Exploring protein stabilized multiple emulsion with permeation enhancer for oral delivery of insulin.

In present study, we have developed W/O/W microemulsion (ME) containing piperine (PiP) as a permeation enhancer and albumin (Alb) serving as a stabilizer for oral delivery of insulin (INS). The resultant formulation, ME(INS)-PiP-Alb exhibited droplet size of 3.35 ± 0.25 µm along with polydispersity index (PDI) of 0.30 ± 0.10. The formulation process employed for developing ME(INS)-PiP-Alb showed no effect on INS's chemical and conformational stability. Further, ME(INS)-PiP-Alb was able to maintain desired attributes (size & PDI) along with INS stability in simulated gastrointestinal fluids. Also, ME(INS)-PiP-Alb rendered higher protection to INS in presence of pepsin and trypsin than ME(INS)-PiP. In qualitative Caco-2 cell uptake, INS loaded ME's showed higher uptake in comparison to free INS. Whereas, in permeability studies ME(INS)-PiP-Alb showed ~4 and ~1.5-fold enhanced permeation than free INS and ME(INS) without PiP groups respectively. Also, in ex vivo intestinal permeation studies similar fold increment in permeation were observed. Interestingly, the pharmacodynamic studies revealed ~3.2-fold higher hypoglycemic effect in animals treated with ME(INS)-PiP-Alb in comparison to ME(INS)-PiP. Similarly, the pharmacokinetic studies also revealed ~1.6 fold higher AUC for ME(INS)-PiP-Alb than ME(INS)-PiP. Thus, in vivo results suggested that Alb as a stabilizer can assist in improving the hypoglycemic effect of the developed ME with PiP. Hence, this strategy can also be extrapolated for delivering other bio-macromolecules orally.

Significance of the antiangiogenic mechanisms of thalidomide in the therapy of diabetic retinopathy.

Diabetic retinopathy is an ocular complication associated with the chronic endocrine disorder of diabetes mellitus. Angiogenesis is adjudged as a prime modulatory event in this complication. The formation of new blood vessels on the pre-existing vasculature gives rise to an abundance of anatomical and physiological alterations which ultimately results in vision loss. The drastic consequences of this complication prompt the obligation of developing effective therapies for its cure. The existing therapy mainly includes destructive techniques such as laser photocoagulation. Owing to the various drawbacks associated with this technique, there is a need to develop alternative therapies which could halt the progression of diabetic retinopathy without causing considerable damage to the retinal cells. One such possible alternative treatment being researched upon is the antiangiogenic therapy. Since angiogenesis is a critical event during the progression of this disorder, targeting this event may perhaps prove effective in its treatment. Amongst several antiangiogenic agents, thalidomide holds a reputable position due to its effectiveness in terminating angiogenesis during various pathological conditions. This review focuses on the diverse molecular mechanisms proposed to explain the antiangiogenic properties of thalidomide and their applicability in diabetic retinopathy.

Implications of the endogenous PPAR-gamma ligand, 15-deoxy-delta-12, 14-prostaglandin J2, in diabetic retinopathy.

Diabetic retinopathy, a common secondary complication of diabetes mellitus, involves extensive damage to the retinal microvasculature. Retina, being a susceptible target, is highly prone to hyperglycemia-induced molecular damages. PPAR receptor, chiefly gamma subtype, mediates numerous responses related to glucose metabolism and hence is utilized, through its agonism, for the restoration of normal insulin sensitivity and glucose homeostasis in the body. Although a number of synthetic PPAR-gamma receptor agonists have been developed and are being employed for treatment purposes, the role of its endogenous ligand in the prevention of diabetic retinopathy is poorly acknowledged. Activation of PPAR-gamma receptor, via endogenous agents, provides a natural defensive shield against various hyperglycemia-induced pathological conditions. Although the biological levels of 15d-PGJ2 (an endogenous agonist of PPAR-gamma receptor) are found to be below the concentration required to trigger PPAR-gamma-mediated actions, employment of several advanced methods for the exogenous administration of this ligand might provide a beneficial option. Besides, 15d-PGJ2-induced defense is better than any of the newly developed alternative therapies, such as anti-inflammatory, anti-angiogenic or anti-apoptotic agents, of diabetic retinopathy, since it singularly provides, virtually, a complete protection package against all these pathological eventualities. Therefore, the physiology of this endogenous PPAR-gamma ligand might, possibly, be exploited to a great extent for the development of prophylactic agents, in order to restrict the progression of diabetic retinopathy.

Role of leukotrienes in diabetic retinopathy.

The pathophysiology of diabetic retinopathy is highly complex and encompasses the detrimental roles of numerous factors/mediators in inducing various molecular pathological alterations. Although the roles of many inflammatory mediators, involved in the progression of this complication, have been thoroughly researched and studied, the part played by leukotrienes remains widely neglected. This review focuses on leukotrienes-induced mediation and aggravation of the pathological pathways, such as inflammation, oxidative stress and retinal angiogenesis, responsible for exhibition of various characteristic events including leukostasis, macular edema, retinal neovascularization and vitreous hemorrhages, hence, marking the advent of diabetic retinopathy. Acknowledging these roles, it might be possible to potentially utilize leukotrienes antagonists for suppressing or reducing the intensity of the mentioned pathological alterations. Hence, leukotrienes antagonists may act as an effective adjuvant therapy either along with other developing novel therapies (such as anti-VEGF or anti-TNF-α therapy), or with the established conventional laser photocoagulation treatment, to provide additional symptomatic relief or, possibly prevent the progression of diabetic retinopathy.

Implication of oxidative stress in progression of diabetic retinopathy.

Diabetic retinopathy, a severe sight-threatening complication of diabetes mellitus, accounts for a large number of cases of acquired, yet potentially avoidable, blindness. The principal mechanism of its pathogenesis appears to be alterations in the microvasculature of retina as the result of hyperglycemia. The elevated concentration of blood glucose is a harbinger of numerous molecular changes. These lead to various responses that result in microangiopathy. Oxidative stress, one such response, is attributed to disruption in the homeostasis of free radical production during the various vital processes such as the electron transport chain reaction and the scavenging mechanisms designed to neutralize these damaging molecules. This imbalance has been linked to the pathophysiology of diabetic retinopathy. Excessive formation of free radicals influences almost all pathways involved in normal human physiology. Thus, hyperglycemia-induced oxidative stress is one of the factors associated with biochemical changes. These changes are further responsible for the various structural and functional abnormalities seen in diabetic retinopathy.

Role of endocannabinoids in the progression of diabetic retinopathy.

In the past decades, the role of numerous factors in the pathophysiology of diabetic retinopathy has been explored, following which marked progress has been made in developing several novel therapeutic options, such as anti-vascular endothelial growth factor, anti-tumor necrosis factor-alpha and various other anti-inflammatory and anti-angiogenic agents, for the treatment of diabetic retinopathy. However, the involvement of endocannabinoid system in its pathogenesis has not been much explored. This review aims at unveiling every aspect of association of the endocannabinoid system and its interactions with various physiological and pathological pathways to induce disease progression. The various alterations induced by endocannabinoids, such as anandamide and 2-arachidonylglycerol, in retina during hyperglycaemia clearly demonstrate and verify their involvement in aggravating the pathological conditions, hence leading to the progression of diabetic retinopathy. Exploring this involvement furthermore, in greater depths, might be beneficial in acknowledging and understanding the hidden aspects of the pathogenesis of this complication even better and might provide a therapeutically beneficial alternative target to combat and restrict its progression amongst diabetic patients.

Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus is a clinical sub-type of a diversely expounded disorder, named diabetes insipidus. It is characterized by inability of the renal cells to sense and respond to the stimulus of vasopressin. Amongst its various etiologies, one of the most inevitable causes includes lithium-induced instigation. Numerous studies reported marked histological damage to the kidneys upon long-term treatment with lithium. The recent researches have hypothesized many lithium-mediated mechanisms to explain the damage and dysfunction caused in the kidneys following lithium exposure. These mechanisms, widely, intend to justify the lithium-induced electrolyte imbalance, its interference with some vital proteins and a specific steroidal hormone, obstruction caused to a certain imperative transducer pathway and the renal tubular acidification defect produced on its prolonged therapy. Thorough study of such mechanisms aids in better understanding of the role of lithium in the pathophysiology of this disorder. Hence, the ameliorated knowledge regarding disease-pathology might prove beneficial in developing therapies that aim on disrupting the various lithium-mediated pathways. Hence, this may effectively lead to the demonstration of a novel treatment for nephrogenic diabetes insipidus, which is, at present, limited to the use of diuretics which block lithium reuptake into the body.

The Apollo Accreditation Program: A web-based Joint Commission International standards compliance management tool.

Creating and implementing processes to deliver quality care in compliance with accreditation standards is a challenging task but even more daunting is sustaining these processes and systems. There is need for frequent monitoring of the gap between the expected level of care and the level of care actually delivered so as to achieve consistent level of care. The Apollo Accreditation Program (AAP) was implemented as a web-based single measurable dashboard to display, measure and compare compliance levels for established standards of care in JCI accredited hospitals every quarter and resulted in an overall 15.5% improvement in compliance levels over one year.

A combined process of activated carbon adsorption, ion exchange resin treatment and membrane concentration for recovery of dissolved organics in pre-hydrolysis liquor of the kraft-based dissolving pulp production process.

To recover dissolved organics in pre-hydrolysis liquor (PHL) of the kraft-based dissolving pulp production process, a new combined process concept of sequential steps of activated carbon adsorption, ion exchange resin treatment, and membrane concentration, was proposed. The removal of lignin in the PHL was achieved in the activated carbon adsorption step, which also facilitates the subsequent operations, such as the membrane filtration and ion exchange resin treatment. The ion exchange resin treatment resulted in the removal/concentration of acetic acid, which opens the door for acetic acid recovery. The membrane filtration is to recover/concentrate the dissolved sugars. The combined process resulted in the production of PHL-based concentrate with relatively high concentration of hemicellulosic sugars, i.e., 22.13%.