Exploring Astrocytes Involvement and Glutamate Induced Neuroinflammation in Chlorpyrifos-Induced Paradigm Of Autism Spectrum Disorders (ASD).

Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.

The role of implants and implant prostheses on the accuracy and artifacts of cone-beam computed tomography: an in-vitro study.

To assess the accuracy of CBCT in implant-supported prostheses and to evaluate metal artifacts with and without implants or implant prostheses. Accuracy and artifacts were assessed in the dried mandible at three points on the buccal and lingual cortical plates on the mandible's body near the crest and the base. On the buccal cortical plate, these points were labelled as A, B and C near the crest and D, E and F near the base of the body of the mandible. Similarly, points a to f were marked on the lingual cortical plate corresponding to points A to F. The study had two control groups, C0 for physical linear measurement (PLM) and C1 for radiographic linear measurement (RLM) and artifact assessment. There were seven test groups, TG 1 to 7, progressing from a single implant to implant full-arch prosthesis. For accuracy assessment, PLM was compared to RLM. CBCT artifacts were investigated in images integrated at 0.25 mm, 10 mm, and 20 mm at regions of interest on concentric circles at different intersecting angles by comparing grayscale values at C1 and TG1 to 7. The data were collected and statistically analyzed. A significant difference was observed between C0 and C1, and RLM in test groups at the superior axial plane. Similarly, PLM and test RLM in the sagittal plane at A-B, B-C, and D-E were statistically significant. A significant difference between PLM and RLM was also observed in the vertical plane at A-D, B-E, and C-F. Quantification of CBCT artifacts in the presence of implants or prostheses revealed that full-arch prostheses had the highest mean grayscale value, whereas single implants with a prosthesis had the lowest. The mean grayscale change was greatest around the implant and implant prosthesis. The mean grayscale value was maximum at 20 mm voxel integration scales (VIS) and lowest at 0.25 mm. CBCT is a clinically reliable device. Metal in implants or implant-supported prostheses prevents true assessment of the peri-implant area; therefore, lower VIS is suggested in the presence of implants or implant prostheses.

An In Vitro Comparison of Zirconia and Hybrid Ceramic Crowns With Heavy Chamfer and Shoulder Finish Lines.

Purpose This in vitro study aimed to compare the marginal fit and internal adaptation of computer-aided designed and computer-aided manufactured (CAD-CAM) zirconia and hybrid ceramic crowns on heavy chamfer and shoulder finish line designs using silicon replica method. Materials and methods Forty die samples were divided into four groups of 10 dies each. Out of 40 diecasts scanned, zirconia crowns were milled on 20 casts (10 prepared with shoulder and 10 prepared with heavy chamfer finish line design), while hybrid ceramic crowns were milled on the rest of the 20 casts. After milling crowns, the silicone replica technique measured the marginal fit and internal adaptation. Results The heavy chamfer finish line design provided a better marginal fit than the shoulder finish line design for zirconia and hybrid ceramic crowns. Hybrid ceramic crowns had a better marginal fit and internal adaptation than zirconia crowns, both at heavy chamfer and shoulder finish line design. The gap at the margin was less than the axial and occlusal walls, and the maximum gap was observed in the occlusal area. In addition, the marginal gap was less than the internal gap, which showed a positive correlation with each other. Conclusion The study concluded that the difference in CAD-CAM materials and finish line designs influences marginal fit and crown restoration's internal adaptation. A heavy chamfer finish line design provides a better marginal fit for zirconia and hybrid ceramic crowns than a shoulder finish line design. Hybrid ceramic crowns have a better marginal fit and internal adaptation than zirconia crowns in heavy chamfer and shoulder finish lines.

Enhanced Bioavailability and Higher Uptake of Brain-Targeted Surface Engineered Delivery System of Naringenin developed as a Therapeutic for Autism Spectrum Disorder.

BACKGROUND: Neuroinflammation resulting from oxidative and nitrosative stress is associated with various neurological disorders and involves the generation of pro-inflammatory cytokines and microglial activation. Dietary phytochemicals are safer and more valuable adjunct neurotherapeutic agents which can be added to the therapeutic regimen. These compounds provide neuroprotection by the modulation of various signaling pathways. INTRODUCTION: Naringenin (NGN) is a phytochemical having low oral bioavailability because of poor solubility, and adding to this limitation is enhanced efflux by P-glycoprotein transporters in neuroinflammatory diseases. METHODS: Hence, as a solution for these limitations, naringenin encapsulated poly-lactic-co-glycolic acid (PLGA) nanocarriers were developed using the nanoprecipitation technique and coated with 1% glutathione (GSH) and 1% Tween 80 to enhance brain delivery. RESULTS: Coated and uncoated NGN-PLGA nanoparticles (NGN-PLGA-NPs) were spherical, monodispersed, stable, and non-toxic, with a particle size of less than 200 nm. They had negative zeta-potential values, 80% entrapment efficiency, and sustained drug release of 81.8% (uncoated), 80.13%, and 78.43% (coated) in 24 hours. FT-IR, DSC, PXRD, and NMR confirmed the drug encapsulation and coating over nanoparticles. In vivo brain uptake showed greater fluorescence intensity of the coated nanoparticles in the brain than uncoated nanoparticles. In addition, there was a 2.33-fold increase in bioavailability after coating compared to naringenin suspension and enhanced brain uptake. CONCLUSION: Present studies indicate sustained and targeted brain delivery of naringenin via the ligandcoated delivery system by inhibiting enhanced P-glycoprotein (P-gp) efflux occurring in autism spectrum disorders due to neuroinflammation.

Evaluation of clinical and radiographic outcome of friction fit conical abutment system in implant-supported dental prostheses: An in vivo study.

Aim: The purpose of this clinical study was to analyze the clinical feasibility of friction fit conical abutment system in implant-supported fixed dental prostheses as an alternative to cement and screw retention. Settings and Design: This was an in vivo longitudinal study. Materials and Methods: A total of 10 prostheses were designed as 3- or 4-unit fixed dental prostheses supported by two implants. All the subjects selected were evaluated for pocket probing depth (PPD) and marginal bone loss at the time of implant placement (T1), at the time of placement of friction fit prostheses (T2), and 12 months after placement of friction fit prostheses (T3). Marginal bone loss at T2 and T3 was measured with respect to bone levels at T1 and T2, respectively. The patient satisfaction was assessed at T2 and T3 using FDI clinical criteria and scoring system (modified by Monaco et al.). Statistical Analysis Used: Shapiro-Wilk test was employed to test the normality of data. Paired sample t-test was performed for quantitative variables. Results: A total of twenty implants were inserted in ten partially edentulous spaces; the average patient age was 50.2 years. No significant difference was seen between T2 and T3 for PPD. Comparison of marginal bone loss using paired t-test showed a statistically highly significant difference at T2 and T3 with higher value at T2. No prostheses were dislodged during postprosthetic follow-up. The survival rate was 100% for both the abutments and implants. No change in surface luster was observed 12 months following prosthetic rehabilitation in any case. No prostheses or framework fracture was reported and all patients were satisfied with the prosthesis received. Conclusions: Friction fit conical abutment system can act as a novel approach for the retention of implant-supported fixed dental prostheses.

Guidance Prostheses for Partial Mandibulectomy Patients: A Case Series.

This case series discusses the fabrication of guidance prostheses (GPs) for patients who presented to the Department of Prosthodontics with marked mandibular deviation, resulting in facial disfigurement and deranged occlusion. These GPs guide the mandible to the unresected side to achieve stable occlusion. This case series included three approaches to reducing mandibular deviation: a maxillary guidance ramp, a mandibular guidance prosthesis, and a twin occlusal appliance. These approaches were used in conjunction with a well-planned mandibular exercise regimen. The earlier mandibular guidance therapy is started, the better the outcome. GPs are used until good occlusal relationships and proprioception are restored. These GPs can be discarded or used occasionally once a good occlusal relationship has been achieved.

Full Mouth Rehabilitation Using the Twin Stage Procedure in a Patient with Amelogenesis Imperfecta: A Case Report.

Amelogenesis imperfecta (AI) refers to a group of inherited odontological disorders that alter enamel formation. The AI variant is based on the primary enamel defect, classified as hypoplastic type I, hypo maturation type II, hypo calcification type III, and hypo maturation type IV. AI is commonly linked with the loss of the normal occlusal plane, the loss of the vertical dimension of occlusion (VDO), and impaired functions and esthetics. This case report describes the Hobo and Takayama twin-stage procedure for the rehabilitation of a patient with hypoplastic AI.

A Novel Technique for Retention of the Immediate Obturator Following Maxillectomy in Mucormycosis: A Case Report.

Mucormycosis is an aggressive opportunistic fungal infection that affects blood supply-rich areas such as the maxilla. Because of the compromised immune system caused by coronavirus disease 2019 (COVID-19) infection and diabetes, this infection has spread at a rapid rate. Early detection and treatment can reduce disease mortality and morbidity. However, the difficulties of prosthetic rehabilitation and the lack of multidisciplinary planning negatively influence the quality of life (QOL). This case report uses the novel concept of magnet-retained immediate prosthetic rehabilitation in such a case.

Comparative Evaluation of the Clinical Efficacy of Four Different Gingival Retraction Systems: An In Vivo Study.

INTRODUCTION: There are numerous gingival retraction systems available on the market. This study aimed to evaluate the clinical efficacy of four gingival retraction systems, namely, impregnated retraction cord, gingival retraction capsule, retraction paste, and polyvinyl acetate strips. METHODS: A total of 20 people were chosen for the study, and 100 specimens were collected. The specimens were classified into five groups based on the materials used for gingival displacement. On the first day, a baseline impression without gingival displacement was made. Afterward, impressions were made with any of the following four gingival retraction systems: impregnated retraction cord (SURE-Cord® Plus; Sure Dent Corporation, Jungwon-gu, South Korea), retraction capsule (3M ESPE astringent retraction paste capsule; 3M Corporation, St. Paul, MN), retraction paste (Traxodent® Hemodent® Paste Retraction System; Premier Dental Co., Plymouth Meeting, PA) and polyvinylacetate strips (Merocel; Merocel Co., Mystic, CT), with a 14-day interval between each system. The amount of gingival displacement was measured using an optical microscope as the distance from the tooth to the gingiva crest in a horizontal plane. RESULTS:  All experimental groups had higher gingival displacement than the control group (P < 0.01). Among the experimental groups, polyvinyl acetate strips had the highest gingival displacement value (541.65 µm), followed by impregnated retraction cord (505.37 µm), retraction capsule (333.57 µm), and retraction paste (230.63 µm). CONCLUSION:  Within the limits of this in vivo study, significant differences in horizontal gingival displacement were discovered among the four evaluated systems. The horizontal displacement requirements of 200 µm were exceeded by all four systems. The maximum value for gingival displacement was found in polyvinyl acetate strips (Merocel), followed by impregnated retraction cord (SURE-Cord), and retraction capsule (3M ESPE), and the lowest value was found in retraction paste (Traxodent).

Microstrain Analysis of Selective Pressure Techniques for Mandibular Complete Denture Impression: An In Vivo Study.

Aim The present in vivo study was undertaken for microstrain analysis of the selective pressure impression technique using strain gauges in mandibular complete denture impression. Methodology Ten completely edentulous patients undergoing complete denture treatment were selected for the study. For each patient, mandibular casts were made, and two custom trays were fabricated on the mandibular cast. These mandibular trays were divided into two groups: those with mandibular impressions made in the custom tray with the use of a spacer (MST) and those without a spacer (MWS). For each patient, a primary impression was made by using an impression compound. After that, the primary cast was obtained, and the custom tray was fabricated by using auto polymerizing resin. Then strain gauges were attached to the particular areas of the tray. The customized tray with zinc oxide eugenol impression material was seated in the patient's mouth for the final impression. The strain produced during impression making at different areas was recorded by a multi-channel (six) strain amplifier and data logger (8-channel digital strain indicator NIC, Jaipur, India). The data obtained were subjected to statistical analysis using an independent t-test (for quantitative data within two groups). The level of significance was set at p=0.05 (p<0.05-significant, p<0.01-highly significant, p<0.0001-very highly significant). Results The comparison of the percentage of microstrain produced at the relief area with and without spacer tray design showed a statistically significant (p=0.001) result with a greater number of percentages of microstrain among those without spacers (94.19) than with spacer (72.09) tray design. Conclusion The use of a tray with relief for selective pressure impression of an edentulous mandible resulted in a desirable pressure distribution at the alveolar crests and buccal shelves.

Influence of surface modification of titanium implants on improving osseointegration: An in vitro study.

STATEMENT OF PROBLEM: The effect of aging and the surface treatment of implants on osseointegration needs to be evaluated. PURPOSE: The purpose of this in vitro study was to evaluate the effects of aging and the surface treatment of titanium with ultraviolet (UV) radiation and fibroblast growth factor (FGF) on hydrophilicity and cell growth and thus on osseointegration. MATERIAL AND METHODS: A total of 28 specimens were divided into 2 groups to measure hydrophilicity (n=14) and cell growth (n=14). Each group was further divided into 4 groups according to surface modification. These include the control group (CG) (nascent specimens), aged group (AG) (nascent specimens aged for 4 weeks), photofunctionalized group (PG) (aged specimens UV-A treated), and mimed group (MG) (aged specimens UV-A and FGF2 treated). The PG and MG specimens were treated with UV-A light for 40 minutes. The biomimetic surface modification was performed for MG. Hydrophilicity was measured by using the contact angle in relation to the surface of titanium disks with the help of a drop shape analyzing device (KRUSS), and cell growth was measured by calculating the number of stem cells per cm2 with the help of a scanning electron microscope (SEM). The data obtained were subjected to statistical analysis with a statistical software program (α=.05). RESULTS: The lowest contact angle values were found in PG (13.52 ±0.90 degrees) and the highest in AG (70.54 ±1.72 degrees). The highest number of cells per cm2 (2880 ±99.33) were found for MG, and the lowest number of cells per cm2 (760 ±9.17) for AG. CONCLUSIONS: Aging decreased the hydrophilicity and cell adhesion, migration, and growth on the titanium surface. UV treatment improved the hydrophilicity, cell adhesion, migration, and growth for both CG and AG. FGF2 treatment increased the cell adhesion, migration, and growth for CG, AG, and PG.

Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors.

Autism spectrum disorder (ASD) is a complex heterogeneous consortium of pervasive development disorders (PDD) which ranges from atypical autism, autism, and Asperger syndrome affecting brain in the developmental stage. This debilitating neurodevelopmental disorder results in both core as well as associated symptoms. Core symptoms observed in autistic patients are lack of social interaction, pervasive, stereotyped, and restricted behavior while the associated symptoms include irritability, anxiety, aggression, and several comorbid disorders.ASD is a polygenic disorder and is multifactorial in origin. Copy number variations (CNVs) of several genes that regulate the synaptogenesis and signaling pathways are one of the major factors responsible for the pathogenesis of autism. The complex integration of various CNVs cause mutations in the genes which code for molecules involved in cell adhesion, voltage-gated ion-channels, scaffolding proteins as well as signaling pathways (PTEN and mTOR pathways). These mutated genes are responsible for affecting synaptic transmission by causing plasticity dysfunction responsible, in turn, for the expression of ASD.Epigenetic modifications affecting DNA transcription and various pre-natal and post-natal exposure to a variety of environmental factors are also precipitating factors for the occurrence of ASD. All of these together cause dysregulation of glutamatergic signaling as well as imbalance in excitatory: inhibitory pathways resulting in glial cell activation and release of inflammatory mediators responsible for the aberrant social behavior which is observed in autistic patients.In this chapter we review and provide insight into the intricate integration of various genetic, epigenetic, and environmental factors which play a major role in the pathogenesis of this disorder and the mechanistic approach behind this integration.

Dietary Phytochemicals as Neurotherapeutics for Autism Spectrum Disorder: Plausible Mechanism and Evidence.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicals such as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done on the development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD.

Arterolane maleate plus piperaquine phosphate for treatment of uncomplicated Plasmodium falciparum malaria: a comparative, multicenter, randomized clinical trial.

BACKGROUND: Artemisinin-based combination therapy is the first-line treatment for uncomplicated falciparum malaria. This study assessed the antimalarial efficacy and safety of a combination of 150 mg of arterolane maleate and 750 mg of piperaquine phosphate (AM-PQP) in comparison to Coartem (artemether and lumefantrine) in patients with acute uncomplicated P. falciparum malaria. METHODS: In this open-label, randomized, multicentric, parallel group clinical trial, 240 patients were randomized to receive AM-PQP (160 patients) or Coartem (80 patients). Patients with P. falciparum monoinfection and initial parasite densities ranging from 1000 to 100 000 asexual parasites/µL of blood were followed for 28 days. Polymerase chain reaction-corrected adequate clinical and parasitologic response on day 28, parasite clearance time, and fever clearance time were evaluated. RESULTS: A total of 151 (94.4%) of 160 patients in the AM-PQP group completed the trial, while 77 (96.3%) of 80 patients in the Coartem group completed the trial. No treatment failure was noted in the AM-PQP group, while one patient receiving Coartem failed treatment on day 28. There was no difference in the median parasite clearance time (30 hours in both groups) or median fever clearance time (24 hours in both groups) after administration of the 2 study treatments. CONCLUSIONS: The available data support the evaluation of a drug combination in a larger population as a fixed-dose combination. Clinical Trials Registration. CTRI/2007/091/000031.

Bioavailability of a lipidic formulation of curcumin in healthy human volunteers.

Numerous publications have reported the significant pharmacodynamic activity of Curcumin (CRM) despite low or undetectable levels in plasma. The objective of the present study was to perform a detailed pharmacokinetic evaluation of CRM after the oral administration of a highly bioavailable lipidic formulation of CRM (CRM-LF) in human subjects. Cmax, Tmax and AUC0-¥ were found to be 183.35 ± 37.54 ng/mL, 0.60 ± 0.05 h and 321.12 ± 25.55 ng/mL respectively, at a dose of 750 mg. The plasma profile clearly showed three distinct phases, viz., absorption, distribution and elimination. A close evaluation of the primary pharmacokinetic parameters provided valuable insight into the behavior of the CRM after absorption by CRM-LF. CRM-LF showed a lag time (Tlag) of 0.18 h (around 12 min). Pharmacokinetic modeling revealed that CRM-LF followed a two-compartment model with first order absorption, lag time and first order elimination. A high absorption rate constant (K01, 4.51/h) signifies that CRM-LF ensured rapid absorption of the CRM into the central compartment. This was followed by the distribution of CRM from the central to peripheral compartment (K12, 2.69/h). The rate of CRM transfer from the peripheral to central compartment (K21, 0.15/h) was slow. This encourages higher tissue levels of CRM as compared with plasma levels. The study provides an explanation of the therapeutic efficacy of CRM, despite very low/undetectable levels in the plasma.

Pharmacodynamic and pharmacokinetic profile of RBx 343E48F0: a novel, long acting muscarinic receptor antagonist.

RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M(3) receptor and a 60-fold selectivity for the M(3) receptor over the M(2) receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK(B) of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED(50) value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24h.

RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes.

Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC(50) values of 32, 31 and 39nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150-300 fold) and other proline-specific proteases (>200-2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect (∼25% AUC of △ blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/kg) in Wistar rats with the oral bioavailability (F(oral)) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.

Pharmacokinetics and pharmacodynamics of arterolane maleate following multiple oral doses in adult patients with P. falciparum malaria.

Arterolane (RBx 11160) maleate is a novel, rapidly acting synthetic trioxolane antimalarial compound being developed by Ranbaxy Research Laboratories (Haryana, India). It is presently under phase III in combination with piperaquine phosphate. The present work reports the relationship between pharmacokinetic (PK) parameter (AUC(0-8h) on day 0/day 6) and indices of pharmacodynamic (PD) response (50% parasite clearance [PC(50)], 90% parasite clearance [PC(90)], parasite clearance time [PCT], recrudescence) from a phase II, double-blind, multicenter, randomized, parallel-group, dose-ranging trial. Patients with acute uncomplicated P. falciparum malaria were randomized to 1 of 3 arterolane maleate (50, 100, and 200 mg) doses for 7 consecutive days. Plasma concentration data were available from 78, 76, and 75 patients receiving a 50-, 100-, and 200-mg dose, respectively. Based on PD modeling, its limitations and assumptions, minimum 150-mg dose arterolane maleate was recommended to optimize the probability of maximum therapeutic benefits for an adult. Doses higher than 100 mg are unlikely to reduce the probability of recrudescence. This study re-stresses the need of combining short and long-acting drugs to prevent resistance development and minimize recrudescence.

Integration of physicochemical and pharmacokinetic parameters in lead optimization: a physiological pharmacokinetic model based approach.

There have been major strides in the development of novel ways of investigating drug like properties of new chemical entities (NCE) in the last three decades. Identification of ideal properties of a clinical candidate that would give a clinical proof of concept (POC) is the most critical step in the discovery process. Besides the biological dose-response relationship, the pharmacokinetic parameters play the most vital role in influencing the therapeutic response or toxicity of NCE. While there are numerous techniques to understand various drug-like properties individually, the behavior of an NCE in a dynamic in vivo system which influences its therapeutic or toxic effects is a composite function of its various physicochemical and pharmacokinetic parameters. This implies the need to understand the collective influence of various measured parameters, and knowing how variations made in them can result in favorable pharmacodynamic or toxicokinetic properties. Understanding this behavior holds the key to a successful and time efficient lead optimization process. Physiological based pharmacokinetic models (PBPK) are of great interest in this context as they involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior (an ideal behavior identified may be addressed generally as Target Product Profile) in vivo. In the current review, various physiological pharmacokinetic models addressing absorption, tissue distribution and clearance are discussed along with their application in integrating various physicochemical and ADME parameters to predict human pharmacokinetics helping lead optimization.

Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum malaria: a phase II, multicenter, randomized, dose-finding clinical trial.

BACKGROUND: Drug-resistant Plasmodium falciparum malaria necessitates development of novel drugs for treatment.The present study assessed the efficacy and safety of 3 dose levels of arterolane (RBx 11160), a synthetic trioxolane, for treatment of acute uncomplicated falciparum malaria. METHODS: In this randomized, double-blind, multicenter, parallel-group, dose-finding, phase II trial, 230 patients from 4 centers in Thailand, India, and Tanzania (mainland and Zanzibar) received either 50 mg (n=78), 100mg (n=76), or 200 mg (n=76) of arterolane once daily for 7 days. Patients (aged 13-65 years) with asexual parasite density of 1000-100,000 parasites/microL were included and were followed up for 28 days. The median time to 90% parasite clearance (PC90) was evaluated. RESULTS: The median PC90 was longer in the group receiving the 50-mg dose (19.4 h), compared with the groups receiving the 100-mg dose (12.8 h) and 200-mg dose (12.6 h) (P < .01). The polymerase chain reaction-corrected adequate clinical and parasitological responses on day 28 were 63%, 71%, and 72% for the groups receiving the 50-mg, 100-mg, and 200-mg doses, respectively, by intention-to-treat analysis (odds ratio, 1.55; 95%confidence interval, 0.78-3.06, for comparison of the 200-mg and 50-mg dose groups). Treatment was generally well tolerated. No patient died or experienced any serious adverse event. Mild complaints were reported in <10%of the patients and were similar in the 3 groups. Biochemistry and hematological analyses did not show any signof drug toxicity in any patient. CONCLUSION: Arterolane at daily doses of 100 and 200 mg is a rapidly acting, effective, and safe synthetic antimalarial drug, which may potentially represent an alternative to artemisinin derivatives in antimalarial combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00362050.