Search

With a clinical trial failure rate of 99.6% for Alzheimer's Disease (AD), early diagnosis is critical. Machine learning (ML) models have shown promising results in early AD prediction, with survival ML models outperforming typical classifiers by providing probabilities of disease progression over time. This study utilized various ML survival models to predict the time-to-conversion to AD for early (eMCI) and late (lMCI) Mild Cognitive Impairment stages, considering their different progression rates. ADNI data, consisting of 291 eMCI and 546 lMCI cases, was preprocessed to handle missing values and data imbalance. The models used included Random Survival Forest (RSF), Extra Survival Trees (XST), Gradient Boosting (GB), Survival Tree (ST), Cox-net, and Cox Proportional Hazard (CoxPH). We evaluated cognitive, cerebrospinal fluid (CSF) biomarkers, and neuroimaging modalities, both individually and combined, to identify the most influential features. Our results indicate that RSF outperformed traditional CoxPH and other ML models. For eMCI, RSF trained on multimodal data achieved a C-Index of 0.90 and an IBS of 0.10. For lMCI, the C-Index was 0.82 and the IBS was 0.16. Cognitive tests showed a statistically significant improvement over other modalities, underscoring their reliability in early prediction. Furthermore, RSF-generated individual survival curves from baseline data facilitate clinical decision-making, aiding clinicians in developing personalized treatment plans and implementing preventive measures to slow or prevent AD progression in prodromal stages., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright: © 2024 Saeed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mobile robots are increasingly employed in today's environment. Perceiving the environment to perform a task plays a major role in the robots. The service robots are wisely employed in the fully (or) partially known user's environment. The exploration and exploitation of the unknown environment is a tedious task. This paper introduces a novel Trimmed Q-learning algorithm to predict interesting scenes via efficient memorability-oriented robotic behavioral scene activity training. The training process involves three stages: online learning and short-term and long-term learning modules. It is helpful for autonomous exploration and making wiser decisions about the environment. A simplified three-stage learning framework is introduced to train and predict interesting scenes using memorability. A proficient visual memory schema (VMS) is designed to tune the learning parameters. A role-based profile arrangement is made to explore the unknown environment for a long-term learning process. The online and short-term learning frameworks are designed using a novel Trimmed Q-learning algorithm. The underestimated bias in robotic actions must be minimized by introducing a refined set of practical candidate actions. Finally, the recalling ability of each learning module is estimated to predict the interesting scenes. Experiments conducted on public datasets, SubT, and SUN databases demonstrate the proposed technique's efficacy. The proposed framework has yielded better memorability scores in short-term and online learning at 72.84% and in long-term learning at 68.63%., (© 2023. The Author(s).)

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT 2A receptor (5-HT 2A R) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT 2A R knockout (5-HT 2A R -/- ) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT 2A R in dorsal root ganglion (DRG) neurons of 5-HT 2A R -/- littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT 2A R -/- animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT 2A R expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The outstanding research outcomes and registrations of myriads of probiotic strains have flooded the health market with various innovative probiotic-based products and their patents. The study of patented formulations of probiotics can give an overall insight into its existing application. A landscaping review of patents for probiotic-based preparations is presented in the current work. The patent search was performed over commercially available patent databased and analysis tool-PatSeer Pro®. Search strings containing words "Formulation" and "Composition" resulted in more than 3700 patents. Landscaping review of 400 + patents from the last 20 years (2000-2020) was performed using the Text-Mining approach. Text-Mining helped to identify 19 technological clusters which represent these patents. These clusters include the patents of probiotic preparations on animal feed, human food, cosmetics, antimicrobial, antidiabetic, arthritis, etc. A review of this massive number of patents unveiled many exciting preparations. Probiotic-based innovative products for depression, diabetes, Parkinson's, tumor, acne, and animal husbandry are reviewed comprehensively. The present work also unravels a few new-flanged products like probiotic layered condoms, products for acute alcoholism, and traditional Chinese medicine with probiotics. The patent landscape of probiotic-based preparations has presented a whole scenario of probiotic-based preparations. It has also revealed many unexplored areas where innovation can be excelled., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Known classic psychedelic serotonin 2A receptor (5-HT 2A R) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT 2A R can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HT 2A R as measured by [ 3 H]ketanserin binding displacement, Ca 2+ mobilization, and accumulation of the canonical G q/11 signaling pathway mediator inositol monophosphate (IP 1 ) in vitro and in vivo . Additionally, quipazine induced via 5-HT 2A R an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HT 2A R antagonist M100907 and absent in 5-HT 2A R knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HT 3 R activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine's profile matches that of classic psychedelic 5-HT 2A R agonists at cellular signaling and behavioral pharmacology levels.

Membrane trafficking processes regulate G protein-coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT 2A receptors (5-HT 2A Rs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through a mechanism that required their assembly as heteromers in mammalian cells. In the absence of agonists, 5-HT 2A R was primarily localized within intracellular compartments, and coexpression of 5-HT 2A R with mGluR2 increased the intracellular distribution of the otherwise plasma membrane-localized mGluR2. Agonists for either 5-HT 2A R or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT 2A R-mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT 2A R blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT 2A R and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT 2A R-mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT 2A R-dependent effects on mGluR2 subcellular distribution. The expression of 5-HT 2A R also augmented intracellular localization of mGluR2 in mouse frontal cortex pyramidal neurons. Together, our data suggest that GPCR heteromerization may itself represent a mechanism of receptor trafficking and sorting., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

G protein-coupled receptors (GPCRs) are critical mediators of cell signaling. Although capable of activating G proteins in a monomeric form, numerous studies reveal a possible association of class A GPCRs into dimers/oligomers. The relative location of individual protomers within these GPCR complexes remains a topic of intense debate. We previously reported that class A serotonin 5-HT 2A receptor (5-HT 2A R) and class C metabotropic glutamate 2 receptor (mGluR2) are able to form a GPCR heterocomplex. By introducing the photoactivatable unnatural amino acid p-azido-L-phenylalanine (azF) at selected individual positions along the transmembrane (TM) segments of mGluR2, we delineate the residues that physically interact at the heteromeric interface of the 5-HT 2A R-mGluR2 complex. We show that 5-HT 2A R crosslinked with azF incorporated at the intracellular end of mGluR2's TM4, while no crosslinking was observed at other positions along TM1 and TM4. Together, these findings provide important insights into the structural arrangement of the 5-HT 2A R-mGluR2 complex., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Chyluria is a rare condition where chyle is excreted into the urine. Clinically, most patients manifest with intermittent passage of milky urine. Patients may also present with dysuria, urinary frequency, urgency, retention, or with the sequelae of chronic malnutrition., Case Report: We present a 55-year-old African American man who presented to the emergency department complaining of milky white urine, dysuria, decreased urine output, and suprapubic abdominal pain once a day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients may present to the emergency department complaining of milk-colored urine, hematuria, urinary retention, or the sequelae of malnutrition. Initial evaluations should include laboratory investigations of common causes of chyluria and the severity of the potential malnutrition. If the patient presents with urinary retention, after relieving the obstruction in the emergency department, assessment for clot/chyle burden and likelihood of recurrence of urinary retention should be performed by urology. Arrangements for proper outpatient follow-up should be made if the disease manifestations are not severe enough to warrant admission., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The serotonergic and glutamatergic neurotransmitter systems have both been implicated in the pathophysiology of schizophrenia, and there are multiple lines of evidence to demonstrate that they can interact in a functionally relevant manner. Particularly, it has been demonstrated that serotonin (5-hydroxytryptamine) 2A (5-HT 2A ) receptors and metabotropic glutamate type 2 (mGlu2) receptors can assemble into a functional heteromeric complex and modulate each other's function. This heteromeric complex has been implicated in the mechanism of action of hallucinogens as well as antipsychotic agents, and its role has been demonstrated in both in vitro and in vivo systems. Additionally, the difference in the changes in G i/o and G q/11 protein activity when a ligand binds to the heteromeric complex can be used as an index to predict the pro- or antipsychotic properties of an agent. Signaling via the heteromer is dysregulated in postmortem human brain samples of schizophrenia subjects, which may be linked to altered cortical functions. Alternative routes for the functional crosstalk between mGlu2 and 5-HT 2A receptors include synaptic and epigenetic mechanisms. This Review highlights the advances made over the past few years in elucidating the structural and functional mechanisms underlying crosstalk between 5-HT 2A and mGlu2 receptors in preclinical models of schizophrenia.

Background Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results There were 187 enrollments on 37 phase I trials. Median age was: 59 (29-83) years and number of prior therapies: 3 (0-8). The clinical benefit rate (CBR): response (5.6%) + stable disease, was 43.1%. Median progression free survival (PFS) and overall survival (OS) was 7.7 weeks and 43.7 weeks, respectively. The MVA identified age > 60 years (HR 1.63, p < 0.004), albumin<3.5 g/dL (HR 3.69, p < 0.001), direct bilirubin>ULN (HR1.69, p < 0.01), and WBC ≥ 5.2 k/uL (HR 1.97, p < 0.001) as negative prognostic factors. A risk score based on the MVA revealed that patients with a score of 0-1 had an improved OS (58.7 weeks) compared to a score of 2 (49.9 weeks, p < 0.01) and 3 (14.1 weeks, p < 0.001). Conclusions Phase 1 trials may offer similar or better clinical outcome for mCRC patients than standard third line therapies; the prognostic model could assist in selecting appropriate patients.

Pharmacophore models for 5-HT 2A receptor antagonists consist of two aromatic/hydrophobic regions at a given distance from a basic amine. We have previously shown that both aromatic/hydrophobic moieties are unnecessary for binding or antagonist action. Here, we deconstructed the 5-HT 2A receptor antagonist/serotonin-dopamine antipsychotic agent risperidone into smaller structural segments that were tested for 5-HT 2A receptor affinity and function. We show, again, that the entire risperidone structure is unnecessary for retention of affinity or antagonist action. Replacement of the 6-fluoro-3-(4-piperidinyl)-1,2-benz[ d]isoxazole moiety by isosteric tryptamines resulted in retention of affinity and antagonist action. Additionally, 3-(4-piperidinyl)-1,2-benz[ d]isoxazole (10), which represents less than half the structural features of risperidone, retains both affinity and antagonist actions. 5-HT 2A receptor homology modeling/docking studies suggest that 10 binds in a manner similar to risperidone and that there is a large cavity to accept various N 4 -substituted analogues of 10 such as risperidone and related agents. Alterations of this "extended" moiety improve receptor binding and functional potency. We propose a new risperidone-based pharmacophore for 5-HT 2A receptor antagonist action.

The present study focused on the development of magnesium-functionalized graphene oxide (FGO) coating on titanium alloy (Ti6Al4V) by electrophoretic deposition. Graphene oxide (GO) was synthesized by modified Hummers' method and functionalized with magnesium ions. X-ray diffraction, infrared spectroscopy (IR) and Raman spectroscopy were employed to confirm the synthesis of GO and GO-coatings on Ti6Al4V. Functionalization of GO with Mg ions was confirmed by energy dispersive X-ray spectroscopy. The surface morphology of coated samples was examined through scanning electron microscopy. Reduction of FGO coating (labelled as rFGO) by heating at 200 °C was confirmed by IR. The rFGO coated Ti6Al4V was found to be hydrophilic in nature as determined by contact angle measurement which showed reduction in the contact angle of Ti6Al4V from 95.4° to 42.1°. The percent cell viability over the coated sample was appreciably improved compared to as-received Ti6Al4V sample owing to hydrophilicity of the former. The positive shift in open circuit potential and increase in polarization resistance was observed after coating Ti6Al4V samples with FGO. The significant decrease in the corrosion current density and negative polarization loop in the reverse scan of samples also confirmed the improved corrosion resistance of rFGO-coated Ti6Al4V over uncoated Ti6Al4V in the PBS solution. Furthermore, the impedance spectroscopy revealed that the preferential adsorption of ionic species (indicated by large R ads ) at the surface improved the barrier characteristics of rFGO coated samples and exhibited an order of magnitude higher R ct compared to as-received samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Historically, arthroplasty in systemic lupus erythematosus (SLE) patients has been less successful than for patients with osteoarthritis (OA). It is not known if SLE remains an independent risk factor for poor arthroplasty outcomes or if other factors, such as avascular necrosis (AVN), continue to play a role., Methods: A case-control study using data from a single-institution arthroplasty registry compared SLE total hip arthroplasty (THA) and total knee arthroplasty (TKA) with OA controls matched by age, gender and presence of AVN. Baseline, two-year administrative and self-report data, and diagnosis leading to arthroplasty were evaluated., Results: A total of 54 primary SLE THA and 45 primary SLE TKA were identified from May 2007 through June 2011. AVN was present in 32% of SLE THA and no TKA. SLE THA had worse preoperative WOMAC pain (42.5 vs. 52.7; p = 0.01) and function (38.8 vs. 48.0; p = 0.05) compared with OA. However, at two years there was no difference in WOMAC pain (91.1 vs. 92.1; p = 0.77) or WOMAC function (86.4 vs. 90.8; p = 0.28). SLE TKA were similar to OA in both preoperative pain (42.6 vs. 48.4; p = 0.14) and function (42.1 vs. 46.8; p = 0.30) and two-year pain (85.7 vs. 88.6; p = 0.50) and function (83.7 vs. 85.1; p = 0.23). Compared to OA, SLE THA and TKA patients had more renal failure (14% vs. 1%; p = 0.007) and hypertension (52% vs. 29%; p = 0.009). In a multivariate linear regression, SLE was not predictive of either poor pain or poor function., Conclusions: While SLE patients have more comorbidities than OA, and SLE THA have worse preoperative pain and function compared with OA controls, SLE was not an independent risk factor for poor short-term pain or function after either hip or knee arthroplasty., (© The Author(s) 2015.)

Objective: The objective of the study is to determine the efficacy of oral granisetron (a long-acting 5-HT3 receptor antagonist) in stopping vomiting subsequent to discharge from emergency department (ED), in 6-month-old to 8-year-old patients with gastroenteritis-related vomiting and dehydration, who had failed an initial trial of oral rehydration (ORT)., Methods: Eligible patients were offered ORT on a slowly advancing schedule. Patients who tolerated the initial ORT were discharged home. Patients who vomited were randomized to receive either 40 μg/kg of granisetron or placebo, and ORT was resumed. Patients who tolerated the postrandomization ORT were discharged home with another dose of the study drug. Parents were contacted by telephone every 24 hours until complete resolution of symptoms. The primary outcome was the proportion of patients with vomiting at 24 hours., Results: Of the 900 eligible patients, 537 (60%) tolerated the initial ORT and were discharged home. Of the patients who vomited during the initial ORT, 165 were included in the final study sample (placebo, n = 82; granisetron, n = 83). There was no statistically significant difference in the proportion of patients with vomiting at 24 hours (granisetron, n = 38; placebo, n = 45; odds ratio, 0.64; 95% confidence interval, 0.34-1.19; P = .16). A similar trend in the proportion of patients with vomiting was noted for the entire follow-up period (granisetron, n = 43; placebo, n = 47; odds ratio, 0.73; P = .33; 95% confidence interval, 0.39-1.36)., Conclusion: Granisetron was not effective in controlling gastroenteritis-related vomiting subsequent to discharge from ED. It did not change the expected course of the illness., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background & Aim: Acute lower respiratory infections are the most frequent illnesses globally in children less than 5 years old. The aim of this randomized double blind controlled trial is to assess the effectiveness of zinc gluconate supplementation for 2 months period compared to placebo in reducing respiratory morbidity in acute lower respiratory infected children up to 5 years of age living in zinc poor population., Methods: Children were randomly assigned to receive either 10 mg zinc gluconate or placebo for 60 days. Demographic and clinical data were collected at baseline and every two weeks for 180 days., Results: The final analysis included 96 children allocated equally to the two groups. The number of episodes of acute lower respiratory infections and severe acute lower respiratory infections were significantly lower in zinc group compared to placebo group (20.8% vs. 45.8% (P = 0.009) and 21.7% vs. 58.3% (P < 0.001), respectively). The acute lower respiratory infections free days were higher in the zinc supplemented group (P < 0.001). The median recovery time of morbidity was significantly shorter in zinc group (P < 0.001)., Conclusions: Zinc supplement may result in significant reduction in respiratory morbidity among children with acute lower respiratory infections in zinc poor population. This study was registered under ClinicalTrials.gov Identifier no. NCT00536133., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

We report a rare case of progressive familial intrahepatic cholestasis type 2 from India. The diagnosis was confirmed on the basis of gene mutation analysis. The child had intense pruritus refractory to conventional medical management. As liver biopsy did not reveal any cirrhosis, partial external biliary diversion was considered as an alternative to liver transplant. We performed cholecystoappendicostomy rather than the conventional method of using an ileal loop as a conduit between the gall bladder and abdominal wall. Child recovered completely.

Migraine is the most common cause of acute recurrent headaches in children. The pathophysiological concepts have evolved from a purely vascular etiology to a neuroinflammatory process. Clinical evaluation is the mainstay of diagnosis and should also include family history. Investigations help to rule out secondary causes. The role of new drugs in treatment of migraine is discussed and trials are quoted from literature. Indications for starting prophylaxis should be evaluated based on frequency of attacks and influence on quality of life. For management of acute attacks of migraine both acetaminophen and ibuprofen are recommended for use in children. Many drugs like antiepileptic drugs (AED), calcium channel blockers, and antidepressants have been used for prophylaxis of migraine in children. The data for use of newer drugs for migraine in children is limited, though AEDs are emerging a popular choice. Biofeedback and other nonmedicinal therapies are being used with promising results.

Pentylenetetrazole (PTZ)-induced convulsions and the maximal electroshock (MES) seizure test were employed to study the anticonvulsant effects of nifedipine (2, 3.5 and 5 mg kg-1), flunarizine (10, 20 and 40 mg kg-1) and diltiazem (10, 15 and 30 mg kg-1). Nifedipine and flunarizine prolonged the latent period and reduced the mean duration of PTZ induced seizures. They also reduced the severity of convulsions and the number of deaths due to PTZ significantly. Nifedipine was more potent in this regard (P < 0.01). All these drugs prolonged the latent period and reduced the duration of tonic extensor phase of MES seizures in a significant manner. Flunarizine was most potent in this test. Complete protection from tonic extensor phase was observed in 10-50% animals pretreated with nifedipine and flunarizine in a dose dependent manner. The response of diltiazem was weak in both these tests. It is concluded that all three calcium channel blockers possess an important but different anticonvulsant effect and their significant clinical use can be made while keeping in view the characteristics of their pharmacological action.

Spontaneous motor activity, rotarod test and observational rating of sedation were employed to study effect of nifedipine on sedation produced by reserpine, clonidine and propranolol. Reserpine (2 mg kg-1), clonidine (4 mg kg-1), and propranolol (40 mg kg-1) significantly reduced spontaneous motor activity and staying capacity of animals on accelerating rotarod (P < 0.01). Observational sedation was also caused significantly as indicated by a higher score in test. Nifedipine (2 mg kg-1) produced no sedation or excitation on its own. Reduction in spontaneous motor activity produced by reserpine and clonidine was partially reversed in animals treated with nifedipine (P < 0.01). A similar effect of nifedipine was also evident on the observational sedation induced by reserpine and clonidine. Effect of these drugs on rotarod times was nearly totally antagonised by nifedipine. Nifedipine did not oppose the sedation produced by propranolol which actually became significantly greater in the animals pretreated with nifedipine in all three tests. It is concluded that nifedipine antagonizes the sedation produced by reserpine and clonidine, probably by blocking central alpha 2-adrenoceptors. The sedative effect of propranolol can be potentiated by nifedipine possibly because of a pharmacokinetic interaction.

Diphenylhydantoin (DPH) (20 x 10(-6) to 80 x 10(-6) M/kg) blocked the depressor responses to isoproterenol in spinal, bilaterally vagotomized and atropine pretreated cats; depressor responses to histamine were unaffected; DPH shifted the isoproterenol concentration-response curve to the right in isolated guinea pig tracheal chain preparation, isolated rabbit ileum and isolated perfused heart of frog. The results suggest that DPH has a specific beta-adrenoceptor blocking action and the blockade appears to be competitive in nature as shown by PA2 and PA10 values.

Growth inhibitory effect of pentazocine was studied in young rats for a duration of 4 weeks. The animals were subjected to various drug treatments, namely (1) distilled water 0.5 ml/kg s.c.; (2) pentazocine 10 mg/kg s.c.; (3) pentazocine 10 mg/kg s.c. plus metoclopramide 10 mg/kg s.c., and (4) pentazocine 10 mg/kg s.c. plus l-dopa 100 mg/kg s.c. Body weight was taken as a measure for the assessment of growth rate. The results of group 2 were compared with group 1 and that of groups 3 and 4 were compared with group 2. Pentazocine alone markedly inhibited the growth from the second to fourth weeks of treatment. Dopamine antagonist metoclopramide has almost completely prevented the growth inhibitory effect of pentazocine. Combination of l-dopa with pentazocine produced a significant growth inhibition in the first week but subsequently this effect was significantly less marked as compared to that of pentazocine alone. The growth inhibitory effect of pentazocine may possibly be mediated through alterations in dopaminergic mechanisms which are known to exert controlling influence on the release of several of the pituitary hormones.

The effect of three recently introduced beta-adrenoceptor blockers practolol, USVC 6524 and Inpea was studied on various skeletal muscle preparations. Practoloo, USVC 6524 and Inpea produced a dose related inhibition of acetylcholine induced contractions of rectus abdominis muscle of frog. These drugs also blocked neuromuscular transmission when tested on in vitro rat phrenic nerve diaphragm preparation; the blockade was partially reversed by physotigmine, KCl and adrenaline and was potentiated by d-tubocurarine. In gastrocnemius sciatic muscle-nerve preparation only Inpea exhibited neuromuscular blocking activity, while practolol and USVC 6524 did not show any effect up to a dose of 10 mg/kg (intraarterially). The apparent discrepancies between the results of in vitro and in vivo experiments could not be adequately explained. It has been discussed that the neuromuscular blockade caused by presently investigated beta-adrenoceptor blocking agents is essentially due to curare-like activity and to a small extent may be due to local anaesthetic activity.

Prostaglandin (PG) release was measured from the isolated perfused rabbit heart. The effects of beta-adrenergic stimulation and blockade suggest that PG synthesis is regulated in part by adrenergic mechanisms.