Alzheimer's disease (AD) is an immutable neurodegenerative disease featured by the two hallmark brain pathologies that are the extracellular amyloid s (As) and intraneuronal tau protein. People carrying the APOE4 allele are at high risk of AD concerning the ones carrying the e3 allele, while the e2 allele abates risk. ApoE isoforms exert a central role in controlling the transport of brain lipid, neuronal signaling, mitochondrial function, glucose metabolism, and neuroinflammation. Regardless of widespread indispensable studies, the appropriate function of APOE in AD etiology stays ambiguous. Existing proof recommends that the disparate outcomes of ApoE isoforms on Aβ accretion and clearance have a distinct function in AD pathogenesis. ApoE-lipoproteins combine diverse cell-surface receptors to transport lipids and moreover to lipophilic Aβ peptide, that is believed to begin deadly events that generate neurodegeneration in the AD. ApoE has great influence in tau pathogenesis, tau-mediated neurodegeneration, and neuroinflammation, as well as α-synucleinopathy, lipid metabolism, and synaptic plasticity despite the presence of Aβ pathology. ApoE4 shows the deleterious effect for AD while the lack of ApoE4 is defensive. Therapeutic strategies primarily depend on APOE suggest to lessen the noxious effects of ApoE4 and reestablish the protective aptitudes of ApoE. This appraisal represents the critical interactions of APOE and AD pathology, existing facts on ApoE levels in the central nervous system (CNS), and the credible active stratagems for AD therapy by aiming ApoE. This review also highlighted utmost ApoE targeting therapeutic tactics that are crucial for controlling Alzheimer's pathogenesis.

APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meet clinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD.

Combination Drug Therapy for the Management of Alzheimer’s Disease

pdf/circadian-and-sleep-dysfunction-in-alzheimer-s-disease-tuv3jf32xd.pdf

Circadian and sleep dysfunction in Alzheimer's disease.

Neurodegenerative disorders (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis have various disease-specific causal factors and pathological features. A very common characteristic of NDs is oxidative stress (OS), which takes place due to the elevated generation of reactive oxygen species during the progression of NDs. Furthermore, the pathological condition of NDs including an increased level of protein aggregates can further lead to chronic inflammation because of the microglial activation. Carotenoids (CTs) are naturally occurring pigments that play a significant role in averting brain disorders. More than 750 CTs are present in nature, and they are widely available in plants, microorganisms, and animals. CTs are accountable for the red, yellow, and orange pigments in several animals and plants, and these colors usually indicate various types of CTs. CTs exert various bioactive properties because of its characteristic structure, including anti-inflammatory and antioxidant properties. Due to the protective properties of CTs, levels of CTs in the human body have been markedly linked with the prevention and treatment of multiple diseases including NDs. In this review, we have summarized the relationship between OS, neuroinflammation, and NDs. In addition, we have also particularly focused on the antioxidants and anti-inflammatory properties of CTs in the management of NDs. 

Therapeutic promise of carotenoids as antioxidants and anti-inflammatory agents in neurodegenerative disorders.

In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction and decline. Acetylcholinesterase (AChE) remains a highly feasible target for the symptomatic improvement of AD. Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AChE for myasthenia gravis had effectively proven that AChE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEIs) have been continued to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs which are under development and their respective mechanisms of actions.

Cholinesterase Inhibitors for Alzheimer's Disease: Multitargeting Strategy Based on Anti-Alzheimer's Drugs Repositioning.

Hyperglycemia exerts toxic effects on the pancreatic β-cells. This study investigated the hypothesis that the antidiabetic drugs glibenclamide and metformin, in combination with hydroxychloroquine (HCQ) offer additional protection for the pancreas against oxidative stress and produce hepatoprotective effect in alloxan-induced diabetic rats. Diabetes was induced in male Long-Evans rats by a single dose of alloxan (120 mg/kg; i.p.). Different groups of diabetic animals were treated with glibenclamide (10 mg/70 kg, i.p.), metformin (850 mg/70 kg, i.p.), HCQ (300 mg/70 kg, i.p.) and combination of both glibenclamide and metformin with HCQ, separately for a period of 28 days. Diabetic rats had significantly elevated levels of serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT), while catalase (CAT) and superoxide dismutase (SOD) activity were significantly reduced. Glibenclamide and metformin produced no significant effects on antioxidant enzymes but both showed significant (p<0.05) result in reducing SGOT and SGPT level in diabetic rats. In contrast, the combination of glibenclamide or metformin with HCQ showed better effect on up-regulation of CAT and SOD activity and down-regulation of SGOT and SGPT activity in comparison with the antidiabetic drug alone. These findings suggest that, HCQ potentiates the effect of glibenclamide and metformin to protect pancreas against oxidative stress and produce hepatoprotective effect in diabetic rats. Bangladesh Pharmaceutical Journal 18 (1): 72-77, 2015

/pdf/antidiabetics-in-combination-with-hydroxychloroquine-improve-jce0awpmt2.pdf

Antidiabetics in combination with hydroxychloroquine improve antioxidant and hepatoprotective activities in alloxan-induced diabetic rats

Objective: To determine the feasibility, safety, efficacy and short term outcome of using new surgical technique for repair of anterior urethral stricture Introduction: The conventional approach for management of long segment anterior urethral stricture is a two stage Johansons repair along with the use of free grafts if required. Now a days the preferred management of urethral stricture involving long segments of anterior urethra is dorsal only oral mucosa Augmentation urethroplasty which requires circumferential mobilization of urthera that might cause ischaemia of urethra in addition of chordee. For that we adopted new technique (kulkarnis) of dorsolateral onlay buccal mucosal graft one sided anterior urethroplasty in which only unilateral urethral mobilization done through perineal approach. Materials and Methods: A total of 50 patients underwent urethroplasty for anterior urethral strictures using dorsolateral onlay BMG from April 2010 to December 2012 at NIKDU, JBFH, BSMMU and BDM Hospital. We selected 16 to 70 years old male (mean age 39 years) underwent a one-sided dorsolateral oral mucosal graft urethroplasty. The mean (range) stricture length was 6.5 (4.5-9) cm in patients with single bulbar urethral involvement and 10.5 (8.5–15.0) cm in patients with panurethral strictures. Free graft was taken from oral mucosa either lower lip or cheeks. Follow up was done by uroflowmetry at 3rd week, after removal of penile catheter and repeat at 3rd and at 6th month. In addition to uroflometry – RGU & MCU was done at 3rd month and Urethrocystoscopy was done at 6th month follow up. The results were classified into the following outcomes. Success was defined as a maximum flow rate of >10 ml/sec, normal RGU, and/or urethroscopy (with a 19 Fr. sheath). Failure was defined as the presence of obstructive urinary tract symptoms, Qmax <10 ml/sec, stricture diagnosed on retrograde urethrogram/ urethroscopy, and the need for any postoperative urethral intervention. Result: The overall follow up was 12-30 months. Of the 50 patients 45 (90%) had a successful outcome and 5(12%) had failure. 3 failure treated by OIU and 2 by meatal dilatation. No significant donor site defect was observed. Conclusions: Dorsolateral OMG onlay urethroplasty is feasible, tolerable, and safe for any length of anterior urethral stricture with good short term success. Bangladesh J. Urol. 2013; 16(2): 37-42

Outcome of Dorsolateral OnlAy OMG Urethroplasty for Anterior Urethral Stricture

Background Neurological disorders represent one of the most prominent causes of morbidity and mortality that adversely affect the lifestyle of patients and a major percentage of these diseases exists in developing countries. Purpose The objective of this study was to examine the prevalence and prescription pattern for outpatients with neurological disorders in Bangladesh. Methods The study was conducted on 1,684 patients in 6 hospitals (National Institute of Neurosciences and Hospital, Dhaka Medical College and Hospital, Bangabandhu Sheikh Mujib Medical University, Shaheed Suhrawardy Medical College, Sir Salimullah Medical College, and Apollo Hospitals Dhaka) of the Dhaka City from March 2014 to June 2015. Data were collected through a predesigned questionnaire from the patients that contain information about gender, age, marital status, occupation, residential status, affected disease, self-medicated medicines, and prescribed medicines. Results Out of 1,684 patients, 28.38% patients were aged 51-60 years and male, 57.19% predominance. The study exposed headache and migraine for 29.75% patients, followed by stroke for 23.93% patients and seizure for 7.07% patients. Genetic reason for the neurological disorders was seen only among 12.35% patients. In this study, 16.98% patients had been affected by neurological disorders for more than 2 years and 19% of patients for less than 6 months. Most extensively prescribed medicines were multivitamins and multiminerals used by 17.89% of patients followed by nonsteroidal anti-inflammatory drugs and other analgesic by 14.84%; afterwards antiulcerants were used by 12.62%, subsequently anticoagulants were used by 11.61% followed by antihyperlipidemic medicines by 10.26% and antiepileptic drugs by 8.08% of patients. The crucial reasons for the selection of prescribed medicines were the confidence that patients had with the physician's prescribed medicines, which was shown for 40.97% patients and knowledge of the medicines was reported for 35.04% patients. The period of prescribed medicine usage was 1-3 months for 39.73% patients and 3-6 months for 29.16% patients. The patient's compliance for prescribed medicines was satisfactory for 34.56% patients, good for 28.15% patients, and side effects were reported for 23.22% patients. Conclusion In Bangladesh, it is not surprising to note that neurological diseases are more prevalent than other different diseases among different age groups and genders. Headache and migraine, stroke and seizure are most frequently encountered neurological disorders here. Treatment procedure of these disorders is not quite suitable due to the anomalies of health care management systems. Appropriate management of the health care system, especially the placement of hospital and community pharmacy can overcome the existing inconsistencies as well as increase the knowledge, awareness, and perception of the patients about health and neurological disorders.

/pdf/spectrum-of-disease-and-prescription-pattern-for-outpatients-1zhnq5jih1.pdf

Spectrum of Disease and Prescription Pattern for Outpatients with Neurological Disorders: An Empirical Pilot Study in Bangladesh.

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Antidiabetics in combination with hydroxychloroquine improve antioxidant and hepatoprotective activities in alloxan-induced diabetic rats

Outcome of Dorsolateral OnlAy OMG Urethroplasty for Anterior Urethral Stricture

Spectrum of Disease and Prescription Pattern for Outpatients with Neurological Disorders: An Empirical Pilot Study in Bangladesh.