CYP3A4 mediated pharmacokinetics drug interaction potential of Maha-Yogaraj Gugglu and E, Z guggulsterone

Background: In this study, we investigate the in vitro and in vivo chondrogenic capacity of a novel photopolymerizable cartilage mimetic hydrogel, enhanced with extracellular matrix analogs, for cartilage regeneration. Purpose: To (1) determine whether mesenchymal stem cells (MSCs) embedded in a novel cartilage mimetic hydrogel support in vitro chondrogenesis, (2) demonstrate that the proposed hydrogel can be delivered in situ in a critical chondral defect in a rabbit model, and (3) determine whether the hydrogel with or without MSCs supports in vivo chondrogenesis in a critical chondral defect. Study Design: Controlled laboratory study. Methods: Rabbit bone marrow–derived MSCs were isolated, expanded, encapsulated in the hydrogel, and cultured in chondrogenic differentiation medium for 9 weeks. Compressive modulus was evaluated at day 1 and at weeks 3, 6, and 9. Chondrogenic differentiation was investigated via quantitative polymerase reaction, safranin-O staining, and immunofluorescence. In vivo, a 3 mm–wide × 2-mm-deep chondral defect was created bilaterally on the knee trochlea of 10 rabbits. Each animal had 1 defect randomly assigned to be treated with hydrogel with or without MSCs, and the contralateral knee was left untreated. Hence, each rabbit served as its own matched control. Three groups were established: group A, hydrogel (n = 5); group B, hydrogel with MSCs (n = 5); and group C, control (n = 10). Repair tissue was evaluated at 6 months after intervention. Results: In vitro, chondrogenesis and the degradable behavior of the hydrogel by MSCs were confirmed. In vivo, the hydrogel could be delivered intraoperatively in a sterile manner. Overall, the hydrogel group had the highest scores on the modified O’Driscoll scoring system (group A, 17.4 ± 4.7; group B, 13 ± 3; group C, 16.7 ± 2.9) ( P = .11) and showed higher safranin-O staining (group A, 49.4% ± 20%; group B, 25.8% ± 16.4%; group C, 36.9% ± 25.2%) ( P = .27), although significance was not detected for either parameter. Conclusion: This study provides the first evidence of the ability to photopolymerize this novel hydrogel in situ and assess its ability to provide chondrogenic cues for cartilage repair in a small animal model. In vitro chondrogenesis was evident when MSCs were encapsulated in the hydrogel. Clinical Relevance: Cartilage mimetic hydrogel may offer a tissue engineering approach for the treatment of osteochondral lesions.

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human CYP3A4 and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50mg/kg resveratrol), and group C (150mg/kg resveratrol ). After 30 minutes administration of resveratrol, a single dose of ticagrelor (18mg/kg) was administered orally. The vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated UHPLC-MS/MS methods. In vivo study, the AUC and Cmax of ticagrelor in group B and C appeared to be significantly higher than the control group, while Vz/F and CLz/F of ticagrelor in group B and C were significantly decreased. In vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The IC50 values of resveratrol were 56.75μM，69.07μM and 14.22μM, respectively. Our results indicated that resveratrol had a inhibitory effect on the metabolism of ticagrelor in vitro and vivo. It should be paid more attention to the clinical combination of resveratrol with ticagrelor and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

An experiment was designed to answer the question as to whether or not the neural elements of the statoacoustic ganglion complex have a trophic effect upon the histodifferentiation of the sensory structures of the embryonic mouse inner ear anlage as it develops in vitro. The embryonic inner ear anlage with associated otic mesenchyme and statoacoustic ganglion complex was excised from 11, 12, and 13-day CBA/C57 mouse embryos. The inner ear explants of each gestational age group were further divided into two groups: the first group “A” (with) statoacoustic ganglion was explanted to the organ culture system without further surgical intervention; the second group “B” (without) statoacoustic ganglion underwent further surgical manipulation during which their statoacoustic ganglion complexes were dissected away prior to explantation to in vitro. The explanted embryonic inner ears were allowed to develop in organ culture until the equivalent of gestation day 21 in vivo was reached for each group; then all cultures were fixed and histologically processed and stained by a nerve fiber stain, in combination with a stain for glucoprotein membranes. Each specimen was code labeled and scored for histodifferentiation of sensory structures. Light microscopic observations confirmed that in group “A” cultures, statoacoustic ganglion neurons and their nerve fibers were present in association with the developed sensory structures; neither ganglion cell neurons nor their nerve fibers were found to be present in the sensory structures that developed in the group “B” organ culture specimens. Quantification revealed no consistent trend of greater occurrence of any sensory structure in the groups of explants analyzed. The presence of such a trend would have signified the probable existence of a trophic effect of the statoacoustic ganglion neural elements upon development of inner ear sensory structures in the group “A” explants of the 11, 12, and 13-day embryo inner ear organ culture specimens when compared to the aganglionic group “B” cultures. Microscopic comparison of the sensory structures and their sensory hair cells that developed in the organ cultures revealed no differences in the quality of the histodifferentiation of either group “A” or group “B” explants. A base to apex pattern of histodifferentiation of the organ of Corti sensory structures, which has been described to occur in vivo, was noted to occur in the in vitro developed cochlear ducts of all of the explanted inner ears without respect to whether neural elements were present (“A”) or absent (“B”) during development. It was concluded from the quantification of histodifferentiation data and the above observation on the pattern of differentiation of Corti's organ that no trophic effect of neural elements of the statoacoustic ganglion complex influencing the histodifferentiation of sensory structures of 11, 12, and 13-gestation day mouse embryo inner ear explants as they differentiate in vitro could be demonstrated.

Abstract Full-unit transfusions of RBC enzymatically converted from group B to group O by treatment with alpha-galactosidase (ECO RBC) to group O and A normal healthy individuals exhibit excellent in vivo survival times (24-hour survival 95.1% +/- 2.3%, T50 36.9 +/- 4.6 days). These results confirm our earlier findings describing ECO RBC in vitro viability and normal in vivo survival time after small-volume infusions. No significant increase in pretransfusion anti-B titer or score is observed in either group O or A subjects provided that sufficient enzyme is used to treat the cells: Cells transfused to group O recipients require higher levels of enzyme (185 to 200 U/mL RBC) than those infused to group A (90 U/mL RBC). Two separate single-unit transfusions of ECO RBC to one group O recipient (4.5 months apart) also survived normally (24-hour survival 96% and 92%, T50 40 and 36 days) and did not increase preexisting anti-B levels in this subject. ECO RBC were not agglutinated or lysed by recipient sera before or after transfusion. Similarly, no antibody development to the alpha- galactosidase used in cell treatment (and washed from the product before transfusion) could be detected in any subject. The sustained increase in hemoglobin levels after transfusion of ECO RBC suggests that this product will be useful in treatment of acute and chronic anemia.

The sex ratio of newborn calves and embryos produced in vivo is ~1:1. However, numerous studies on bovine in vitro-produced embryos suggest that the sex ratio may differ from 1:1 and that the rate of development may be influenced by the sex of the embryo under certain culture conditions. The duration of sperm-oocyte interaction and sperm pre-incubation also affect the sex ratio of bovine embryos produced in vitro. It is well documented that in vitro male embryos reach the more advanced stages earlier than do their female counterparts. Selection of developmentally more advanced embryos in anticipation that they have a greater developmental capacity may be one of the underlying causes of the disproportionate number of males among offspring born after transfer of in vitro-produced embryos. The aim of the present study is to test whether a pre-incubation of sperm before IVF might improve the developmental rates and also influence the sex ratio of the resulting embryos. Bovine cumulus-oocyte complexes were recovered from abattoir-derived ovaries by the slicing method. After 24h of maturation, fertilization was realised using a standard protocol. Prior to IVF, sperm cells from 2 different bulls were treated as follows: sperm within group A were pre-incubated in IVF medium for one hour. This step was omitted for sperm in group B (control). After 19h of co-culture of COC and sperm, presumptive zygotes were cultured in SOFaa for a period of 7 days. Cleavage and developmental rates were recorded at Day 3 and 7 (Day 0=IVF). Day 7 blastocysts from all groups were sexed using bovine and Y chromosome-specific primers. Data were analysed by ANOVA. As shown in Table 1, sperm pre-incubation did not affect the cleavage and developmental rates for the individual bull (P>0.05). On average, at Day 7 of development a higher number of blastocysts was determined when embryos had been produced from pre-incubated sperm (P ≤ 0.05). This held true for both bulls. The shift in favour of male embryos was detectable in all groups of embryos, with a drastic one for bull 1 after sperm pre-incubation. In conclusion, sperm pre-incubation accelerated embryo development and possibly enhanced the proportion of male embryos, which was already shifted toward males. Table 1.Developmental rates, developmental kinetics and sex ratio of embryos after sperm pre-incubation before IVF (mean±standard deviation)

Abstract Background: Neurosurgical patients often require administration of both, mannitol and hydroxyethyl starch (HES). A recent in vitro study demonstrated that HES in combination with mannitol could disturb coagulation parameters and should be avoided in neurosurgical practice. The aim of our study was to evaluate coagulation abnormalities due to mannitol when administered alone and in combination with HES in patients undergoing craniotomy for various intracranial brain tumours. Materials and Methods: We enrolled 30 adult patients undergoing craniotomy. Patients were randomised into two groups using a computer generated randomisation chart. Interventions: Group A: Patients received 10 ml/kg 0.9% normal saline and 1 g/kg mannitol and Group B: Patients received 10 ml/kg, HES 130/0.4, and 1 gm/kg mannitol; immediately after induction of general anaesthesia. Rotational thromboelastography was done immediately after induction of general anaesthesia and 5 min after administration of mannitol. Measured parameters of blood coagulation were clotting time (CT) and clot formation time (CFT) with EXTEM and maximum clot firmness (MCF) with EXTEM and (FIBTEM). Results: Fourteen patients in each group completed the study. Insignificant change was noted in CT; CFT altered significantly from the baseline in both the groups (P < 0.05). MCF with FIBTEM did not change significantly from baseline (P > 0.05), but significantly differed between groups (P = 0.001). However, all values were in normal range. Conclusion: Mannitol 1 g/kg and HES 10 ml/kg can be safely administered in patients undergoing craniotomy for supratentorial tumours, without clinically significant changes in coagulation parameters.