Structural basis for ligand reception by anaplastic lymphoma kinase.

The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.

A hypothalamic pathway for Augmentor α-controlled body weight regulation.

Augmentor α and ß (Augα and Augß) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Augα functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Augα fragment and monomeric Augß also bind to Alk and potently stimulate cellular responses. While previous studies demonstrated that oncogenic Alk mutants function as important drivers of a variety of human cancers, the physiological roles of Augα and Augß are poorly understood. Here, we investigate the physiological roles of Augα and Augß by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Augα single knockout and double knockout of Augα and Augß exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Augα-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Augß-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Augα is robustly expressed and metabolically regulated in agouti-related peptide (AgRP) neurons, cells that control whole-body energy homeostasis in part via their projections to the paraventricular nucleus (PVN). Moreover, both Alk and melanocortin receptor-4 are expressed in discrete neuronal populations in the PVN and are regulated by projections containing Augα and AgRP, respectively, demonstrating that two distinct mechanisms that regulate pigmentation operate in the hypothalamus to control body weight. These experiments show that Alk-driven cancers were co-opted from a neuronal pathway in control of body weight, offering therapeutic opportunities for metabolic diseases and cancer.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Parasitological, molecular, and epidemiological investigation of Trypanosoma evansi infection among dromedary camels in Balochistan province.

Surra is a zoonotic disease caused by Trypanosoma evansi (T. evansi), which affects a wide variety of animals worldwide. The disease has a severe impact on the productivity, health, and working capacity of camels and causes mortality and extensive economic losses if not diagnosed early. This is the first comprehensive report on the prevalence of T. evansi infection in dromedaries in Balochistan province. In the present study, 393 blood samples (indigenous, n = 240; imported, n=153) were collected from one-humped camels (Camelus dromedarius) and were tested by molecular methods to estimate the prevalence of T. evansi in three districts (Pishin, Nushki, and Lasbella) of Balochistan province. The overall prevalence of T. evansi among examined camel samples was 28.24% (95% confidence interval (CI): 24.02-32.89%). The risk of T. evansi infection in adult camels (> 10 years) is higher than that in young ones (odd-ration (OR) = 2.7; 95% CI: 1.3357-5.3164%). Moreover, male camels were six times more likely to get an infection than female camels. The detection of T. evansi infection in camels sampled in summer and spring was 3.12- and 5.10-fold higher, respectively, than in camels sampled in winter. In conclusion, our findings showed a high rate of T. evansi infection in camels from the three districts. Our study emphasizes the need for a strict surveillance program and risk assessment studies as prerequisites for control measures.

Seroprevalence of SARS-CoV-2 antibodies in pediatric hospital surgical unit: a lower-middle-income country perspective.

BACKGROUND: The objective of our study was to measure and give insight into the seropositivity of anti-SARS-CoV-2 antibodies in the patients in our pediatric hospital surgical unit in Pakistan. METHODS: A prospective cohort study was conducted at a tertiary care pediatric hospital surgical unit in Pakistan between 1 January 2021 and 1 June 2021 on the enrolled neonates and children aged 1 day to 13 years. All patients from three different pediatric strata [neonates (<1 month), infants (1 to 12 months) and children (>1 year)] were enrolled in the study. RESULTS: Six-hundred patients were enrolled, and 426 patients were included in the study. Among 426 patients, 234 (54.9%) were male, and 192 (45.1%) were female. Overall only 118 (27.7%) patients developed symptoms. The other 308 (72.3%) were asymptomatic of which 28 (9.1%) had fever, 28 (9.1%) had cough, 38 (12.33%) had body aches, 292 (94.8%) had vomiting/diarrhea, and only 28 (9.1%) developed loss of smell and taste. Our results showed seropositivity of 27.7% (n = 118), while 72.3% (n = 308) had negative antibody titers. CONCLUSION: A much higher pediatric SARS-CoV-2 burden of 27.7% was found in our pediatric surgical unit than has previously been reported in the literature of 6.8% for children in pediatric hospitals or pediatric surgical units. Contrary to reporting early in the COVID-19 pandemic, this study determined that children experience a significant burden of COVID-19 infection. Thus, children appear very important in SARS-CoV-2 pandemic, from harboring the virus and further studies need to be done to find if they are transmitting the disease silently.

Enhancing Data Protection in Dynamic Consent Management Systems: Formalizing Privacy and Security Definitions with Differential Privacy, Decentralization, and Zero-Knowledge Proofs.

Dynamic consent management allows a data subject to dynamically govern her consent to access her data. Clearly, security and privacy guarantees are vital for the adoption of dynamic consent management systems. In particular, specific data protection guarantees can be required to comply with rules and laws (e.g., the General Data Protection Regulation (GDPR)). Since the primary instantiation of the dynamic consent management systems in the existing literature is towards developing sustainable e-healthcare services, in this paper, we study data protection issues in dynamic consent management systems, identifying crucial security and privacy properties and discussing severe limitations of systems described in the state of the art. We have presented the precise definitions of security and privacy properties that are essential to confirm the robustness of the dynamic consent management systems against diverse adversaries. Finally, under those precise formal definitions of security and privacy, we have proposed the implications of state-of-the-art tools and technologies such as differential privacy, blockchain technologies, zero-knowledge proofs, and cryptographic procedures that can be used to build dynamic consent management systems that are secure and private by design.

Data Provenance in Healthcare: Approaches, Challenges, and Future Directions.

Data provenance means recording data origins and the history of data generation and processing. In healthcare, data provenance is one of the essential processes that make it possible to track the sources and reasons behind any problem with a user's data. With the emergence of the General Data Protection Regulation (GDPR), data provenance in healthcare systems should be implemented to give users more control over data. This SLR studies the impacts of data provenance in healthcare and GDPR-compliance-based data provenance through a systematic review of peer-reviewed articles. The SLR discusses the technologies used to achieve data provenance and various methodologies to achieve data provenance. We then explore different technologies that are applied in the healthcare domain and how they achieve data provenance. In the end, we have identified key research gaps followed by future research directions.

Patterns and predictors of periodontal disease and tooth loss among users of smokeless tobacco.

BACKGROUND: Smokeless tobacco (SLT) products of several different types are widely used in several South Asian countries including Pakistan. These products are consumed in different forms and with different names. The study aims to determine adverse effects of the SLT consumption on periodontal tissues. METHODS: This cross sectional study was conducted in Karachi, Pakistan. It recruited 377 users of (SLT) with 231 males (61.3%) and 146 females (38.7%) of age 15 to 45 years. After obtaining informed consent, quantitative data were collected via a questionnaire followed by intra oral clinical examination to determine presence of periodontal diseases using community periodontal index (CPI). To determine the association between periodontal diseases and smokeless tobacco consumption habits, Chi Square test was conducted. RESULTS: Gingival recession (Class II-IV) (65.8%) was the most prevalent periodontal disease among SLT users. CPI score was high (CPI score 3 and 4) in 31.3% participants, whereas tooth loss was found in 21%. Among types of SLT products, gutka (28.6%) and betel quid (23.3%) were most commonly used. Using SLT for five or more years was found to be associated with a high CPI score, gingival recession (Class II-IV), moderate to severe tooth mobility, and presence of tooth loss. CONCLUSIONS: The study found statistically significant association between duration in years of using SLT and periodontal disease including gingival recession, tooth mobility and tooth loss. However, no significant results were found between retention during single use and frequency of SLT use per day. However, the link of these factors with the periodontal disease cannot be eliminated.

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy. METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete. FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy. INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. FUNDING: The US National Institutes of Health and the Dana-Farber Cancer Institute.

Pharmacokinetics of Midazolam in preterm neonates with an insight in brain Tissue: A PBPK approach.

Physiological maturity is a gradual process taking place throughout infancy and childhood. Though for years anatomical growth has been the basis for dose calculation in pediatric population, physiological immaturity can-not be overlooked especially in neonates. The potential difference in physiology can significantly affect the outcomes of treatment and may result in under dosing or over-dosage. For many ethical and logistic constrains, carrying out pharmacokinetic studies of pharmacological agents in neonatal population remains a challenging task and such data is therefore, insufficient. This work presents Physiologically Based Pharmacokinetic modeling approach to predict the disposition of IV Midazolam in preterm neonates of different gestational ages, validated by the experimental studies. Furthermore, midazolam concentration in brain tissue of these neonates- the major site of its action- has been noted. The predicted and observed plasma pharmacokinetic parameters are comparable. This article demonstrates the usefulness of in-silico approach for finding out the PK parameters in neonates which may aid in deciding the frequency of drug administration in this population.

Review of eosinophilic oesophagitis in children and young people.

Eosinophilic oesophagitis is a relapsing inflammatory disorder involving oesophagus identified over 30 years ago. Diagnosis is made by upper gastrointestinal endoscopy and oesophageal biopsies. There is huge variation in management practices across the globe. Therapeutic options include the use of proton pump inhibitors, topical steroids, and elimination diet. Biologics and immunomodulator drugs are being explored but not yet recommended in children. Long-term treatment may be required to control symptoms and to prevent complications such as fibrosis/stricture.Conclusion: Even though clinicians have better understanding of eosinophilic oesophagitis, further research is warranted in exploring the unmet needs of developing a highly sensitive non-invasive biomarker for its diagnosis and response to treatment along with a robust and easily deliverable therapeutic option. What is Known: •Incidence of eosinophilic oesophagitis has increased over the recent years. •Diagnostic confirmation requires upper gastrointestinal endoscopy and therapeutic options include elimination diet and/or topical steroids. What is New: •There is a lack of consensus ion management strategy with wide variation across the globe. •There is a need to develop a highly reliable and non-invasive biomarker to diagnose eosinophilic oesophagitis and to monitor the response to treatment.

Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α).

Elucidating the physiological roles and modes of action of the recently discovered ligands (designated ALKAL1,2 or AUG-α,ß) of the receptor tyrosine kinases Anaplastic Lymphoma Kinase (ALK) and Leukocyte Tyrosine Kinase (LTK) has been limited by difficulties in producing sufficient amounts of the two ligands and their poor stability. Here we describe procedures for expression and purification of AUG-α and a deletion mutant lacking the N-terminal variable region. Detailed biochemical characterization of AUG-α by mass spectrometry shows that the four conserved cysteines located in the augmentor domain (AD) form two intramolecular disulfide bridges while a fifth, primate-specific cysteine located in the N-terminal variable region mediates dimerization through formation of a disulfide bridge between two AUG-α molecules. In contrast to AUG-α, the capacity of AUG-α AD to undergo dimerization is strongly compromised. However, full-length AUG-α and the AUG-α AD deletion mutant stimulate similar tyrosine phosphorylation of cells expressing either ALK or LTK. Both AUG-α and AUG-α AD also stimulate a similar profile of MAP kinase response in L6 cells and colony formation in soft agar by autocrine stimulation of NIH 3T3 cells expressing ALK. Moreover, both AUG-α and AUG-α AD stimulate neuronal differentiation of human neuroblastoma NB1 and PC12 cells in a similar dose-dependent manner. Taken together, these experiments show that deletion of the N-terminal variable region minimally affects the activity of AUG-α toward LTK or ALK stimulation in cultured cells. Reduced dimerization might be compensated by high local concentration of AUG-α AD bound to ALK at the cell membrane and by potential ligand-induced receptor-receptor interactions.

MobChain: Three-Way Collusion Resistance in Witness-Oriented Location Proof Systems Using Distributed Consensus.

Smart devices have accentuated the importance of geolocation information. Geolocation identification using smart devices has paved the path for incentive-based location-based services (LBS). However, a user's full control over a smart device can allow tampering of the location proof. Witness-oriented location proof systems (LPS) have emerged to resist the generation of false proofs and mitigate collusion attacks. However, witness-oriented LPS are still susceptible to three-way collusion attacks (involving the user, location authority, and the witness). To overcome the threat of three-way collusion in existing schemes, we introduce a decentralized consensus protocol called MobChain in this paper. In this scheme the selection of a witness and location authority is achieved through a distributed consensus of nodes in an underlying P2P network that establishes a private blockchain. The persistent provenance data over the blockchain provides strong security guarantees; as a result, the forging and manipulation of location becomes impractical. MobChain provides secure location provenance architecture, relying on decentralized decision making for the selection of participants of the protocol thereby addressing the three-way collusion problem. Our prototype implementation and comparison with the state-of-the-art solutions show that MobChain is computationally efficient and highly available while improving the security of LPS.

Discovery and characterization of small molecules that target the GTPase Ral.

The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and (1)H-(15)N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.

Synthesis, characterization and SEM studies of novel 1-indanyl isoniazid and hydrazide Schiff base derivatives as new anti-tubercular agents.

The aim of study was to synthesize 1-indanyl isoniazid and sixteen other hydrazide Schiff base derivatives from 1-indanone. All synthesized derivatives were screened for the inhibitory activity against Mycobacterium tuberculosis on three Mycobacterial strains ATCC H37Rv, known INH-sensitive (INH-S) and INH-resistant strains (INH-R) by proportion method. The derivatives were characterized using different spectroscopic techniques such as UV-Visible, FTIR, 1H NMR, and HREIMS. In addition, to gain more insight into morphology of the structures, Scanning electron microscopy (SEM) was also performed. The results revealed that 1-indanyl isoniazid derivative (UN-1) exhibited more potent and high anti-mycobacterial activity against both INH-sensitive and INH-resistant strains of Mycobacterium tuberculosis when compared to standard anti-tubercular drug isoniazid which might be a novel isoniazid derivative as a new anti-tubercular agent.

A flavonoid driven phyto-pharmacological effects of Capparis decidua Edgew. in rodents.

This study elicits the underlying mechanism(s) of Capparis decidua when used for different gut disorders. HPLC chromatogram of C. decidua extract (CD.Cr) and its respective fractions showed a variety of phytochemicals of which, kaempferol being in a high proportion. In mice, CD.Cr at doses of 70 and 150 mg/kg enhanced the wet feces output to 33 and 44% respectively as compared to carbachol (47.6%), while doses of 500 and 700 mg/kg, presented 41 and 70% safety against castor oil-driven diarrhea, respectively. Its flavonoid constituent, kaempferol at doses of (50 and 100 mg/kg) produced 51.7 and 82% safety when compared to nifedipine which provided 95% safety at dose of 40 mg/kg against castor oil-driven diarrhea like loperamide. In isolated jejunum preparations, C. decidua extract and its respective fractions (except pet-ether) produced atropine-sensitive inhibitory effects, whereas kaempferol and nifedipine showed atropine insensitive effects. Against high K+-induced contractions, C. decidua's fractions and kaempferol both exhibited a concentration-related non-specific inhibition while displacing the Ca++ -CRCs to right-ward with suppression in maximal response like nifedipine. In isolated rat ileal preparations, CD.Cr and respective fractions elicited atropine-sensitive gut excitatory responses. In summary, this article reports C. decidua's laxative effect through cholinergic receptor activation as well as its antidiarrheal effects, where its flavonoid constituent kaempferol produces Ca++ antagonist like activity, thus justifying C. decidua folk use in constipation and diarrhea.

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.

WB-PBPK approach in predicting zidovudine pharmacokinetics in preterm neonates.

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB-PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post-natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 µmol min/L, Cmax 6.46 ± 0.74 µmol/L, half-life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 µmol/min/L, Cmax 6.10 µmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.

Evaluation of prokinetic and laxative effects of Hippophae rhamnoides in rodents.

Hippophae rhamnoides (Family; Elaeagnaceae) fruit extract was investigated for prokinetic and gut excitatory effects to rationalize its therapeutic utility in gastrointestinal complaints like delayed gastric emptying and constipation. The fruit extract of Hippophae rhamnoides (Hr.Cr) prepared in hydro-methanol (30:70) was verified for flavonoids, tannins, coumarins and terpenes as plant constituents. In mice, Hr.Cr administration caused an increased in faecal production and charcoal meal transport (50-300mg/kg, per-oral.), similar to activity pattern of carbamylcholine (1 mg/kg). Laxative and prokinetic effects of Hr.Cr were found partially atropine-sensitive. On challenge with isolated intestinal tissues, Hr.Cr charged a dose-dependent spasmogenic effect on jejunum (0.01-1mg/mL) preparations of rabbit and in ileal tissues (guinea-pig) at the dose range of 0.03 to 3mg/mL, following predominant relaxing impact at increased concentrations. Unlike carbamylcholine, stimulant effect of Hr.Cr was partly antagonized in atropine incubated tissues. These data attest the laxative, prokinetic and gut excitatory activities of Hippophae rhamnoides probably mediated through partial activation of muscarinic receptors. Further in agreement of the current findings with earlier reports on gastric emptying effects of Hippophae rhamnoides seed oil, this is the first study of its kind providing insight into mechanism to the laxative potential of Hippophae rhamnoides fruit, thus rationalizing its medicinal use in constipation.

Pharmacological basis for the medicinal use of Alcea rosea in airways disorders and chemical characterization of its fixed oils through GC-MS.

Alcea rosea L. also known as Althea rosea belongs to the Malvaceae family. This medicinal herb, traditionally used to treat several conditions including airway disorders like asthma and chronic bronchitis. This study evaluated the bronchodilatory effects and possible mechanism of A. rosea on guinea-pig tracheal tissues. Moreover lipophilic profiling of A. rosea has been carried out by using Gas-Chromatography-Mass-Spectrometry. A total of 19 compounds have been identified from the plant, n-hexane fraction. These compounds have been further confirmed from their Van den Dool and Kratz (I) Indices. Major class of metabolite identified from the plant includes fatty acid, saturated and unsaturated fatty acid esters. Hydrocarbons have also been detected from the n-hexane fraction. These fatty acid esters have not been reported previously by GC-MS and were identified first time from the flowers of Alcea rosea. In-vitro experiments were performed on guinea-pig tracheal tissues, mounted in Kreb's solution at 37°C and bubbled with carbogen. In isolated guinea-pig trachea, A. rosea inhibited carbamylcholine and K+ (80 mM)-induced contractions, potentiated isoprenaline concentration-response curves (CRCs) and suppressed Ca2+ CRCs. These results suggest that A. rosea cause bronchodilation through dual inhibition of phosphodiesterase enzyme and Ca2+ influx, which substantiate its potential in airways disorders.