Advances in oral transmucosal drug delivery

Original article can be found at : http://sciencedirect.com/ Copyright ElsevierThe successful delivery of drugs across the oral mucosa represents a continuing challenge, as well as a great opportunity. Oral transmucosal delivery, especially buccal and sublingual delivery, has progressed far beyond the use of traditional dosage forms with novel approaches emerging continuously. This review highlights the physiological challenges as well as the advances and opportunities for buccal/sublingual drug delivery. Particular attention is given to new approaches which can extend dosage form retention time or can be engineered to deliver complex molecules such as proteins and peptides. The review will also discuss the physiology and local environment of the oral cavity in vivo and how this relates to the performance of transmucosal delivery systems.Peer reviewe

Pulmonary renal syndrome: treatment of acute renal failure secondary to double positive goodpasture syndrome

This is a case of a 34 year old female who presented with lower epigastric pain, flank pain and hematuria. Her symptoms started two days after being treated on Trimethoprim+Sulfamethoxazole for urinary tract infection. Worsening of her symptoms despite switching to Cephalexin prompted her to come to the emergency department. On admission, her creatinine was 5.3 mg/dL with potassium of 5.2 mEq/L and albuminuria of 100 mg/dL. Chest computed tomography (CT) without contrast revealed findings consistent with goodpasture disease. Biopsy of the kidney confirmed diffuse necrotizing and crescentic glomerulonephritis consistent with anti-glomerular basement membrane antibody disease. She was treated with plasmapheresis and steroids with complete resolution of symptoms at follow up

INVESTIGATING APOPTOSIS PATHWAY IN CHRONIC LYMPHOCYTIC LEUKEMIA: STROMAL INFLUENCE AND THERAPEUTIC ACTIVATION

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy. High levels of Bcl-2 and IAP family proteins are responsible for apoptotic-resistance and accumulation of mature CLL lymphocytes in bone-marrow, lymph nodes and peripheral blood. Besides pro-survival proteins, supporting stromal cells as well as soluble factors in the microenvironment of bone-marrow and lymph nodes provide survival advantage to CLL leukemic cells. Though the stromal – leukemia cell interactions has been studied extensively, in-depth-knowledge on the regulation of apoptotic pathway proteins in the context of microenvironment is still limited. To address this, the first part of our study focused on comprehensive analysis of 93 gene transcripts from seven families that are key regulators of apoptosis such as Bcl-2, IAPs, NF-kB, Caspase, TNF receptor superfamily (TNFRSF), Death Domain (DED) and Caspase Activation and Recruitment Domain (CARD) families using “real-time PCR apoptosis array-card”. While shorter incubations with supporting stromal cells induced significant changes in 22/93 transcripts including Bcl-2 (6/22), TNFRSF (5/22), DED (5/22), Caspase (2/22) family members, longer incubations induced significant changes in 8/93 transcripts from NF-kB (4/8) and Bcl-2 (2/8) family members. At the protein level, decrease or stable expressions in pro-apoptotic proteins, but a significant increase in anti-apoptotic proteins was observed. The second portion of this study involved therapeutic manipulation of executioner caspases in restoring apoptotic pathway that is frequently blocked by upstream anti-apoptotic Bcl-2 family members. A novel therapeutic approach that can potentially bypass the functional pro-survival proteins and directly activate terminal executioner procaspases to induce apoptosis was investigated. Executioner procaspase activities are blocked by zinc and zinc removal releases this inhibition. CLL primary cells express high levels of executioner procaspases-7 and -3 compared to normal lymphocytes providing a basis for therapeutic selectivity. Our studies with L14R8, a second generation PAC-1 analog [Procaspase activating compound-1 (PAC-1; Vanquish Oncology)] revealed that L14R8-induced cell death was specific to CLL cells and was independent of prognostic markers and microenvironmental factors. Mechanistically, L14R8 acted through direct activation of executioner procaspases -3 and -7 by removing labile Zinc ions. In summary, our investigations demonstrate cytotoxic actions of L14R8 and elucidate utility of this novel approach for combating CLL

Arrhythmia-related Hospitalization and Comorbid Cannabis Use Disorder: Trend Analysis in US Hospitals (2010-2014)

Objective To study the trends of arrhythmia hospitalizations with cannabis use disorders (CUDs) in terms of demographic characteristics and inpatient outcomes. Methods We used the nationwide inpatient sample (NIS) data during the post-legalization period (2010-2014) and included 570,556 arrhythmia inpatients (age, 15-54 years), and 14,426 inpatients had comorbid CUD (2.53%). We used the linear-by-linear association test and independent-sample T-test for assessing the change in hospital outcomes in inpatients with CUD. Results Arrhythmia hospitalizations with CUD increased by 31% (2010-2014). This increasing trend was seen in adults (45-54 years, P < 0.001) and was predominant in males (77.6%). Hypertension (40.6%), hyperlipidemia (17.6%), and obesity (15%) were prevalent medical comorbidities with variable trends over the five years. Among substance use disorders, tobacco (50.9%), and alcohol (31.4%) were major comorbidities with a variable trend (P = 0.003 for each). There was a 71.4% increase in the inpatient mortality rate between 2010 (0.7%) and 2014 (1.2%). The mean length of stay was three days, and the total hospitalization charges have been increasing (P < 0.001), averaging $35,812 per hospital admission. Conclusion Chronic cannabis use or abuse worsens hospitalization outcomes in arrhythmic patients, and more clinical studies are needed to study the causal association between these conditions due to the rising mortality risk

Problematic Cannabis Use and Risk of Complications in Patients with Chronic Hepatitis C

Objectives To evaluate the risk of complication in hospitalized chronic hepatitis C (CHC), patients with cannabis use disorder (CUD). Methods We conducted a retrospective study using the nationwide inpatient sample (NIS), and included 31,623 patients (age 15-54) with a primary international classification of diseases, ninth revision (ICD-9) diagnosis for CHC and grouped by co-diagnosis of CUD (1101, 3.5%). Logistic regression model adjusted for confounders was used to evaluate the odds ratio (OR) of CUD and complications during CHC hospitalization. Results Comorbid CUD was prevalent in males (73.2%), Caucasians (59.9%), and from low-income families (65.7%). The most prevalent complications in patients with CUD were ascites (44.9%), alcoholic cirrhosis (42.8%) and non-alcoholic cirrhosis (41.1%). The odds of association for hepatic encephalopathy was 2.2 times higher (95% CI 1.477-3.350) in 2.8% CHC inpatients with CUD compared to 1.2% non-CUD inpatients. Hepatic encephalopathy had higher odds of association with a male by 1.4 times (95% CI 1.094-1.760), and African American by 1.7 times (95% CI 1.293-2.259). Conclusion CUD is significantly associated with 122% increased likelihood for hepatic encephalopathy that may worsen overall hospitalization outcomes in CHC patients. Hence, we need to consider the complex relationship between CUD and CHC and manage them optimally to improve the health-related quality of life

A Possible Positive Feedback Modulation of Acetylcholine Release through the Stimulation of Alpha-7 Nicotinic Acetylcholine Receptors on Bipolar Neurons in Pig Retina

Glaucoma is associated with excitotoxicity in which increased glutamate release leads to apoptotic death of retinal ganglion cells (RGCs). Acetylcholine (ACh) has shown neuroprotection of RGCs through the stimulation of RGCs’ nicotinic acetylcholine receptors (nAChRs). The cholinergic amacrine cells are the only cells in retina which synthesize and release ACh. They get excitatory inputs from bipolar cells. The presence of α7nicotinic acetylcholine receptors (α7nAChRs) on the cholinergic amacrines, bipolar cells and RGCs is documented. Recently, stimulation of presynaptic nAChRs of cholinergic cells was shown to enhance ACh release in the rat superior cervical ganglion. Therefore, we hypothesized that α7nAChRs stimulation by tropisetron and PNU282987 (α7nAChR agonists) could induce ACh release through either direct stimulation of cholinergic amacrine α7nAChRs or indirect stimulation of bipolar α7nAChRs. For ACh release studies, pig eyes were dissected and cholinergic amacrine cells were labeled with 40μCi of 3H-choline in which the retina was flashed with light (3Hz) for 30 minutes to maximize 3H-choline uptake. Then, the eyecup was transferred to a perfusion chamber, washed for 20 minutes. 1 minute output fractions were collected into vials and prepared for liquid scintillation counting. To assess the viability of the preparation, light and kainate were applied. Light (2-3 fold increase), kainate (3-4 fold; 10-100μM), α7nAChR agonists (2-4 fold; 0.01-100nM) evoked ACh release greater than the baseline in the absence of DNQX (a glutamate receptor antagonist). In the presence of DNQX, which blocked bipolar input to cholinergic cells, α7nAChRs stimulation did not increase ACh release from baseline. Hence, the possibility of indirect input of bipolar α7nAChRs for ACh release was supported. Our results indicate that ACh release through α7nAChRs stimulation is possible and specifically the bipolar α7nAChRs release of ACh via an indirect positive feedback mechanism. During excitotoxicity, ACh released by amacrine cells, might feedback on bipolar nAChRs to increase ACh release. The neuroprotective effect of tropisetron on α7nAChRs on isolated RGCs is documented. Our study suggests that tropisetron might also protect RGCs through increased ACh release by possible indirect modulation. This study indicates the possibility of dual therapeutic targets of α7nAChRs in the retina for neuroprotection against RGC excitotoxicity

Controlled Release of Dipyridamole from Floating Matrices Prepared Using Glyceryl Behenate

Peer reviewe

Influence of Drug to Lipid Ratio and Release Modifier on Dipyridamole Release from Floating Lipid Granules

Peer reviewe

Self correcting monolithic floating matrix tablets of dipyridamole : Influence of formulation variables

The present investigation describes the influence of content of polyethylene oxide and ratio of lactose to starch 1500 on dipyridamole release from self correcting floating matrix tablets using 32 full factorial design. Tablets were evaluated for in vitro floating ability and drug release study using USP 24 type II apparatus using 0.1 N HCI at 100 rpm and temperature of 37±0.50. Multiple regression analysis and two way analysis of variance followed by Tukey test were performed for dependent variables. All formulations floated within 2 min regardless of factors studied and had total floating time of more than 12 h. It was observed that both the factors had significant influence on all dependent variable studied ( P 0.05) except the ratio of lactose to starch 1500 did not significantly contribute for Q1 ( P > 0.05). As content of polymer increased the release rate declined with increase in value of diffusion exponent giving anomalous drug release to zero order drug release ( P 0.05). It was observed that above a certain threshold level of polymer content further increase did not contribute significantly for percentage drug release. Lactose gave higher drug release with release mechanism towards zero order compared to starch 1500 which gave slower release with release mechanism towards diffusion based. Although both the factors significantly contribute for percentage drug release at different time point, the content of polymer dominated. It was observed that polymer content was a dominant controlling factor for drug release kinetics and it could be controlled by employing various blends of fillers.Peer reviewe

Synergistic effect of hydrotrope and surfactant on solubility and dissolution of atorvastatin calcium : Screening factorial design followed by ratio optimization

Date of Acceptance: 10/09/2014The present study was aimed at investigating the effect of hydrotrope and surfactant on poor solubility of atorvastatin calcium. Excipients screening followed by factorial design was performed to study effect of excipients and manufacturing methods on solubility of drug. Three independent factors (carrier, surfactant and manufacturing method) were evaluated at two levels using solubility as a dependant variable. Solid-state characterisation was performed using Fourier transform infrared spectroscopy and differential scanning calorimetry. Optimised complex were incorporated into orally disintegrating micro tablets and in vitro dissolution test was performed. Nicotinamide, Plasdone and sodium dodecyl sulphate were emerged as promising excipients from excipient screening. General regression analysis revealed only the type of carrier has significantly enhanced (P<0.05) the solubility of drug while other factors were found to be nonsignificant. Ratio optimisation trial revealed that drug to nicotinamide ratio is more critical in enhancing the solubility of drug (40 fold increases in solubility compared to pure drug) in comparison to drug-surfactant ratio; however the presence of surfactant deemed essential. Significantly higher rate and extent of dissolution was observed from solid dispersion complex and tablets compared to dissolution of pure drug (P<0.05). Study revealed hydrotrope and surfactant have synergistic effect on solubility and dissolution of atorvastatin calcium and this can be explored further.Peer reviewe