Discovery of SARS-CoV-2 papain-like protease (PLpro) inhibitors with efficacy in a murine infection model.

Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PLpro inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).

Brown-top millet: an overview of breeding, genetic, and genomic resources development for crop improvement.

MAIN CONCLUSION: Brown-top millet is a lesser-known millet with a high grain nutrient value, early maturation, and drought tolerance that needs basic research to understand and conserve food security. Brown-top millet [Urochloa ramosa (L.)] is currently cultivated in some developing countries (especially in India) for food and fodder, although it is less known among the small millets. Like other millets, it contains macro- and micronutrients, vitamins, minerals, proteins, and fiber, all of which have rich health benefits. The nutritional importance and health benefits of brown-top millet are still unknown to many people due to a lack of awareness, wide cultivation, and research. Hence, this millet is currently overshadowed by other major cereals. This review article aims to present the nutritional, breeding, genetic, and genomic resources of brown-top millet to inform millet and other plant researchers. It is important to note that genetic and genomic resources have not yet been created for this millet. To date, there are no genomic and transcriptomic resources for brown-top millet to develop single nucleotide polymorphisms (SNP) and insertion/Deletions (InDels) for breeding studies. Furthermore, studies regarding nutritional significance and health benefits are required to investigate the exact nutritional contents and health benefits of the brown-top millet. The present review delves into the nutritional value and health advantages of brown-top millet, as supported by the available literature. The limitations of producing brown-top millet have been enumerated. We also cover the status of marker-assisted breeding and functional genomics research on closely related species. Lastly, we draw insights for further research such as developing omics resources and applying genome editing to study and improve brown-top millet. This review will help to start breeding and other molecular studies to increase the growth and development of this cereal.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

Enhancing Tone and Strength in a Patient With Autoimmune Encephalitis and Guillain-Barré Syndrome Using Rood's Facilitatory Techniques and Neuromuscular Electrical Stimulation: A Case Report.

This case report documents the comprehensive management of a 21-year-old female resident of Gadchiroli presenting with a 10-day history of fever, altered consciousness, and neurological sequelae following a traumatic incident. The patient exhibited a Glasgow Coma Scale score of 6/15, hypotonia in both upper and lower limbs, diminished deep tendon reflexes, and respiratory complications. This case study describes a thorough physiotherapeutic strategy that focuses on tone facilitation and muscle weakness improvement. The intervention used Rood's facilitative approaches as well as neuromuscular electrical stimulation (NMES). Rood's treatments, which emphasized mobilizing touch and tactile stimulation, brushing, quick icing, quick stretching, tapping, massaging the skin, heavy joint compression, and rolling, were used deliberately to move the patient from flaccidity to better muscle tone. These techniques' repetitive and task-specific nature coincided with motor learning principles, enabling adaptive modifications in brain networks. Concurrently, NMES was used to improve muscle activation, create a controlled environment for neurorehabilitation, and promote strength increases. The successful integration of various modalities highlights the possibility of favorable neuronal adaptations and functional improvements in individuals suffering from complicated neuromuscular disorders. This case demonstrates the need for individualized and diversified physiotherapeutic techniques in improving rehabilitation outcomes.

Impact of Early Rehabilitation in a Four-Year-Old Patient With Developmental Dysplasia of the Hip: A Case Report.

Developmental dysplasia of the hip (DDH) represents a complex spectrum of hip abnormalities, varying from mild dysplasia to severe dislocation, significantly impacting biomechanics and joint stability. This study explores the intricate pathogenesis of DDH, emphasizing its articular and periarticular anatomical anomalies and their profound implications. Factors such as breech positioning, advanced maternal age, postmaturity, and intrauterine crowding contribute to the complexity of DDH's etiology. The fetal development of the hip joint, crucial for understanding DDH, involves intricate processes starting from the fourth week of gestation. Any disruption during this period can lead to abnormal hip development, necessitating early detection and intervention. This is a case presentation of a four-year-old girl with bilateral DDH in detail, highlighting the clinical findings, diagnostic procedures, and physiotherapeutic management employed. A tailored physiotherapy plan was implemented, focusing on pain management, pressure sore prevention, respiratory care, and muscle strength preservation. This study highlights the need for further research in this area by illuminating the complexities of DDH. Despite difficulties and limitations in the literature, interest in researching different facets of DDH is expanding.

Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules.

BACKGROUND: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy. METHODS: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed. RESULTS: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria. CONCLUSIONS: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters.

Physiotherapy Rehabilitation for Above-Knee Amputation Secondary to Infected External Fixation: A Case Report.

This case study examines the total physiotherapy care of a 50-year-old male patient, who had a right-sided displaced distal tibia and fibula fracture, a talus fracture due to a road traffic accident, and an above-knee amputation due to a serious infection. Enhancing muscle strength, reducing pain from phantom limbs, avoiding problems, maintaining range of motion, increasing endurance, and promoting functional independence in the postoperative period were the main goals of the patient's rehabilitation. The recovery plan included an intensive four-week program of physiotherapy care. The regimen included a variety of interventions, such as pain management, edema control, wound healing techniques, range of motion (ROM) exercises, muscle strengthening activities, mobility and transfer exercises, cardiovascular endurance training, psychosocial support, education on prosthetic use, and independence in daily living activities. ROM measures, manual muscle testing, and functional independence measure scores were used to evaluate the patient's improvement. The patient's physical health and level of functional independence both exhibited significant improvements, according to the statistics. Following treatment, the patient's ROM, muscle strength, and overall functional independence all improved. The study highlights the positive impacts of physical therapy interventions on the patient's quality of life, mobility, and self-sufficiency following the amputation and subsequent recovery. These findings support the patient's transition to a more self-sufficient and active lifestyle by providing valuable insights into the efficient use of physiotherapy and the comprehensive post-amputation treatment plan.

Diet-inducing hypercholesterolemia show decreased O-GlcNAcylation of liver proteins through modulation of AMPK.

O-GlcNAcylation, a nutritionally driven, post-translational modification of proteins, is gaining importance because of its health implications. Changes in O-GlcNAcylation are observed in various disease conditions. Changes in O-GlcNAcylation by diet that causes hypercholesterolemia are not critically looked into in the liver. To address it, both in vitro and in vivo approaches were employed. Hypercholesterolemia was induced individually by feeding cholesterol (H)/high-fat (HF) diet. Global O-GlcNAcylation levels and modulation of AMPK activation in both preventive and curative approaches were looked into. Diet-induced hypercholesterolemia resulted in decreased O-GlcNAcylation of liver proteins which was associated with decreased O-linked N-acetylglucosaminyltransferase (OGT) and Glutamine fructose-6-phosphate amidotransferase-1 (GFAT1). Activation of AMPK by metformin in preventive mode restored the O-GlcNAcylation levels; however, metformin treatment of HepG2 cells in curative mode restored O-GlcNAcylation levels in HF but failed to in H condition (at 24 h). Further, maternal faulty diet resulted in decreased O-GlcNAcylation in pup liver despite feeding normal diet till adulthood. A faulty diet modulates global O-GlcNAcylation of liver proteins which is accompanied by decreased AMPK activation which could exacerbate metabolic syndromes through fat accumulation in the liver.

Perks of Rehabilitation in a Patient Who Underwent Total Hip Replacement Surgery Twice: A Case Report.

The hip joint is called as the coxafemoral or femoroacetabular joint, and it is the articulation of the acetabulum of the pelvis and the head of the femur. The most common surgery in adults is total hip arthroplasty (THA). In this technique, biocompatible materials are used to replace sections of the upper femur and acetabulum. A postoperative patient needs physical rehabilitation and it is necessary to focus on strength and functional status. Instability appears to be a complication in both initial and repeat THA. A 56-year-old male met with an accident, and on consulting with an orthopedic surgeon, an X-ray scan was taken and was then advised for total hip replacement, post-surgery, he developed an infection and was again advised for hip replacement. Post-surgery, the patient received physiotherapy. The four elements of the physiotherapy rehabilitation regimen are therapeutic physical activity, transfers, gait training, and education in daily living skills. Following surgery, physiotherapy rehabilitation may be provided at various times, including right away afterward (within the first five days) and during the initial phase of recovery (within the first three months after discharge). Postural stability can be attained by rehabilitation. Thus, a proper physiotherapy rehabilitation program can improve the quality of life.

Rehabilitation in Systemic Lupus Erythematosus With Class 4 Lupus Nephritis Secondary to Pneumonia: A Case Report.

We herein report an undisclosed case of systemic lupus erythematosus (SLE) with class 4 lupus nephritis (LN). It is an autoimmune disease that occurs when the body's immune system attacks its tissues. It results in significant tissue damage and inflammation in the afflicted organs. It may affect the kidneys, brain, lungs, skin, joints, and blood vessels. A 30-year-old female presented to Acharya Vinoba Bhave Rural Hospital (AVBRH) with the complaint of breathlessness, cough with expectoration, and fever for two months. The patient is having musculoskeletal renal difficulties and psychological effects. The objective is to reduce the symptoms and to improve the quality of life. A multidisciplinary treatment approach is used, which includes physiotherapy intervention and patient education. In conclusion, this case report mainly focuses on a multidisciplinary treatment approach to improve patient outcomes and quality of life.

Vitamin D Mitigates Hyperglycemia-Induced Cognition Decline in Danio rerio (Zebrafish) through the Activation of Antioxidant Mechanisms.

Hyperglycemia contributes to the development of cognition impairment and related disorders, induces oxidative stress in neuronal cells; thereby, impairs normal signaling mechanisms involved in cognition processes. Studies have shown a significant decrease in the vitamin D in individuals with hyperglycemia and cognition impairment. But whether supplementing vitamin D has any beneficiary impact on mitigating hyperglycemia-induced cognition impairment is unknown. We have first tested the impact of hyperglycemia on the induction of cognition deficiency in a zebrafish model. Next, the molecular mechanisms related to oxidative stress, which are deregulated in hyperglycemic zebrafish brains, have been explored. Subsequently, the impact of supplementing the water with vitamin D and a known activator of nuclear factor erythroid-2 related factor 2 (Nrf2) i.e., sulforaphane (SFN) on learning and memory functions were assessed. We showed a significant increase in the oxidative stress in the brain tissue of zebrafish residing in hyperglycemic water (111 mM glucose). Addition of vitamin D and SFN increased Nrf2, but differentially modulated its target genes (NQO1, SOD, GPx etc) activity in zebrafish and neuronal cell lines thereby improved the hyperglycemia-induced decline of cognition impairment. Mechanistically, vitamin D binds to the Keap1 protein; thereby, interfering with its binding to Nrf2, which leads to the activation of antioxidant mechanisms in the cells. In summary, reducing the oxidative stress through vitamin D treatment is a possible option for controlling the cognition impairment in diabetic population, but studies testing this possibility in clinical trials are currently needed.

Disposition of Nirmatrelvir, an Orally Bioavailable Inhibitor of SARS-CoV-2 3C-Like Protease, across Animals and Humans.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients. Disposition studies on nirmatrelvir in animals and in human reagents, which were used to support clinical studies, are described herein. Plasma clearance was moderate in rats (27.2 ml/min per kg) and monkeys (17.1 ml/min per kg), resulting in half-lives of 5.1 and 0.8 hours, respectively. The corresponding oral bioavailability was moderate in rats (34%-50%) and low in monkeys (8.5%), primarily due to oxidative metabolism along the gastrointestinal tract in this species. Nirmatrelvir demonstrated moderate plasma protein binding in rats, monkeys, and humans with mean unbound fractions ranging from 0.310 to 0.478. The metabolism of nirmatrelvir was qualitatively similar in liver microsomes and hepatocytes from rats, monkeys, and humans; prominent metabolites arose via cytochrome P450 (CYP450)-mediated oxidations on the P1 pyrrolidinone ring, P2 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and the tertiary-butyl group at the P3 position. Reaction phenotyping studies in human liver microsomes revealed that CYP3A4 was primarily responsible (fraction metabolized = 0.99) for the oxidative metabolism of nirmatrelvir. Minor clearance mechanisms involving renal and biliary excretion of unchanged nirmatrelvir were also noted in animals and in sandwich-cultured human hepatocytes. Nirmatrelvir was a reversible and time-dependent inhibitor as well as inducer of CYP3A activity in vitro. First-in-human pharmacokinetic studies have demonstrated a considerable boost in the oral systemic exposure of nirmatrelvir upon coadministration with the CYP3A4 inhibitor ritonavir, consistent with the predominant role of CYP3A4 in nirmatrelvir metabolism. SIGNIFICANCE STATEMENT: The manuscript describes the preclinical disposition, metabolism, and drug-drug interaction potential of PF-07321332 (nirmatrelvir), an orally active peptidomimetic-based inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease, which has been granted emergency use authorization by multiple regulatory agencies around the globe for the treatment of coronavirus disease 2019 (COVID-19) in COVID-19-positive adults and pediatric patients who are at high risk for progression to severe COVID-19, including hospitalization or death.

Risk stratification of parotid neoplasms based on intraoperative frozen section and preoperative fine needle aspiration cytology.

PURPOSE: This study aims to determine the relationship of frozen section (FS) to final histology and determine how incorporating FS may change preoperative malignancy risk estimates based on preoperative fine needle aspiration cytology (FNAC). The secondary aim is to determine if FS is useful in influencing intraoperative decision-making. METHODS: Retrospective review of 426 intraoperative FS for parotidectomies performed for primary parotid lesions. RESULTS: Risk of malignancy with a benign FS was 2.5%, with indeterminate 36.1%, and with malignant 100%. Incorporating FS to fine needle aspiration for cytology helped to stratify malignancy risk especially in the Milan categories of atypia of undetermined significance, neoplasm of uncertain malignant potential and non-diagnostic categories, where a malignant FS increased malignancy risk significantly. FS was only able to identify 11% of high-risk histological subtypes for which a neck dissection would be recommended. CONCLUSIONS: FS may be used to stratify malignancy risk intraoperatively but has limited utility in clinical decision-making to perform a neck dissection and more extensive parotid resection in high-risk histological subtypes.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.

Composition and structure elucidation of bovine milk glycosaminoglycans and their anti-adipogenic activity via modulation PPAR-γ and C/EBP-α.

The structure function relation of Glycosaminoglycans from bovine milk (bmGAGs) has not been studied in detail. In the present study bmGAGs was isolated and structurally characterized. Chondroitin sulphate was one of the major GAGs present and had 65% of ΔDi-diSB (GlcA(2S)-GalNAc(4S)), followed by 18% of ΔDi-4S(Δ4,5HexUAα1 â†’ 3GalNAc). Further, bmGAGs exhibited a marked anti-adipogenic effect in 3 T3-L1 cells without affecting cell viability at the concentration used. The triglyceride content treated with bmGAGs was significantly decreased as assessed by Oil-Red O staining. Peroxisome proliferator activated receptor γ (PPAR-γ) and CCAAT/enhancer-binding proteins (C/EBPα) the critical transcription factors in adipogenesis showed significant decrease in both gene and protein levels. Sterol regulatory element-binding protein 1c (SREBP-1c) that promotes the adipocyte differentiation by enhancing the activity of PPAR-γ was inversely affected by bmGAGs and the fatty acid synthase (FAS) expression was modulated. Thus, the present work is among the firsts to demonstrate an anti-adipogenic activity of bmGAGs by modulating the adipogenesis-related marker proteins and hence bmGAGs may be used as a supplement/therapeutic in the management of obesity.

Together let us confront it: An outbreak investigation of hepatitis B in Pathanamthitta district, Kerala.

INTRODUCTION: Hepatitis B is a potentially life-threatening liver infection caused by the Hepatitis B virus (HBV). The established routes of transmission are from mother to infant, sexual contact, and exposure to blood or body fluids. Though HBV is preventable by vaccine and robust infection control practices, outbreaks of HBV infection do occur in India. However, the state of Kerala with its health parameters, one among the best in the country, cannot afford to have continuing outbreaks. An unusual increase in the reported cases of Hepatitis B in a rural area of Pathanamthitta district of Kerala, called for an outbreak investigation. AIMS: To describe the epidemiological features, to determine the risk factors associated with HBV transmission, and to suggest measures to prevent future transmission. METHODS: A community-based case-control study (1:2) was undertaken. A total of 162 participants (54 cases and 108 age, gender, and neighborhood matched controls) took part in the study. Focus group discussions were conducted with subject experts to develop an interview schedule assessing 40 risk factors. It was further reviewed by the University of Sydney. Data was collected by trained Junior Health Inspectors and Junior Public Health Nurses of the Primary Health Centers. Data was analyzed using SPSS v. 20. Proportions were compared by Univariate analysis, sub-group analysis, and logistic regression. Population Attributable Risk (PAR) was also calculated. RESULTS AND CONCLUSION: More than 90% of the infections were IgM anti-HBc positive, suggesting a recent infection. Interventions during hospitalization [OR: 7.98 (95% CI - 2.17--29.4)], family history of Hepatitis B [OR. 4.14 (95%CI - 1.73--9.9)], and laboratory investigations [OR: 3.99 (1.72--9.31)] were found to be significant risk factors. PAR was highest for laboratory interventions (32%). Vaccinating household contacts and strict enforcement of infection control practices could substantially reduce the burden of this fatal disease.

Platelet enhancement by Carica papaya L. leaf fractions in cyclophosphamide induced thrombocytopenic rats is due to elevated expression of CD110 receptor on megakaryocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Carica papaya leaf juice/decoction has been in use in folk medicine in Srilanka, Malaysia and in few parts of India for enhancing the platelet counts in dengue. In Siddha medicine, a traditional form of medicine in India, papaya leaf juice has been used for increasing the platelet counts. Papaya leaf has been reported to enhance blood volume in ancient Ayurveda books in India. Carica papaya leaf is well known for its platelet enhancement activity. Although many preclinical and clinical studies have demonstrated the ability of papaya leaf juice for platelet enhancement, but the underlying mechanisms are still unclear. AIM OF THE STUDY: The study is aimed at identifying the key ingredients of papaya leaf extract and elucidate the mechanism (s) of action of the identified potent component in mitigating thrombocytopenia (Thp). MATERIALS AND METHODS: C. papaya leaf juice was subjected for sequential fractionation to identify the anti-thrombocytopenic phytochemicals. In vivo, stable thrombocytopenia was induced by subcutaneous injection of 70 mg/kg cyclophosphamide (Cyp). After induction, rats were treated with 200 and 400 mg/kg body weight papaya leaf juice and with identified fractions for 14 days. Serum thrombopoietin level was estimated using ELISA. CD110/cMpl, a receptor for thrombopoietin on platelets was measured by western blotting. RESULTS: Administration of cyclophosphamide for 6 days induced thrombocytopenia (210.4 ± 14.2 × 103 cells/µL) in rats. Treating thrombocytopenic rats with papaya leaf juice and butanol fraction for 14 days significantly increased the platelet count to 1073.50 ± 29.6 and 1189.80 ± 36.5 × 103 cells/µL, respectively. C.papaya extracts normalized the elevated bleeding and clotting time and decreased oxidative markers by increasing endogenous antioxidants. A marginal increase in the serum thrombopoietin (TPO) level was observed in Cyp treated group compared to normal and treatment groups. Low expression of CD110/cMpl receptor found in Cyp treated group was enhanced by C. papaya extracts (CPJ) and CPJ-BT. Furthermore, examination of the morphology of bone marrow megakaryocytes, histopathology of liver and kidneys revealed the ability of CPJ and fractions in mitigating Cyp-induced thrombocytopenia in rats. CONCLUSION: C. papaya leaf juice enhances the platelet count in chemotherapy-induced thrombocytopenia by increasing the expression of CD110 receptor on the megakaryocytes. Hence, activating CD110 receptor might be a viable strategy to increase the platelet production in individuals suffering from thrombocytopenia.

Harnessing Preclinical Data as a Predictive Tool for Human Brain Tissue Targeting.

One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest (e.g., the CNS) for Neuroscience targets or to restrict drug access to the CNS for all other therapeutic areas. Both neuroscience and non-neuroscience therapeutic areas have struggled to quantitatively estimate brain penetration or the lack thereof with compounds that are substrates of efflux transport proteins such as P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) that are key components of the blood-brain barrier (BBB). It has been well established that drug candidates with high efflux ratios (ER) of these transporters have poor penetration into brain tissue. In the current work, we outline a parallel analysis to previously published models for the prediction of brain penetration that utilize an alternate MDR1-MDCK cell line as a better predictor of brain penetration and whether a correlation between in vitro, rodent data, non-human primate (NHP), and human in vivo brain penetration data could be established. Analysis of structural and physicochemical properties in conjunction with in vitro parameters and preclinical in vivo data has been highlighted in this manuscript as a continuation of the previously published work.

Methods to optimize CNS exposure of drug candidates.

Among the most devastating disorders of our time, neurologic and psychiatric diseases combine to cause more disability than any other disease area. One of the key objectives within the medicinal chemistry discipline is to design molecules that penetrate into the target tissue. The objective of tissue specificity can be to gain or restrict drug access to the compartment of interest. This article briefly reviews the progress of CNS drug discovery over the past few decades. Included are the most recent efforts to harness structural and physicochemical properties assessment coupled with the impact of efflux transporters in determining brain penetration and the translation from rodent to human brain tissue targeting.