolic and mean arterial blood pressures, and HR) at various intervals with higher values for Group 2 (P < 0.001) and for the duration of action of local anesthesia (LA), with higher values for Group 1 (P < 0.001). CONCLUSIONS: Clonidine as an additive to lignocaine has proved to have the onset of action, vasoconstrictive properties, and pain control, equivalent to adrenaline. However, with better stability of hemodynamic variables and prolonged duration of action of LA with clonidine, it can be considered as a better, safer, and more effective additive to lignocaine than adrenaline.

Bilateral maxillary sinus floor augmentation with tissue-engineered autologous osteoblasts and demineralized freeze-dried bone.

The pneumatization of the maxillary sinus often results in a lack of sufficient alveolar bone for implant placement. In the last decades, maxillary sinus lift has become a very popular procedure with predictable results. Sinus floor augmentation procedures are generally carried out using autologous bone grafts, bone substitutes, or composites of bone and bone substitutes. However, the inherent limitations associated with each of these, have directed the attention of investigators to new technologies like bone tissue engineering. Bone marrow stromal cells have been regarded as multi-potent cells residing in bone marrow. These cells can be harvested from a person, multiplied outside his body using bioengineering principles and technologies and later introduced into a tissue defect. We present a case where tissue-engineered autologous osteoblasts were used along with demineralized freeze-dried bone for sinus floor augmentation.

Development and evolution of distraction devices: Use of indigenous appliances for Distraction Osteogenesis-An overview.

An attempt has been made to review various devices as well as the outstanding studies done in the past for understanding the methodology of distraction for regeneration of bone. Lengthening of underdeveloped bones inclusive of the maxillofacial complex has been obtained by distraction osteogenesis by many authors. This could be achieved by the use of various extraoral or intraoral devices. Devices used for distraction osteogenesis must have a minimum of 2 important characteristics - they should be able to transfer distraction forces directly to the bone and secondly, should offer adequate rigidity for osseous consolidation to occur. With advanced technology and biomechanical engineering, preformed intraoral distraction devices are now available worldwide. The introduction of these intraoral bone-bourne devices have eliminated the need for bulky, cumbersome extraoral distraction devices which had problems such as external scars, pin tract infections, nerve or tooth bud injuries and poor patient compliance. The design of completely internalized custom made appliance has opened new vistas in the field of Oral and Maxillofacial Surgery. Indigenous internal devices are also economical and locally available.