Minutes Of Drug Administration Research Articles

Trial design and protocol of randomized controlled trial comparing the efficacy of oral mefenamic acid, paracetamol and placebo for analgesic prophylaxis in childhood vaccination (MAP VaC trial)

<p class="abstract"><strong>Background:</strong> Needle related pain has been one of the most important concerns for parents of children receiving vaccination. Non-steroidal anti-inflammatory drugs (NSAIDs) like paracetamol and mefenamic acid have been commonly used as analgesics in pediatric population. However, prophylactic administration of these drugs for analgesia during vaccination has not been studied. The main objective of this study is to compare the efficacy of prophylactic paracetamol, mefenamic acid and placebo on needle pain associated with vaccination.</p><p class="abstract"><strong>Methods:</strong> This is a three-arm parallel, triple blind, randomized controlled trial. Children aged 6 weeks to 7 years who need immunization as per national immunization schedule and reporting to pediatric outpatient department (OPD) at tertiary level hospital, AIIMS Mangalagiri, Andhra Pradesh, will be included. All participants will be randomly allotted to any of the three groups by computer based block randomization. Each participant will be given any one of the three drugs as per their allocation. Vaccination will be done as per national immunization schedule after 30 minutes of drug administration. Face, legs, activity, cry, consolability (FLACC) scoring will be done immediately after vaccine administration and repeated at 15 minutes and 30 minutes. All personnel involved in randomization, drug and vaccine administration, FLACC scoring and statistical analysis will be blinded along with parents and children enrolled in the study.</p><p class="abstract"><strong>Conclusions: </strong>If this intervention study shows evidence of a difference between drug and placebo signifying reduction in vaccine related pain with these drugs, this will have a huge impact on National Immunization programme by improving compliance, vaccine coverage and by reducing vaccine hesitancy.</p><p class="abstract"><strong>Trial registration:</strong> Clinical trials registration number is CTRI/2021/01/030239.</p>

Intrathecal Injection of Scorpion Venom Peptide, BmK AGAP Inhibits KCNQ2/3, TRPV1 and Decreases TNF-α and IL-1β Expression to Attenuates Pain in Rat

The current study was designed to test the hypothesis that Recombinant Buthus martensii Kasch Analgesic-Antitumor Peptide (rBmK AGAP) potentiates lidocaine induced analgesia. The chronic constrictive injury was performed on 72 rats to induce a rapid onset and long-lasting pain. The rats were randomly assigned to one of six groups; Group A (n=12) received an intrathecal injection of saline, Group B (n=12) received an intrathecal injection of lidocaine alone, Group C (n=12) received an intrathecal injection of rBmK AGAP alone, Group D, E, and F (n=12 each) received an intrathecal injection of lidocaine + rBmK AGAP (0.5, 1, or 2 mg.kg-1). The von Frey filaments were used to assessed mechanical allodynia. Nav1.7 and TRPV1 currents were recorded by whole-cell aspiration patch-clamp technique, and KCNQ2/3 currents were recorded by whole-cell drilling patch-clamp technique. We performed qPCR, ELISA and western blot to determine the expression of TNF-α, IL-1β, IL-6, IL-10, p65/NF-κB, p-p65/NF-κB, IKKα, IκBα in rats following rBmK AGAP treatment. The rats from the lidocaine + BmK AGAP group exhibited significantly increased Paw Withdrawal Threshold (PWT) after 30 minutes of drug administration which gradually decreased to baseline PWT at 360 minutes. The whole-cell aspiration patch-clamp technique showed that rBmK AGAP significantly inhibited KCNQ2/3 and TRPV1 currents to potentiate lidocaine induced analgesia. We observed significantly decreased expression of TNF-α and IL-1β following the combined treatment compared with lidocaine or rBmK AGAP alone. Intrathecal injection of rBmK AGAP inhibits KCNQ2/3, TRPV1 and decreases pro-inflammatory cytokines, TNF-α, and IL-1β expression and potentiates lidocaine induced analgesia. Funding Statement: This study was supported by the Key Laboratory of Liaoning Provincial Education Department (Grant NO: LZ2016002) and Liaoning Natural Science Foundation (Grant NO: 20170540290). Declaration of Interests: All authors declared no conflict of interests. Ethics Approval Statement: The animal ethics committee of the Dalian Medical University approved all the study protocols and were by the declaration of the national institutes of health guide for the care and use of laboratory animals.

Intramuscular Versus Buccal Midazolam for Pediatric Seizures: A Randomized Double-Blinded Trial

BackgroundWe compared the efficacy and safety of intramuscular with buccal midazolam as first-line treatment for active seizures in children brought to the emergency department. MethodsIn a double-blind, double-dummy randomized trial, patients with an active seizure lasting more than five minutes received blinded treatments on arrival. We employed deferred consent. The proportion of patients with cessation of seizure within five minutes of drug administration was the primary efficacy outcome; proportions needing additional medication to control seizure, duration of seizure activity, and side effects were secondary outcomes. ResultsWe enrolled 150 children presenting with active seizure, age range 4.5 to 167.5 months. Cessation of seizure occurred in 61% of the intramuscular and 46% of the buccal treatment groups, (P = 0.07, difference 15.5%, 95% confidence interval for the difference −1.0 to 32.0%). Proportions requiring additional anti-seizure treatment were 39% in the intramuscular and 51% in the buccal groups. Mean duration of seizure activity after administration of study medication was 15.9 minutes (S.D. 28.7) in the intramuscular and 17.8 minutes (S.D. 27.5) in the buccal group. One patient in the intramuscular group developed respiratory depression and hypotension; there were no side effects attributed to investigational treatment in the buccal group. ConclusionsEfficacy and safety of intramuscular midazolam as first-line treatment for pediatric seizures compare favorably to that of buccal midazolam.

Effectiveness of Intravenous Ketorolac versus Intravenous Morphine Sulfate on Pain Control in Patients with Acute Renal Colic: A Phase 3 Randomized Clinical Trial

Introduction: Renal colic is an acute syndrome for which relieving the pain is known to be the best treatment. The aim of this randomized clinical trial was comparing the efficacy of intravenous ketorolac with intravenous morphine sulfate in relieving the acute pain of renal colic in patients referred to the emergency department of a tertiary care teaching hospital.Methods: 98 cases were selected via convenience sampling method from patients with a presumptive diagnosis of renal colic admitted in the emergency department of Besat Nahaja hospital of Tehran, Iran from March to May 2014 and randomly divided into two groups of equal size, ketorolac, and morphine sulfate. The patients’ vital signs and pain intensity were observed at baseline of the study and after 10, 30, 60, 120 and 180 minutes of drug administration. Patients were also followed for side effects. The areaunder- the-curve (AUC) was used for pain assessment. Data were analyzed in SPSS 19 using T- test, Chi-square test, and Mann-Whitney test at significance level < 0.05.Results: Demographic and clinical characteristics of the two groups were similar before drug administration. Both drugs were equally effective in reducing pain over time (P-value = 0.17). Side effects of treatment with ketorolac, were significantly less than using morphine sulfate. The most common adverse effects caused by morphine sulfate, were dizziness and vomiting while nausea and vomiting were the most frequent side effects of using ketorolac.Conclusions: Findings of this study indicated that ketorolac and morphine sulfate were equally effective in relieving the pain of renal colic, but given the severity of side effects, ketorolac is the preferred drug.

An investigation to evaluate the analgesic and central nervous system depressant activities of Solanum nigrum (Linn.) in Homoeopathic potencies in experimental animal models

Background and Objective: In Homoeopathy, Solanum nigrum is clinically used in the treatment of ergotism, meningitis, irritation during dentition and some of the symptoms of neurological disorders but its Central Nervous System (CNS) potential has not been explored experimentally yet. Therefore, a preliminary study was conducted with an objective to evaluate the analgesic and CNS depressant effects of homoeopathic potencies of S. nigrum in experimental animal models. Materials and Methods: The study was conducted in Wistar albino rats using a hot plate, ice plate and Randall-Selitto assay for analgesic; rota-rod and open field test for CNS depressant activities. The different potencies (3X, 6X, 12X and 30C) of Solanum nigrum were administered orally (0.5 ml/rat/day) for 30 days and response was assessed after 30 minutes of drug administration on 10 th , 20 th and 30 th day. Results: The result shows that all the four potencies of Solanum nigrum has increased the latency time required to raise and lick the paws for thermal sensation on hot plate test and for cold sensation on ice plate test and also increased the degree of threshold pressure to mechanically induced pain on Randall-Selitto assay but depressed the motor coordination and locomotor activities. Conclusion: The result obtained from this preliminary study suggests that homoeopathic preparation of Solanum nigrum in different potencies possess analgesic and CNS depressant activities. Further detailed investigations are required for its possible human use.

Investigation of phytochemicals and anti‑convulsant activity of the plant Coleus amboinicus (lour.)

Objectives: The present study has been designed to evaluate the comparative anticonvulsant activity of different parts of Coleus amboinicus as it has been mentioned in the various literatures regarding the use of this plant in the treatment of epilepsy, but no specific scientific reports are available in this regard. Materials and Methods: The in vitro anticonvulsant activity of leaf, stem and roots of C. amboinicus has been evaluated by maximal electric shock‑induced seizures (MES) and Pentylenetetrazole (PTZ)‑induced seizures models in Swiss albino mice. The drug/extracts were administered through intra‑peritoneal route (100 mg/ml), in both experimental models and the effect was compared with Phenytoin in MES and PTZ‑induced convulsion. Results: All the three studied extracts have shown significant anticonvulsant activity in both the models. However, the alcoholic leaf extract has shown highest activity by abolishing the MES‑induced convulsions after 60 minutes of drug administration. The duration of convulsions in PTZ model was also significantly reduced (P < 0.001) compared to the control group. Conclusion: The alcoholic leaf extract of the C. amboinicus has shown the significant anticonvulsant activity in both the studied models, followed by stem and root extracts. The presence of alkaloids, flavonoids, and saponins in these extracts may be responsible for this activity. Key words: Anti‑convulsant, Coleus amboinicus, maximal electric shock, Pentylenetetrazole, Phenytoin

Niegenomowy mechanizm działania glikokortykosteroidów

The review describes current advances in the knowledge on the mechanisms of glucocorticoid (GC) action. According to the classic genomic model, GCs bind to intracellular receptors and subsequently regulate (directly or indirectly) gene transcription and synthesis of proteins responsible for inflammatory processes. The nongenomic effects of GCs, occur rapidly within seconds or minutes of drug administration, are mediated via a cytosolic but first of all by membrane GC receptors and lead to activation of multiple signal transduction pathways of protein kinases (MAPK, Src, PI3K), cation channels or G protein- -coupled receptors. Nongenomic effects may also occur without receptor involvement. The elucidation of nongenomic actions provides new insights for the understanding of their anti-inflammatory and immunosuppressive GC effects.

A comparison of the effects of desflurane, sevoflurane and propofol on QT, QTc, and P dispersion on ECG

The aim of this prospective, randomized, and double-blinded study was to compare the effects of desflurane, sevoflurane, propofol on both atrial and ventricular wall function by measurement of QT dispersion (QTd), corrected QT dispersion (QTcd), and P dispersion (Pd) on electrocardiogram (ECG). Forty-six patients from the American Society of Anesthesiologists class I-II undergoing noncardiac surgery, were enrolled in this study. Patients were randomly allocated to receive desflurane, sevoflurane or propofol anesthesia. ECG recordings were taken before and after 5 minutes of drug administration. Induction with desflurane significantly increased the QTd compared to baseline (38 +/- 2 ms vs. 62 +/- 6 ms, P 0.05). Sevoflurane and propofol anesthesia was not associated with any changes in QTd. QTcd was increased with desflurane induction and decreased with sevoflurane and propofol induction, but this decrease was only significant in the propofol group (67 +/- 5 ms vs. 45 +/- 3 ms, P 0.05). Pd was significantly increased after induction with desflurane (34 +/- 3 vs. 63 +/- 6 ms, P 0.05). There was a significant increase in QTd and Pd in desflurane group, but this increment did not cause any dangerous arrhythmias. QTcd significantly decreased in propofol group. We believe that further investigations are required for using desflurane as safe as sevoflurane and propofol in noncardiac surgery patients who have high cardiac arrhythmia and ischemia risk.

Post-transcriptional and Nongenomic Effects of Glucocorticoids

The ability of glucocorticoids to interfere with post-transcriptional gene regulation has recently been recognized as a potentially important part of their anti-inflammatory property, and the mechanisms governing such activity are under active investigation. Several studies have shown that glucocorticoids can inhibit inflammatory signaling pathways known to control mRNA turnover and translation. Moreover, several glucocorticoid-sensitive determinants have been identified on mRNA molecules of inflammatory genes, and the RNA-binding factors interacting with them might constitute relevant glucocorticoid targets. Glucocorticoids also exert effects characterized as nongenomic, which occur within minutes of drug administration. The mechanisms of action of nongenomic glucocorticoid effects differ from the classical, transcription-dependent glucocorticoid action and involve the production of second-messenger molecules and activation of signal transduction pathways, either by the nuclear glucocorticoid receptor or by a membrane glucocorticoid receptor that has not yet been fully characterized. Ultimately, the discovery of novel pathways involved in mediating the actions of glucocorticoids should lead to improved targets for anti-inflammatory therapy.

Combretastatin A4 phosphate

Combretastatin A4 phosphate (CA4P) is a water-soluble prodrug of combretastatin A4 (CA4). The vascular targeting agent CA4 is a microtubule depolymerizing agent. The mechanism of action of the drug is thought to involve the binding of CA4 to tubulin leading to cytoskeletal and then morphological changes in endothelial cells. These changes increase vascular permeability and disrupt tumor blood flow. In experimental tumors, anti-vascular effects are seen within minutes of drug administration and rapidly lead to extensive ischemic necrosis in areas that are often resistant to conventional anti-cancer treatments. Following single-dose administration a viable tumor rim typically remains from which tumor regrowth occurs. When given in combination with therapies targeted at the proliferating viable rim, enhanced tumor responses are seen and in some cases cures. Results from the first clinical trials have shown that CA4P monotherapy is safe and reduces tumor blood flow. There has been some promising demonstration of efficacy. CA4P in combination with cisplatin is also safe. Functional imaging studies have been used to aid the selection of doses for phase II trials. Both dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and positron emission tomography can measure the anti-vascular effects of CA4P in humans. This review describes the background to the development of CA4P, its proposed mechanism of action, the results from the first clinical trials with CA4P and the role of imaging techniques in its clinical development.

Anesthetic and cardiorespiratory effects of tiletamine-zolazepam-medetomidine in cheetahs

Objective— To evaluate anesthetic and cardiorespiratory effects of an intramuscular injection of a tiletamine-zolazepam-medetomidine combination in cheetahs. Design— Prospective study. Animals— 17 adult captive cheetahs. Procedure— The anesthetic combination was administered intramuscularly via a dart. Induction quality, duration of lateral recumbency, duration of recovery, and quality of anesthetic reversal with atipamezole were assessed. Cardiorespiratory variables (arterial blood gas partial pressures, arterial blood pressure, heart and respiratory rates, end-tidal CO2, oxygen saturation, and rectal temperature) were measured during anesthesia. Results— Sedation and lateral recumbency developed within 1.9 ± 1.0 (mean ± SD) and 4.3 ± 2.0 minutes of drug administration, respectively. Clinically acceptable cardiorespiratory and blood gas values were recorded for at least 87 minutes after drug administration in all but 1 cheetah. Hypoxemia and arrhythmias developed in 1 cheetah breathing room air but resolved after treatment with oxygen. Hypertension developed in all cheetahs. Significant differences in heart and respiratory rates, mean arterial blood pressure, arterial pH, partial pressure of oxygen, and hemoglobin saturation were found between cheetahs that did and did not receive oxygen supplementation. After administration of atipamezole, sternal recumbency and mobility returned within 6.9 ± 5.8 and 47.5 ± 102.2 minutes, respectively. Postreversal sedation, which lasted approximately 4 hours, developed in 4 cheetahs. Clinical Implications— Tiletamine-zolazepam-medetomidine delivered via a dart provided an alternative method for induction and maintenance of anesthesia in cheetahs. Atipamezole at the dose used was effective for reversal of this combination in the initial phase of anesthesia. (J Am Vet Med Assoc 1998:213:1022-1026)

Time course of myocardial amiodarone uptake in the piglet heart using a chronic animal model.

This investigation sought to study single dose pharmacokinetics of amiodarone in a chronic animal model. We developed a new chronic animal model that allows serial direct access to the heart of the immature piglet via an implanted acrylic thoracic window. Following instrumentation and 72-hour recovery, amiodarone (5 mg/kg) was administered as a single intravenous bolus in immature piglets. Timed paired serum samples and myocardial biopsies for amiodarone level were obtained prior to, and up to 72 hours following, amiodarone administration. Peak concentrations of amiodarone in both serum (3.60 +/- 1.02 micrograms/ml) and tissue (84.2 +/- 6.50 ng/mg) occurred within 5 minutes of drug administration. As reported by others, this study demonstrated that the volume of distribution (VD) of amiodarone was large (33.31 +/- 35.21 L/kg), and the clearance (Cl) was low (13.6 +/- 4.4 ml/min/kg). Marked prolongation of both the serum t1/2 (29.98 +/- 29.26 hours) and the myocardial t1/2 (29.20 +/- 29.49 hours) were noted as well. The early, rapid myocardial peak of amiodarone in the immature myocardium corresponds with recent clinical observations of onset of antiarrhythmic efficacy 5 to 10 minutes following intravenous amiodarone administration in young children.

Selective effects of pentobarbital and halothane on c-fos and jun-B gene expression in rat brain.

The effects of pentobarbital and halothane anesthesia on the expression in brain of the immediate-early genes c-fos and jun-B were investigated. Pentobarbital-anesthetized rats (n = 10) received a single intraperitoneal injection of pentobarbital 65 mg/kg in a vehicle of 40% propylene glycol and 10% ethanol and then were placed in a plexiglass box flushed continously with 100% oxygen at 5 l/min. Halothane-anesthetized rats (n = 10) received an intraperitoneal injection of vehicle only and were transferred to a box flushed continuously with oxygen plus 1.5% halothane. Unanesthetized control rats (n = 10) received an intraperitoneal injection of vehicle and were placed in a box flushed continuously with 100% oxygen. Four additional rats received no intraperitoneal injection but were handled and otherwise treated identically to the control group, and six others had a femoral arterial catheter inserted for blood pressure and blood gas measurements. Five animals from the control and both anesthetized groups were killed at 30 and 120 min postinjection and their brains rapidly removed and frozen. The messenger ribonucleic acid transcription products of the genes c-fos, jun-B, and beta-actin from whole cerebral hemispheres were analyzed autoradiographically after Northern blot hybridization with 32P-labeled deoxyribonucleic acid probes. Relative levels of c-fos and jun-B messenger ribonucleic acid were determined from optical density measurements of the autoradiographic bands, with beta-actin measurements being used to correct for sample-to-sample variation. Rats became immobile within minutes of drug administration and remained anesthetized until they were killed.(ABSTRACT TRUNCATED AT 250 WORDS)

Human pharmacokinetics of WR-2721

The pharmacokinetic properties of WR2721 were investigated in 13 cancer patients given a 150 mg/M 2 intravenous bolus dose of the drug. An average plasma clearance value of 2.17 L/min was obtained. Very little of the drug or the two metabolites, WR1065 and WR33278, were excreted in urine obtained after the blood collection schedule. Plasma concentrations of WR2721 decreased by 94% within 6 minutes of drug administration. The mean value of 6.44 L obtained for the steady-state volume of distribution indicates that the extravascuhu space occupied by the drug is small. These observations suggest that in human cancer patients, WR2721 is rapidly taken up by tissues and converted to metabolites.

Inhibition of secretion of rat calcitonin by calmodulin inhibitors.

Studies were designed to investigate the potential importance of calmodulin in release of calcitonin (CT) in response to an increase in the concentration of extracellular Ca. In vitro release of CT from baby rat thyroparathyroids incubated up to 8 h was examined at normal (1 mM) and high (2.5 mM) Ca in serum-free medium in the presence and absence of the potent calmodulin inhibitors, trifluoperazine (TFP) and N-(6-aminohexyl)-5-Cl-1-naphthalene sulfonamide (W-7). The drugs chlorpromazine (CLP) and haloperidol (HAL) which, like TFP, are anti-psychotic agents also were tested. In some studies release of parathyroid hormone (PTH) into medium also was studied. At 2.5 mM Ca, CT release was increased five- tenfold compared with 1 mM Ca while PTH was suppressed by approximately 80%. The increased release of CT induced by 2.5 mM Ca was inhibited 60-90% by 10(-4) M TFP and 10(-4) M W-7, but was unaffected by 10(-4) M CLP or HAL. In the presence of 1 mM Ca, the increased release of PTH also was inhibited significantly by 10(-4) M TFP and 10(-4) M W-7. In related in vivo studies, administration of TFP i.v. to rats just before induction of hypercalcemia with i.v. CaCl2 suppressed the increase in plasma CT normally observed 3 min later in a dose-related manner. The results show that calmodulin inhibitors can inhibit in vitro secretion of CT, and release of PTH as well. Additionally, inhibition of the in vivo CT response to a Ca challenge was observed within minutes of drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Endotracheal versus intravenous epinephrine during electromechanical dissociation with CPR in dogs

The dose-response curves of epinephrine given either IV or endotracheally (ET) were compared during resuscitation from electromechanical dissociation (EMD). Ten anesthetized dogs were subjected to a two-minute period of electrically induced ventricular fibrillation (VF) followed by defibrillation without CPR to produce EMD. Mechanical CPR was followed by injection of either ET or IV epinephrine. Successful response was defined as a return of pulsatile blood pressure within two minutes of drug administration. Using log-dose increments of epinephrine, experimental trials were repeated in each animal. The IV and ET median effective doses were 14 and 130 micrograms/kg, respectively. When the trials were successful, the time between drug administration and either arterial blood pressure increases or return of spontaneous circulation did not differ significantly for the ET and IV groups. These results show that the dosage for epinephrine delivered ET must be higher than the IV dosage to achieve the same response during CPR.

Anaphylactoid Reactions during Anaesthesia

Since 1970 it appears that anaphylactoid reactions to anaesthetic drugs have increased and occur at a frequency of between 1/5000 and 1/20000 anaesthetics with a 4 per cent mortality. Muscle relaxant drugs and Cremophor based drugs cause the majority of reactions. The most common serious clinical manifestation is cardiovascular collapse and bronchospasm the most difficult to treat. The reactions usually occur after induction and within five minutes of drug administration. The patients who react have a higher incidence of allergy, atopy and asthma than non-reacting patients. They may also show increased sensitivity to histamine or a tendency to release increased amounts of histamine. Direct histamine release, complement activation and type I hypersensitivity have all been implicated as mechanisms. The drug responsible is best determined by intradermal testing. Patients who react have an increased risk of further reactions and pharmacological pretreatment cannot be guaranteed to prevent reactions. The patient with a history of a reaction to an anaesthetic drug whould be warned about the nature of the reaction and the risks, and techniques avoiding possible causative drugs used wherever possible.

Reversible effect of dantrolene sodium on twitch tension of rat skeletal muscle.

The effect of dantrolene sodium on twitch tension in skeletal muscle of the rat was studied in short- and long-term experiments. The twitch tension is reduced to 50% of the control values within 20 to 30 minutes of drug administration. The recovery phase is considerably slower than the effect observed on the addition of dantrolene sodium, having a half time of 10 hours. Twenty-four hours after the drug injection, the twitch tension in the treated muscles is indistinguishable from that in the controls. It is shown that the reduction in the magnitude of the twitch produced by dantrolene sodium is slowly and completely reversible.

Splanchnic blood flow in experimental shock.

This paper will examine the role of the splanchnic circulation in experimental shock and reassess the so-called “target organ” or “adrenergic” theories in the pathogenesis of irreversible shock. In the dog, the endogenous catecholamines are mesenteric vasoconstrictors whether injected or infused into the superior mesenteric artery or inferior vena cava. This response appears to be independent of the dose given. Infusion of catecholamines causes vasoconstriction characterized by autoregulatory escape from the adrenergic agonist within minutes of drug administration. In the baboon, the responses to norepinephrine and epinephrine are similar, with one exception: low-dose epinephrine injected or infused into the superior mesenteric artery causes vasodilation. In contrast to the canine models of experimental shock (10), the baboon responds to neither endotoxic or hemorrhagic shock with mesenteric or hepatic ischemia over many hours of observation. Likewise, the subhuman primate exhibits no evidence of pathological change in the intra-abdominal viscera, in contrast to the dramatic changes observed in canine shock. Catecholamine concentrations are equally elevated in both species during either form of experimental shock.