Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease

1. Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.

2. Here, our aim was to study the interaction between BChE and fluoxetine.

3. Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the V_m, K_m, k_cat and k_cat/K_m values were found to be 20.59?±?0.36?U mg^?1 protein, 194?±?14?µM, 1.3?×?10⁸?s^?1 and 6.7?×?10⁵?µM^?1s^?1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC₅₀ value of 104?µM and a K_i value of 36.3?±?4.7?µM.

4. Overall, both the low K_i value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.

     

The preventive role of wheat germ oil against sertraline‐induced testicular damage in male albino rats

Sertraline is an antidepressant medication used extensively in the therapy of depression. The present investigation was intended to estimate the actual protective role of wheat germ oil on sertraline‐caused testicular injury in albino rats. Sertraline (human therapeutic dose, 15.63 mg/kg) was orally administrated to rats for 28 successive days. Sertraline‐administered rats were concurrently supplemented with wheat germ oil (human therapeutic dose, 68.75 mg/kg) for 28 successive days. Sertraline administration induced an elevation in testicular DNA damage and acute testicular damage illustrated by the histopathological alterations including marked degeneration and necrosis of germ cells lining seminiferous tubules, as well as interstitial oedema, congestion of interstitial blood vessel. Wheat germ oil administration potentially mitigated the histopathological alterations of sertraline‐administered rats. Lipid peroxidation, oxidative stress biomarker, showed a significant elevation in testicular tissue of sertraline‐administered rats. Furthermore, glutathione content and catalase activity were decreased in testicular tissue of sertraline‐administered rats. Serum testosterone level was elevated in sertraline‐administered rats. Wheat germ oil significantly reduced lipid peroxidation of testicular tissue and improved the antioxidant defences. Finally, wheat germ oil has a preventive role against testicular damage induced by sertraline in rats probably via its potential to prevent reactive oxygen species.     

The effect of topical parasympathomimetics on corneal epithelial healing in rabbits

Corneal wound healing is an important process that involves interaction between the different corneal cell layers, growth factors, and environmental conditions. More powerful therapies for the treatment of delayed epithelial wound healing are still being proposed. The objective of this study is to investigate the effects of the direct-acting parasympathomimetic agents on the healing process of corneal epithelium in rabbits. The corneal epithelial defects, 10 mm in diameter, were created in 32 eyes of 16 island rabbits by combination of chemical debridement using n-heptanol and mechanical scraping. Animals were randomly divided into four groups. Groups 1, 2 and 3 were treatment groups; each group consisted of four rabbits (8 eyes). The animals in these groups were treated with topical 1% acetylcholine (ACh), 2% pilocarpine, and 0.75% carbachol drops respectively. In group 4, four rabbits (8 eyes) were used as control group and left for spontaneous healing. The length and area of the defect were measured at days 3,6,9,12,15,18 and 22 after wounding. Areas of the photographically documented fluorescein-stained defects were measured by planimetry. All eyes in the treatment groups reepithelialized completely. The duration for reepithelialization in Groups 1 and 2 was 12 days, and 18 days for Group 3. In the control group reepithelialization occurred within 22 days. The healing rates of corneal epithelium were statistically significantly faster in all treatment groups as compared with the control group at all times (p=0.0001 to 0.0279). Although the rates of wound healing varied, all of the parasympathomimetics used in the present study were found to facilitate wound healing. Our results indicate that direct-acting cholinergic agents, especially ACh and pilocarpine, may have an important therapeutic role in the treatment of severe corneal epithelial injury.     

Peripheral seventh nerve palsy due to transorbital intracranial penetrating pontine injury

The case of a child injured by a knitting needle penetrating transorbitally and intracranially, resulting in carotid cavernous fistula and pontine injury, is reported. After receiving medical and endovascular treatment, the only remaining abnormal neurological manifestation was right peripheral facial nerve palsy. The clinical sequences of events and the demonstration of a pontine lesion leading to peripheral facial palsy are presented. Facial nuclear injury with a penetrating trauma is an extremely rare condition. It is important to identify the anatomical regions injured in penetrating traumas. The lesions must be identified by computerized tomography, magnetic resonance imaging, clinical and laboratory investigation.     

Objective and early diagnosis of chylous fistula in the postoperative period.

OBJECTIVE: The study goal was to evaluate whether quantitative analysis of neck drainage contents is an important parameter of objective and early diagnosis of chylous fistula (CF) in the postoperative period. STUDY DESIGN AND SETTING: We prospectively evaluated 103 consecutive neck dissections during a 2-year period at a tertiary academic referral center. Six of the patients (5.8%) had CF. The data obtained from the patients with CF were matched with normal data obtained from patients without CF. RESULTS: A statistically significant difference was found between total drainage volumes of the patients with and those without CF (P < 0.05). In almost all patients with CF, drainage levels of triglycerides and cholesterol on postoperative day 1 were higher than serum levels. The difference between the drainage levels of triglycerides and cholesterol of the patients with and without CF was highly significant (P < 0.001). CONCLUSIONS: Serum and drainage levels of triglycerides and cholesterol on postoperative day 1 can be used as objective and early predictive parameters of CF.     

Effect of valproic acid on withdrawal therapy in patients with overuse of chronic daily headache medications.

Discontinuation of medication is the treatment of choice for patients with chronic daily headache (CDH) who overuse their medications. This treatment may be difficult due to increased headache severity observed in patients immediately after withdrawal. We retrospectively evaluated the efficacy of valproic acid therapy in 66 patients with overuse of CDH medication during withdrawal therapy. Patients were all withdrawn from medications and valproic acid started at 250 mg or 500 mg daily. Forty-two (63.6%) patients had decreased headache severity, including 27.3% objective responses in the first week. At the last visit in the 12th week, 50 patients were headache-free and only one patient had persistent headache. Fifteen patients withdrew from therapy due to side effects and lost to follow-up within this timeframe. Thus, low dose valproic acid appears to be safe and effective in the management of withdrawal therapy.     

Preliminary findings for preemptive analgesia with inhaled morphine: efficacy in septoplasty and septorhinoplasty cases.

OBJECTIVE: The aim of this study was to assess the efficacy of inhaled morphine for preemptive analgesia in patients who undergo septoplasty or septorhinoplasty. STUDY PLAN AND METHODS: Eighty ASA I-II patients scheduled for septoplasty or septorhinoplasty were recruited and randomly divided into 2 groups that received different treatments 10 minutes prior to induction. The preemptive analgesia group (Group P, n = 40) received 65 mug kg(-1) morphine sulphate (a 3-mL volume) via an oral nebulizer, and the control group (Group C, n = 40) received 3 mL 0.9% sodium chloride (physiological saline) via the same type of nebulizer. Blood pressure, oxygen saturation, heart rate, time to first requirement for analgesia, and occurrence of nausea/vomiting were recorded. RESULTS: There were no significant differences between Groups P and C with respect to age, body weight, sex distribution, or duration of surgery. There was also no significant difference between the group frequencies of postoperative nausea/vomiting. The time to first requirement for analgesia was significantly longer in Group P than Group C. CONCLUSION: The results of this preliminary study suggest that a single dose of inhaled morphine administered preemptively prior to septoplasty or septorhinoplasty provides effective postoperative analgesia. EBM rating: B-3b.     

Low molecular weight heparin fractions as an alternative therapy in heparin-induced thrombocytopenia

Eight patients with a delayed-onset heparin-induced thrombocytopenia, with thrombotic complications requiring immediate anticoagulation in 7 of them, were given low molecular weight heparin (LMWH) fractions as alternative therapy. This treatment led to normalization of platelet count within 3-5 days in 6 patients with clinical recovery in 5. In 2 patients, thrombocytopenia persisted despite LMWH therapy. In vitro platelet aggregation tests performed in all patients gave evidence of a relationship between the presence (or absence) of a LMWH-dependent platelet-aggregating factor in the patients' plasma and the persistence (or correction) of the thrombocytopenia with LMWH therapy. Although positive in vitro tests may not necessarily be associated with thrombocytopenia, in vitro testing may prove to be a useful guide before giving LMWH fractions as an alternative therapy in patients with heparin-induced thrombocytopenia requiring immediate anticoagulation.