Computational prognostic evaluation of Alzheimer's drugs from FDA-approved database through structural conformational dynamics and drug repositioning approaches.

Drug designing is high-priced and time taking process with low success rate. To overcome this obligation, computational drug repositioning technique is being promptly used to predict the possible therapeutic effects of FDA approved drugs against multiple diseases. In this computational study, protein modeling, shape-based screening, molecular docking, pharmacogenomics, and molecular dynamic simulation approaches have been utilized to retrieve the FDA approved drugs against AD. The predicted MADD protein structure was designed by homology modeling and characterized through different computational resources. Donepezil and galantamine were implanted as standard drugs and drugs were screened out based on structural similarities. Furthermore, these drugs were evaluated and based on binding energy (Kcal/mol) profiles against MADD through PyRx tool. Moreover, pharmacogenomics analysis showed good possible associations with AD mediated genes and confirmed through detail literature survey. The best 6 drug (darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar) further docked and analyzed their interaction behavior through hydrogen binding. Finally, MD simulation study were carried out on these drugs and evaluated their stability behavior by generating root mean square deviation and fluctuations (RMSD/F), radius of gyration (Rg) and soluble accessible surface area (SASA) graphs. Taken together, darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar displayed good lead like profile as compared with standard and can be used as possible therapeutic agent in the treatment of AD after in-vitro and in-vivo assessment.

Repositioning of tubocurarine as analgesic and anti-inflammatory agent: Exploring beyond myorelaxant activity.

BACKGROUND AND PURPOSE: Tubocurarine (d-TC), a non-depolarizing competitive blocker of nicotinic acetylcholine receptors is extensively utilized for the relaxation of skeletal muscles. Drug repositioning is a forthright approach to reduce the cost and speed up drug development process. Herein, we have attempted to evaluate the analgesic and anti-inflammatory activity of d-TC for its possible repurposing in pain and inflammation-related issues. EXPERIMENTAL APPROACH: We examined the soluble epoxide hydrolase inhibitory (sEHI) activity of d-TC employing in silico high throughput screening protocols, in vitro cell-free sEH inhibitory assay, and in in vivo rodent models for its repositioning in pain and inflammation-related disorders. KEY RESULTS: In molecular docking study, d-TC displayed impressive hydrogen bonding interactions within the cavity of sEH enzyme with good docking score. d-TC also exhibited notable sEH inhibitory activity (IC50 3.72 nm) at the in vitro assay. Oral absorption capability of d-TC (0.1 and 0.2 mg/mL) was determined using an in vitro everted intestinal sac model employing rat ileum tissue that revealed significant oral absorption of d-TC. Besides, in vivo studies revealed that oral administration of d-TC (0.1 and 0.2 mg/kg) in rodents significantly attenuated hyperalgesia (cold plate test, tail immersion test and formalin test) and inflammation (estimation of rectal temperature, acetic acid induced pleurisy test and cotton pellet-induced granuloma test) induced in robust preclinical models. Conclusion and implications These findings are novel and warrant immediate efforts to reposition d-TC as a new therapeutic candidate in the management of hyperalgesia, inflammation, and associated conditions.

Plasmodium falciparum: growth response to potassium channel blocking compounds.

Potassium channels are essential for cell survival and regulate the cell membrane potential and electrochemical gradient. During its lifecycle, Plasmodium falciparum parasites must rapidly adapt to dramatically variant ionic conditions within the mosquito mid-gut, the hepatocyte and red blood cell (RBC) cytosols, and the human circulatory system. To probe the participation of K(+) channels in parasite viability, growth response assays were performed in which asexual stage P. falciparum parasites were cultured in the presence of various Ca(2+)-activated K(+) channel blocking compounds. These data describe the novel anti-malarial effects of bicuculline methiodide and tubocurarine chloride and the novel lack of effect of apamine and verruculogen. Taken together, the data herein imply the presence of K(+) channels, or other parasite-specific targets, in P. falciparum-infected RBCs that are sensitive to blockade with Ca(2+)-activated K(+) channel blocking compounds.

[Neuromuscular monitoring: methods and machines]. / Uberwachung der neuromuskulären Blockade - Methoden und Geräte.

Muscle relaxing agents are clinically in use for general anaesthesia to optimize the conditions to the endotracheal intubation as well as the surgical conditions. Therefore different musclerelaxants with specific pharmacological characteristics are available. Many factors that depend on the condition of the patient and the used musclerelaxant agent influence the duration of the neuromuscular blockade. Rapid reversal of their effects, particularly in cases of profound blockades, proved to be difficult. In cases of postoperative residual paralysis hypoxic complications because of failure of the ventilation increase the morbidity and mortality of the perioperative period. To avoid these complications in cause of postoperative residual neuromuscular blockade it seems to be necessary to evaluate the status of the muscle function. For the tactile or visual assessment or the objective measurement of stimulation the train-of-four (TOF), double-burst (DBS) or tetanus-stimulation of peripheral nerves like the ulnar nerve may be used. Established methods for the objective monitoring of neuromuscular function is the mechanomyography (MMG), the acceleromyography (AMG), the electromyography (EMG), the kinemyography (KMG) and the phonomyography (PMG). A sufficient recovery of the neuromuscular transmission is reached to a TOF-ratio of 0,9 and should be aimed before the extubation at the end of surgery. No subjective evaluation of the neuromuscular recovery is able to identify residual paralysis above a TOF-ratio of 0,5. Recent studies suggest that objective methods should be used to monitor neuromuscular function to avoid postoperative residual blockades.

Status epilepticus treated with a muscle relaxant: the first success.

In 1958, an 11-year-old girl with status epilepticus was given the current treatments which failed to control the convulsions. In order to stop the fits, protect the airway, prevent hypoxia and hyperpyrexia, intermittent positive pressure ventilation (IPPV) and complete muscle paralysis with d-tubocurarine was used for a total of 6 h. The girl made a complete recovery, the first patient to do so using this plan of action.

Tracheal intubation of outpatients with and without muscle relaxants.

PURPOSE: To compare intubating conditions and postoperative myalgias in outpatients after intubation with propofol/alfentanil compared with propofol/alfentanil/succinylcholine with and without precurarisation with d-tubocurarine. METHODS: 144 ASA I-II ambulatory patients for dental extraction under anesthesia were studied. Subjects received either 3 mg d-tubocurarine (Group II) or saline (Groups I, III) i.v. prior to induction of anesthesia with 20 microg x kg(-1) alfentanil and 2.5 mg x kg(-1) propofol followed by 1.5 mg x kg(-1) succinylcholine (II and III) or saline 0.9% (I) for muscle relaxation. The ease of airway management and the postoperative incidence, severity and distribution of muscle pains were examined. RESULTS: Intubation was successful in all patients and there were no differences in jaw mobility, ease of bag-mask ventilation, visualization of the vocal cords or cord position. Limb movement was more common during intubation in Group I (37.5%) than in Group III (8.3%) or Group II (2%), P < 0.05. At home, VAS scores for myalgia were higher in Group III than in Group I and II. Neck myalgia was more common in Group II (72%) than in Groups II (44%) and I (41%), P < 0.05. Myalgias were also more common in Group III patients (P < 0.05). CONCLUSION: Acceptable intubating conditions were achieved with propofol and alfentanil alone. Succinylcholine reduced limb movement during intubation but was associated with postoperative myalgias for up to five days. Precurarisation with tubocurarine reduced the severity of succinylcholine myalgia.

Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?

Administration of alfentanil followed by propofol intravenously (IV) without neuromuscular blockade for induction of anesthesia provides adequate conditions for tracheal intubation. Other hypnotic drugs have not been thoroughly investigated in this regard. Accordingly, 140 ASA physical status I and II premedicated outpatients were randomly assigned to one of seven groups (n = 20/group). Patients in Groups I-VI received alfentanil 40 microg/kg followed by etomidate 0.3 mg/kg, propofol 2 mg/kg, or thiopental 4 mg/kg. One half of these patients (Groups II, IV, VI) also received lidocaine 1 mg/kg IV prior to the administration of the above drugs. Patients in group VII received d-tubocurarine 3 mg followed by thiopental 4 mg/kg and succinylcholine 1 mg/kg. Ninety seconds after induction, laryngoscopy and endotracheal intubation were attempted and graded. Patients in Group V (alfentanil/thiopental) were significantly (P < 0.05) more likely to have a clinically unacceptable response to intubation (55%) (e.g., vigorous coughing, purposeful movement, or requirement for succinylcholine to complete intubation) compared with patients who received propofol (35%) or etomidate (20%). Alfentanil/etomidate yielded intubation conditions comparable to those achieved with alfentanil/propofol and d-tubocurarine/thiopental/succinylcholine. Lidocaine appeared to improve intubating conditions, although this improvement did not reach statistical significance. The results suggest that healthy, premedicated patients with favorable airway anatomy who have received alfentanil 40 microg/kg can be reliably tracheally intubated 90 s after administration of propofol 2 mg/kg or etomidate 0.3 mg/kg.

Clindamycin-induced neuromuscular blockade.

The purpose of this article is to report the case of a patient who developed prolonged neuromuscular block after a large dose of clindamycin (2400 mg). A 58-yr-old, 65 kg woman with severe rheumatoid arthritis was admitted for wrist arthrodesis. After d-tubocurarine (3 mg) and fentanyl (1.5 micrograms.kg-1), anaesthesia was induced with thiopentone (4 mg.kg-1) followed by succinylcholine (1.5 mg.kg-1) and was maintained with N2O in O2 and isoflurane (0.75-1.0% end tidal) and ventilation was controlled. No further neuromuscular relaxants were given although full return of neuromuscular activity in response to train-of-four and 100 Hz tetanic stimulation was observed after succinylcholine. An overdose of clindamycin (2400 mg, instead of the intended 600 mg) was given i.v. soon after the start of surgery. At the end of surgery, 75 min later, the patient made no attempt at spontaneous ventilation, was unresponsive to painful stimuli and naloxone (0.2 mg i.v.) was ineffective. Controlled ventilation was continued in the Recovery Room where neuromuscular testing showed a train-of-four ratio of 0.27 which improved to only 0.47 five minutes after calcium chloride (1.5 mg.kg-1 i.v.), and to 0.62 after edrophonium (20 mg) and neostigmine (2 mg). Nine hours later the patient began to cough, the TOF had returned to 1.0 and two hours later the trachea was extubated and spontaneous ventilation was resumed. Large doses of clindamycin can induce profound, long-lasting neuromuscular blockade in the absence of non-depolarizing relaxants and after full recovery from succinylcholine has been demonstrated.

Phenytoin reduces suxamethonium-induced myalgia.

A prospective, randomised trial was undertaken in 60 healthy adults to determine the efficacy of intravenously administered phenytoin in doses of 5 mg.kg-1 for the prevention of suxamethonium-induced fasciculations, a rise in serum K+ and myalgia. This was compared with tubocurarine pretreatment and no pretreatment (control group). Phenytoin pretreatment significantly reduced myalgia from 45% (nine patients) in the control group to 10% (two patients) (p less than 0.05). It also decreased the duration and mean intensity of fasciculations. Incidentally, phenytoin was also found to decrease significantly mean serum Na+ levels (p less than 0.001) both at 5 and 20 min after administration. Tubocurarine pretreatment (3 mg) resulted in a significant decrease in fasciculations, but myalgia, which occurred in five patients, remained the same. No significant correlation was found between muscle fasciculations, postoperative myalgia and K+ changes, but patients with myalgia had a significant decrease in mean serum Na+ levels at 5 and 20 min after suxamethonium (p less than 0.01).

Muscle pains and biochemical changes following suxamethonium administration after six pretreatment regimens.

The incidence of muscle pains and changes in serum concentrations of potassium, calcium and creatine kinase following suxamethonium were investigated after no pretreatment or pretreatment with intravenous tubocurarine 0.05 mg.kg-1, intravenous chlorpromazine 0.1 mg.kg-1, alphatocopherol (vitamin E) 600 mg in three divided doses orally, aspirin 600 mg orally or intravenous calcium chloride 5 mg.kg-1 in groups of 20 patients each. The incidence of myalgia was reduced significantly by tubocurarine, chlorpromazine and alphatocopherol. However, the increase in creatine kinase was attenuated only in the groups of patients who received tubocurarine and chlorpromazine. The changes in serum potassium and calcium concentrations were within acceptable limits. The intubating conditions were not as good in the patients who received tubocurarine as in the other groups. Effectiveness of chlorpromazine in preventing both the myalgia and the biochemical changes suggests the involvement of phospholipases in the pathogenesis of suxamethonium-induced muscle damage.

A defasciculating dose of d-tubocurarine causes resistance to succinylcholine.

Forty-four patients, ASA physical status I or II, undergoing thiamylal, fentanyl, N2O/O2 anaesthesia were studied to determine the dose-response to succinylcholine (Sch) without prior defasciculation (24 pt - Group 1), or three minutes following d-tubocurarine (dTC), 0.043 mg.kg-1 (20 pt - Group 2). The individual log dose-logit response curve for each patient was determined using a cumulative dose plus infusion technique and integrated EMG monitoring of the first dorsal interosseous muscle. The mean (+/- SEM) ED50, ED90 and ED95 values for Sch in Group 1 were 0.13 +/- 0.01, 0.19 +/- 0.01 and 0.22 +- 0.01 mg.kg-1, and in Group 2 were 0.16 +/- 0.01, 0.25 +/- 0.01 and 0.29 +/- 0.02 mg.kg-1, respectively. The mean ED values in Group 2 were significantly greater than the equivalent values in Group 1 (P less than 0.05). Compared with values in Group 1, ED values in Group 2 represented mean increases of 23, 32, and 32 per cent, respectively. These pharmacodynamic data indicate that the dose of Sch needs to be increased by 32 per cent following a defasciculating dose of dTC 3 mg.70 kg-1 (0.043 mg.kg-1).

Effects of precurarisation on suxamethonium-induced postoperative myalgia during the first trimester of pregnancy.

Two hundred and fifty women undergoing termination of pregnancy during the first trimester under general anaesthesia were studied to determine the effects of precurarisation on suxamethonium-induced postoperative myalgia and on the need for postoperative analgesics after suxamethonium. Either alcuronium (0.03 mg/kg), atracurium (0.04 mg/kg), tubocurarine (0.05 mg/kg), vecuronium (0.01 mg/kg) or saline was administered in a double-blind manner 4 min before giving suxamethonium. An additional 50 patients were studied who received isoflurane rather than precurarisation and suxamethonium. Every pretreatment prevented fasciculations better than did saline (P less than 0.001). In the saline group, 92% of patients had fasciculations and in the other groups this ranged from 8 to 32%, respectively. On the first postoperative day, 76% of the patients in the saline group had myalgia while myalgia was manifested in 28, 54 and 34% of patients given alcuronium, tubocurarine or vecuronium, respectively (P less than 0.05). Atracurium failed in this effect with 62% having myalgia. In the isoflurane group, none of the patients complained of myalgia on the first postoperative morning. The need for analgesics was less (P less than 0.005) in the isoflurane group (8%) and in the pretreatment groups (18-27%) than in the saline group (42%). It is concluded that precurarisation with tubocurarine, vecuronium or, most effectively, with alcuronium but not with atracurium decreases suxamethonium-induced postoperative myalgia and seems to be necessary also during the first trimester of pregnancy.

Role of d-tubocurarine in suppression of cardiovascular responses following endotracheal intubation.

The role of d-tubocurarine in blocking the hypertensive tachycardiac response following laryngoscopy and endotracheal intubation was evaluated in 45 female patients aged 20-40 yr. The patients belonging to grade I (of American Society of Anaesthesiologists) and undergoing elective surgical procedures under general anaesthesia were allocated in 3 equal groups. Patients in the 3 groups received 1.5 mg/kg succinylcholine, 0.6 mg/kg d-tubocurarine and 0.12 mg/kg pancuronium bromide, respectively for intubation. There were no dysrhythmias in any of the groups following endotracheal intubation. There was significant (P less than 0.01) fall in blood pressure following induction prior to intubation in all the three groups. Maximum fall was noted in group II (23.53 +/- 7.21 mmHg in mean arterial pressure). Following endotracheal intubation, blood pressure and heart rate increased significantly (P less than 0.01) in all 3 groups. Maximum increase was observed in group I (26.4 +/- 4.95 mmHg in mean arterial pressure and 19.07 +/- 6.54 beats/min in heart rate). Blood pressure and heart rate increases in groups II and III were comparable. Our findings indicate that hypotension produced by d-tubocurarine through ganglion blockade is not effective in attenuating the cardiovascular responses following endotracheal intubation. It is also possible that increased cardiovascular response following endotracheal intubation may not be due to sympathetic ganglion stimulation.

[Respiratory failure after thymectomy in myasthenia gravis: evaluation of preoperative influencing factors and preventive managements against postoperative respiratory dysfunction].

Postoperative respiratory function was evaluated in 94 patients with myasthenia gravis after thymectomy. Preoperative clinical and pulmonary function data were submitted to statistical analyses. The duration of respiratory support and intratracheal intubation time were significantly correlated to % vital capacity, the clinical stage of myasthenia gravis, and the clinical stage of thymoma. Statistical analyses proved that anticholinesterase drugs taken in immediate postoperative period contributed to the improvement of postoperative respiratory function, and non-depolarizing muscle relaxants, i.e. d-tubocurarine which had been considered to be contraindicated in myasthenia gravis was found to be beneficial immediately after the operation in patients with severely deteriorated respiratory function preoperatively.

Effectiveness of atracurium in preventing succinylcholine myalgia.

A comparison was made of the incidence of postoperative myalgia (POM) and fasciculations when atracurium (ATR) or d-Tubocurarine (DTC) was given prior to succinylcholine (SDC) for facilitation of tracheal intubation. The subjects were 44 ASA physical status I or II outpatient females undergoing laparoscopy. They were assigned to one of three groups: Group 1 received 0.025 mg/kg ATR; Group 2 received 0.05 mg/kg DTC, and Group 3 received saline (NS). Thiopental was administered one minute and 45 seconds after pretreatment. Three minutes after pretreatment, SDC 1.5 mg/kg was given, and fasciculations were recorded on a scale of 0-3. The patients were questioned one and three days postoperatively about POM and their responses recorded using a scale of 0-3. Fasciculations occurred in 79% of patients given saline, in 46% of those receiving ATR and in 12% of those given DTC. Eighty-five percent of ATR patients were free of POM on postoperative day one. The corresponding figures for DTC and NS were 59% and 43%, respectively. The difference between ATR and NS achieved statistical significance, leading to the conclusion that DTC is a better defasciculant than ATR. DTC was, however, not significantly better than NS in the prevention of POM. Findings suggest that ATR may be the drug of choice for the prevention of POM.