Revealing analgesic and anxiolytic potentials of synthetic benzimidazole analogues: An in-vivo and in-silico study.

Certain drugs have potential to affect and alter individual's behavior. On the other hand, pain is a complex phenomenon with various treatment options; analgesic medicines are the primary source. Therefore, this study was based on examining some of the benzimidazole analogues for their analgesic as well as behavioral potential following Tail immersion test and Open field test respectively. In addition, molecular docking was performed to find the interaction of these compounds with the active site using AutoDock Vina which was further visualized through Discovery Studio Visualizer. It was seen that the cyano-methyl benzimidazole derivatives (CMB1-CMB3) showed relief in pain as compared to benzimidazole derivatives (BI1-BI3), CMB2 demonstrated highly potent analgesic effect. Likewise, all structures except BI1 displayed increase locomotion during open field test and can be offered as anxiolytic compounds. Almost all derivatives showed improve binding energies for the tested proteins where the high analgesic action of CMB2 might be correlated to its high binding affinity and interaction at µOR. It was also noticed that all structures except BI showed possible binding interaction with GABAA receptor and hence possessed anxiolytic like potential. Thus, this study offered benzimidazole analogues for further drug development of analgesic and anxiolytic like compounds.

Pharmacological effects of oral vitamin D intake on pulmonary function Test and Interleukin-17 in adult asthmatic patients in Karachi.

Vitamin D is an anti-inflammatory and immuno-modulatory secosteroid. Previous studies showed strong link between childhood and adult onset asthma with vitamin D. Interleukin 17 is an inflammatory cytokine and plays a major role in the worsening of asthma. The aim of this study is to compare the effects of serum vitamin D on serum IL 17 and pulmonary function test (FVC, FEV1, FEV1/FVC) before and after oral vitamin D supplementation. Fifty severe asthmatic patients were selected from out patient department of Chest Medicine Ward, Jinnah post graduate medical center, Karachi. Spirometry was performed by vitalograph compact. Baseline values were as follows: serum vitamin D=13.19±2.37ng/ml, IL-17=20.70±2.13ng/ml, FVC=2.31±0.40L, FEV1=1.40±0.28L,FEV1/FVC=60.15±4.61%. Subjects were given 1000 IU of oral vitamin D capsule per day for six weeks. After this trial all values were found as serum vitamin D=19.03±1.26ng/ml (p<0.001), IL 17=15.40ng/ml (p<0.001), FVC=2.90±0.60 L (p<0.001), FEV1=2.01±0.10L (p<0.001), FEV1/FVC=63.79% ±1.45 (p<0.001). It may be concluded that improvement in serum vitamin D levels improves the status of lung functions, decreases the airway inflammation and hence may decrease the asthma severity.

Inhibition of diet-restriction-induced behavioral deficits by tryptophan administration in rats.

Diet has a great impact on brain health and function. It plays an important role to improve and control a number of psychiatric disorders such as depression, anxiety, hyperactivity and behavioral impulsivity. Anorexia Nervosa (AN) is one of the psychiatric disorder which is associated with diet. In AN, patients show extreme dieting, weight loss, hyperactivity, depression/anxiety, self-control and behavioral impulsivity. Previous studies showed that during diet restriction, tryptophan decreases serotonin (5-hydroxytryptamine; 5-HT) metabolism in the brain due to its less availability and contributes psychiatric problems associated with AN. The present study is designed to investigate the effects of tryptophan administration on 5-HT metabolism in diet-restricted rats. Tryptophan at a dose of 50 or 100mg/kg was given orally to respective freely fed (FF) or diet restricted (DR) animals daily for five weeks. Behavioral activities were also monitored weekly. The results show significant effect (p<0.05) on behavior in activity box, open field and in light/dark transition test by tryptophan administration in diet-restricted rats. This may be associated with the increased in serum tryptophan and brain 5-HT metabolism. Therefore, it is concluded that diet-restriction-induced behavioral changes might be reverted back with the administration of tryptophan and may be helpful to improve psychological problems in AN.

Effect of Leflunomide-Metal Complexes on ROS, TNF, and Brain Indolamines in Comparison with Anti-Depressants as Adjunct Therapy in Rheumatoid Arthritic Model.

Leflunomide is an isoxazole immunomodulating drug used to treat rheumatoid arthritis (RA). It is adopted as a metal-containing molecule to proceed with saturated salts of essential and detected metals; it amends the pharmacokinetic and pharmacodynamics activity of leflunomide to provide [M(Lef)4]X2-type complexes. Earlier it has been reported that after forming complexes with metals, leflunomide anti-arthritic activity was significantly altered in an acute arthritic model. In the present study, we evaluated the possible modification in anti-arthritic activities of leflunomide-metal complexes (Mg+2, Ca+2, Fe+2, Zn+2) with and without an anti-depressant drug, i.e., fluoxetine (10 mg/kg) in a chronic AIA model. Rats (n = 5) were administered with 0.1 mL of CFA into the right hind paw while treated groups received leflunomide and its metal complexes orally (3.2 mg/kg) for 24 days. On the final day of experiment, rats were sacrificed; a specific rat immunoassay ELISA kit was used to assess TNF-α in serum samples and read at 450 nm; a tissue sample of a paw was homogenized in a phosphate buffer using DCFH-DA dye for binding to assess ROS. A rat's brain sample was homogenized and evaluated for tryptophan, serotonin (5-HT), and HIAA by RP-HPLC with EC detector. The overall TNF production was altered in treated rats. In addition, a decreased ROS was observed in all categories, except lef+Mg+2 group. Moreover, depletion in the brain indolamine levels were found in treated groups; an upraised level of these indolamines was observed when fluoxetine was added. It is concluded that metals affect leflunomide activity on complexation and simultaneous administration of fluoxetine cope up with the depression in arthritic-induced rats.

Role of tryptophan in the pathogenesis of hepatic encephalopathy.

OBJECTIVE: To monitor serum levels of total and free tyryptophan in various hepatic dysregulations. METHOD: The study was conducted on 36 adult patients. All were suffering from acute or chronic liver diseases such as hepatitis (n = 12), cirrhosis (n = 12) and Hepatic Encephalopathy (HE) (n = 12). Patients of all age groups and both genders were included. Serum levels of Tyryptophan (TRP) were measured by HPLC-EC. Albumin and bilirubin were analyzed by kit method (Merck). RESULTS: The serum levels of total TRP (p < 0.01) was found in all patients. Free TRP significantly (p < 0.01) increased only in HE. Patients with hepatitis and cirrhosis did not show significant change in serum free TRP. The Albumin levels significantly decreased in hepatitis, cirrhosis and in HE (p < 0.01). All patients exhibited hypoalbuminaemia (p < 0.01). CONCLUSIONS: The results suggest that an increased ratio of free to bound TRP enhances its availability to the brain, which in turn increases 5-HT synthesis thus precipitating encephalopathy.

A case of multiple myeloma coexisting with primary hyperparathyroidism and review of the literature.

Hypercalcemia is a common medical problem with an estimated prevalence of 15% among hospitalized patients. Multiple myeloma (MM) and primary hyperparathyroidism (PHPT) are among the most common causes of hypercalcemia but coexistence of both pathologic processes in a patient is an extremely rare phenomenon. In this paper we have discussed a patient presenting with this rare phenomenon. We have also provided a comprehensive review of the scientific literature published on codiagnosis of MM and PHPT.

Unusual case of osteomyelitis and discitis in a drug user with a background of chronic back pain: do not miss the serious etiologies.

Chronic back pain is a common presenting complaint that is frequently encountered by clinicians. The challenge for clinicians is identifying the relatively few patients with a significant probability of a more serious problem that requires further evaluation. Such individuals require further evaluation for possible occult malignancy, infection, or fracture. We present a case of a 50-year-old male with a past medical history of chronic back pain and IV drug abuse who presented with acute back pain and in whom a diagnosis of vertebral osteomyelitis was missed during multiple visits to the emergency room.

Determination of tryptophan in raw materials, rat brain and human plasma by RP-HPLC technique.

This paper describes tryptophan (TRP) estimation in raw human plasma and rat brain by reversed-phase high-performance liquid chromatography (RP-HPLC). Estimation was carried out on a Purospher STAR C18 column using water-acetonitrile (90:10 v/v, at pH 2.7) mixture at a rate of 1.5 mL/min as mobile phase. Eluents were monitored at 273 nm by an ultraviolet detector. The method was linear (R(2) > 0.999), precise (intra-day and inter-day precision <2%) in the range of 0.25-20 µg/mL. The detection and quantification limits were 0.0144 µg/mL and 0.0437 µg/mL, respectively. In human plasma, Day 1 and Day 2 precision were 0.054-2.29% and 1.66-3.7%; whereas precisions in rat brain were 1.23-2.3% and 0.677-4.2%, respectively. The method was applied to study TRP level in human smokers and in arthritic rat brain. An efficient RP-HPLC method was developed for TRP determination that worked for clinical and research purposes.