A Comprehensive Systematic Review of the Latest Management Strategies for Hepatorenal Syndrome: A Complicated Syndrome to Tackle.

Hepatorenal syndrome (HRS), defined by the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduced renal blood flow and glomerular filtration rate. It is diagnosed with reduced kidney function confirming the absence of intrinsic kidney disease, such as hematuria or proteinuria. HRS is potentially reversible with liver transplantation or vasoconstrictor drugs. The condition carries a poor prognosis with high mortality rates, particularly in patients with advanced cirrhosis. The latest management for HRS involves a combination of pharmacological and non-pharmacological interventions, aiming to improve renal function and reduce the risk of mortality. Pharmacological treatments include vasoconstrictors, such as terlipressin and midodrine, and albumin infusion, which have been shown to improve renal function and reduce mortality in HRS patients. Non-pharmacological interventions, including invasive procedures such as transjugular intrahepatic portosystemic shunt (TIPS), plasma exchange, liver transplantation, and renal replacement therapy, may also be considered. Though TIPS has been shown to be effective in improving renal function in HRS patients, liver transplantation remains at the top of the consideration for the treatment of end-stage liver disease and HRS. Recent studies have placed importance on early recognition and prompt intervention in HRS patients, as delaying treatment can result in poorer outcomes. Although there are numerous reviews that summarize various aspects of HRS, the recent advancements in the management and pathophysiology of HRS are still insufficient. Therefore, in this review, we summarized a brief pathophysiology and highlighted recent advancements in the management of HRS with a quick review of the latest articles.

Matrix type transdermal therapeutic systems of glibenclamide: Formulation, ex vivo and in vivo characterization.

Matrix type transdermal therapeutic systems (TTS) of glibenclamide were formulated using polymers Eudragit RL 100, ethyl cellulose, PVP K-30, and polyvinyl acetate, and citral was used as the penetration enhancer. The polymer films were formulated with Eudragit RL 100 and PVP K-30 in different ratios and subsequently subjected to ex vivo studies (drug permeation through rat skin) followed by interaction studies, skin irritation studies, accelerated stability analysis, and in vivo studies (determination of blood glucose level in rabbits). The drug content of the formulations was found to be 99.1-99.2%. The cumulative percentages of drug permeated through rat skin from the three selected formulations in 48 h were 95.3%, 98.8%, and 99%, respectively. A plot between cumulative percent of drug permeated and square root of time exhibited linear curves, which suggests the Higuchian matrix mechanism of drug release. The formulation containing Eudragit RL 100 and PVP K-30 showed better improvement in hypoglycemic activity in rabbits (56.2-60.8% reduction in blood glucose level, p < 0.05). There were fewer fluctuations in blood glucose level as compared to oral therapy due to controlled release of the active pharmaceutical ingredient, and no interaction was found between the drug and excipients of the formulation. Accelerated stability analysis showed that the formulation was stable up to 5.5 years, with negligible skin irritation. The formulation precluded severe hypoglycemic reactions (side effect of sulfonylureas) and was effective for management of diabetes mellitus up to 48 h, with a single TTS.

Pharmacokinetics of a losartan potassium released from a transdermal therapeutic system for the treatment of hypertension.

Monolithic transdermal therapeutic systems (TTS) were developed for sustained antihypertensive effect of losartan potassium using the polymers Eudragit E 100 and polyvinyl pyrrolidone VA 64. The developed formulations (polymeric films) were evaluated for physical characteristics, ex vivo (histopathology) and in vivo (pharmacokinetic studies). Pharmacokinetic parameters, such as C(max), t(max), and AUC were estimated. The transdermal formulation in the present study was found to enhance the relative bioavailability of losartan potassium by 2.2 times with reference to an oral delivery. The increased bioavailability might be due to elimination of hepatic first pass metabolism. Thus, the transdermal formulation F3E with polymeric composition of Eudragit E 100 and polyvinyl pyrrolidone VA 64 (5:3) was found to provide prolonged steady state concentrations of losartan potassium with minimal fluctuations and improved bioavailability.

Status of herbal medicines in the treatment of diabetes: a review.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia caused by defective insulin secretion, resistance to insulin action, or a combination of both. DM has reached epidemic proportions in the US and more recently worldwide. The morbidity and mortality associated with diabetes is anticipated to account for a substantial proportion of health care expenditures. Although there are several drug treatments currently available, the need for new herbal agents for treatment of diabetes are required. The treatment goals for patients with diabetes have evolved significantly over the last 80 years, from preventing imminent mortality, to alleviating symptoms, to the now recognized objective of normalization or near normalization of glucose levels with the intent of forestalling diabetic complications. The present review stated several findings from an extensive literature search of natural plants that have been assessed for the anti diabetic activity over past 80 years. An attempt has been made to summarize the information in order to highlight those chemical entities and plant species which are of worthy for further investigation as leads to the drug developments. Over 100 plant species from wide range of families containing various chemical classes of compounds have been cited here which are worthy for the researchers and the industrialist concerned to diabetes.

Investigation of a nanoemulsion as vehicle for transdermal delivery of amlodipine.

A novel oil-in-water nanoemulsion system for transdermal delivery of amlodipine was studied. Pseudoternary phase diagrams were developed and various nanoemulsion formulations were prepared using oleic acid (oil phase), Tween 20 (surfactant) and Transcutol P (co-surfactant). The effects of content of oleic acid and surfactant/co-surfactant ratio (S(mix)) on skin permeation of amlodipine were evaluated through excised rat skin using a Franz diffusion cell. Highest permeation rate and permeability coefficient was found at low oil and S(mix) concentration. On increasing the same, fluxes were further decreased, probably due to increased globule size and decreased thermodynamic activity of drug at higher surfactant mixture concentration. The optimum nanoemulsion formulation consisted of 2% oil (oleic acid), 20% surfactant (Tween 20), 10% co-surfactant (S(mix) 2 : 1) and water exhibited highest skin permeation rate of 49.681 +/- 1.98 microg/cm/h and permeability coefficient of 0.497 +/- 0.056 cm2/h. The optimized nanoemulsion was characterized for globules size, morphology, viscosity, and pH. The result suggests that nanoemulsions are potential vehicles for improved transdermal delivery of amlodipine.

Preparation and in vitro characterization of diltiazem hydrochloride loaded alginate microspheres.

The main objective of the present study was to improve bioavailability of diltiazem hydrochloride and decrease the frequency of dosage form administration by increasing the encapsulation efficiency of the drug, residence time of the dosage form at the site of absorption and sustained release of the drug from the delivery system. Alginate microspheres containing diltiazem hydrochloride were prepared by the emulsification-internal gelation method by using barium carbonate as a cross-linking agent with improved encapsulation efficiency. The effect of various factors (concentration of alginate and barium chloride) on the drug loading efficiency and in vitro release were investigated. Fourier transform infrared spectroscopy (FT-IR) analysis confirmed the absence of any drug polymer interaction. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) pattern showed that the crystallinity of the drug was decreased in the dosage forms. The in vitro drug release mechanism was non-Fickian type controlled by swelling and relaxation of polymer. The stability studies of drug-loaded microspheres showed that the drug was stable at different storage conditions.

Antipsoriatic microemulsion gel formulations for topical drug delivery of babchi oil (Psoralea corylifolia).

The aim of this study was to investigate and evaluate a microemulsion gel-based system of babchi oil (Psoralea corylifolia) for the treatment of psoriasis, which could provide improved permeation of the drug through the skin and increased patient compliance. Babchi oil is used because its chief constituent psoralen is a photoactive furocoumarin that binds to DNA when exposed to UV light to form photoproducts with pyrimidine base. This action inhibits DNA synthesis and causes decrease in cell proliferation. Moreover, babchi oil, in addition to providing psoralen, also acts as an oily phase for microemulsion system. The presence of surfactant and cosurfactant increases the permeation. On the basis of qualitative and quantitative estimation of all eight brands of babchi oil, Bakuchi Tail was selected for microemulsion formulation. Microemulsions were prepared by aqueous phase-titration method. Pseudoternary phase diagrams were constructed for the identification of microemulsion existence zones. Prepared microemulsions were subjected to different thermodynamic stability tests and characterized for droplet size, viscosity and refractive index. In vitro skin permeation of babchi oil through rat abdominal skin was determined by the Franz diffusion cell. The in vitro skin permeation profile of formulation F2, which consisted of 1.67% v/v of babchi oil, 8.33% v/v of oleic acid, S(mix) 55% v/v of Tween 80 Transcutol-P (S/Co ratio 1:1) and 35% v/v of distilled water, was significant when compared with other microemulsion formulations (p < 0.05). Formulation F2 was converted into microemulsion gel by adding 1% Carbopol-940 and coded as MGF2. Formulation MGF2 was selected for its in vivo antiinflammatory effects determined by footpad edema. The results suggested that microemulsion gel is a potential vehicle for improved topical delivery of psoralen and that microemulsion gels are potential vehicles for improved topical delivery of babchi oil.

Radiolabeling and evaluation of alginate blend-isoniazid microspheres by 99mTc for the treatment of tuberculosis in rabbit model.

Isoniazid (INH) is the first line anti-tubercular drug that is widely used in the treatment of tuberculosis. (99m)Tc-alginate-INH microsphere scintigraphy has been demonstrated to be a useful noninvasive imaging technique for microsphere deposits located in different organs of the rabbits. The aim of this study was to develop an improved formulation, to validate the formulation for long-time retention, as well as to assess radiotracer stability by novel quality control methods. Our study reports the labeling and evaluation of alginate blends-INH microspheres. The incorporation efficiency of optimized formulation was 89% w/w. The in vitro release study was carried out in simulated intestinal fluid at pH 7.4, and it was found that the formulation delivered the drug for 36 h. The labeling efficiency of (99m)Tc-alginate blends-INH microspheres was seen at various pH (i.e. pH ranging from 5 to 7.5) and different concentration of stannous chloride dehydrate (i.e. 25-200 microg) and it was concluded that 96% labeling efficiency was achieved in case of pH 7.5 and 60 microg stannous chloride. The stability study was carried out in saline and serum and it was found that the complex was highly stable in vitro and in vivo. The blood clearance in rabbits showed bi-exponential pattern depicting that 50% of activity washed out at 2 h with t(1/2(Fast)) was 2.1 h and t(1/2(Slow)) was 12.5 h. Bio-distribution was normal and the experimental mice showed major accumulation of the radiolabeled formulation in liver, intestine, lungs and kidneys, indicating hepatobiliary and renal route of excretion. The distribution of the drugs to the lung was showing its efficiency in the treatment of tuberculosis.

Gelrite microgels for sustained oral drug delivery-formulation and evaluation.

Gelrite is an ion-activated polymer prepared by partial acetylation of gellan gum, an exogeneous polysaccharide present in Pseudomonas elodea. Its unique cation-dependent gelling property at 33 degrees C has been exploited for the formulation of in situ gelling hydrogels for ophthalmic and oral drug delivery. Gelrite based oral formulations are known to sustain the drug levels at acidic pH due to the formation of 3D-lattice by cross-linking of uronic acid groups with cations. An extrusion method for formation of microspheres has been reported for Gelrite. The method cannot be successfully applied for encapsulation of hydrophilic moieties and has thus been modified in the present study. The microparticles prepared were optimized for various encapsulation variables such as particle size, shape, drug entrapment efficiency and in vitro drug release. A maximum of 41.87 +/- 0.2 % drug loading was obtained for the improved method. The drug release was found to be sustained in acidic medium (50% in SGF pH 1.2) for a period of 4 hours while burst release was observed in SIF pH 7.4. The work thus, presents a simplified microencapsulation method for hydrophilic drugs with higher entrapment efficiency for Gelrite, taking rifampicin as the model drug.

Transdermal therapeutic system of enalapril maleate using piperidine as penetration enhancer.

The aim of this work was to formulate transdermal therapeutic system (TTS) of an antihypertensive drug, enalapril maleate (EM) using a new penetration enhancer, piperidine hydrochloride (PH), belonging to the class of Dihydropyridines. The TTS of EM was prepared by solvent evaporation technique using polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w PH as penetration enhancer. The TTS was evaluated for in-vitro drug release using paddle over disc method and ex-vivo skin permeation using modified Keshary and Chein diffusion cell. The interaction studies were carried out by comparing the results of assay, UV and TLC analysis for pure drug and medicated and TTS formulation. Skin irritation potential of TTS was assessed by visual examination of treated rat skin. Stability studies were conducted according to ICH guidelines at a temperature of 40+/-0.5 degrees C and 75+/-5% RH. The optimized formulation was evaluated for preclinical bioavailability and antihypertensive efficacy using albino rat model. The optimized formulation provided 87.3% drug release in-vitro and a flux of 380 microg/cm(2)/hr over a period of 48 hours. No chemical interaction was found between the drug and excipients and there were no signs of skin irritation on application of patch. The optimized formulation was stable with a tentative shelf life of two years. Significant fall in BP (p<0.001) was observed in experimental hypertensive rats which was maintained for 2 days. There was 3 fold improvement in bioavailability with TTS vis-à-vis marketed tablet (AUC(0 to t) : 1253.9 ng.h/ml vs. 422.88 ng.h/ml). These preclinicial studies indicate the feasibility of matrix-type TTS of EM for 2 day management of hypertension. Further studies on human beings are warranted to establish clinical utility of the above TTS.

Reconstituted powder for suspension of antitubercular drugs formulated as microspheres for pediatric use.

The aim of the present investigation was to develop a novel dosage form of rifampicin and isoniazid to minimize degradation of rifampicin in acidic medium, to modulate the release of rifampicin in the stomach and isoniazid in the intestine, and to provide pediatric compliance. Rifampicin slowly diffuses out through this hydrogel matrix, thereby sustaining its release (50.08%). The release of isoniazid was thus very low in an acidic environment, i.e. simulated gastric fluid (SGF) pH 1.2 (18.98%), while in simulated intestinal fluid (SIF) pH 7.4 the release was sustained and prolonged (76.98%). Good results were obtained for a period of 36 h in SIF pH 7.4 with isoniazid-alginate microspheres. The drug content was calculated on the basis of the drug entrapment efficiency of the individual microsphere formulation (gelatin, 82.32% and sodium alginate blends, 89.31%). Results revealed that an optimized formulation had a sedimentation volume of 0.4. This optimized formulation was found to be stable. Degradation of isoniazid was faster than that of rifampicin. The degradation rate constant at 25°C was found to be 1.9286 × 10(-4) (day-1), so the formulation was predicted to have a shelf life of 1.518 years.

Comparative bioavailability of metoprolol tartrate after oral and transdermal administration in healthy male volunteers.

BACKGROUND AND OBJECTIVE: Transdermal drug delivery systems (TDDSs) of metoprolol tartrate have been previously prepared and evaluated in vitro and in vivo in an animal model. This study compares the bioavailability of metoprolol tartrate from a TDDS with that from a conventional marketed tablet in healthy human volunteers. METHODS: This was an open-label, balanced randomised, two-treatment, two-period crossover study with a washout period of 1 week. Volunteers were randomised (by means of a SAS software-generated randomisation schedule) to have a TDDS applied to their chest for 48 hours or to receive a 100 mg conventional marketed tablet of metoprolol tartrate in period I. In period II, the volunteers received the other dosage form. Blood samples were collected through an indwelling cannula placed in the forearm vein of each subject. Metoprolol tartrate concentrations were quantified in plasma samples by a validated high-performance liquid chromatography method. RESULTS: A 3-fold improvement in bioavailability was observed with the TDDS form over oral therapy as shown by the extent of absorption indicated by the mean area under the concentration-time curve from time zero to time t values for tablets (451.98 ng x h/mL) and TDDS (1552.66 ng x h/mL). Although the maximum plasma concentration was higher for the tablet form than the TDDS (77.67 +/- 23.33 vs 51.16 +/- 16.61 ng/mL), the variable absorption profile, which is a characteristic feature of oral therapy, was quite evident. Plasma metoprolol tartrate concentrations plummeted to therapeutically ineffective concentrations as early as 8 hours following oral administration. CONCLUSION: The TDDS developed in our laboratory produced therapeutically effective plasma concentrations for up to 48 hours, with a minimum of 26.09 ng/mL and a maximum of 76.70 ng/mL, which is in good agreement with the therapeutic range (20-100 ng/mL) of metoprolol tartrate. It could be concluded that the TDDS meets the intended goal of 2-day management of hypertension with application of a single patch, obviating the inconvenience of frequent administration and thus improving patient compliance.

Liposomal drug delivery systems: an update review.

The discovery of liposome or lipid vesicle emerged from self forming enclosed lipid bi-layer upon hydration; liposome drug delivery systems have played a significant role in formulation of potent drug to improve therapeutics. Recently the liposome formulations are targeted to reduce toxicity and increase accumulation at the target site. There are several new methods of liposome preparation based on lipid drug interaction and liposome disposition mechanism including the inhibition of rapid clearance of liposome by controlling particle size, charge and surface hydration. Most clinical applications of liposomal drug delivery are targeting to tissue with or without expression of target recognition molecules on lipid membrane. The liposomes are characterized with respect to physical, chemical and biological parameters. The sizing of liposome is also critical parameter which helps characterize the liposome which is usually performed by sequential extrusion at relatively low pressure through polycarbonate membrane (PCM). This mode of drug delivery lends more safety and efficacy to administration of several classes of drugs like antiviral, antifungal, antimicrobial, vaccines, anti-tubercular drugs and gene therapeutics. Present applications of the liposomes are in the immunology, dermatology, vaccine adjuvant, eye disorders, brain targeting, infective disease and in tumour therapy. The new developments in this field are the specific binding properties of a drug-carrying liposome to a target cell such as a tumor cell and specific molecules in the body (antibodies, proteins, peptides etc.); stealth liposomes which are especially being used as carriers for hydrophilic (water soluble) anticancer drugs like doxorubicin, mitoxantrone; and bisphosphonate-liposome mediated depletion of macrophages. This review would be a help to the researchers working in the area of liposomal drug delivery.

Chitosan phthalate microspheres for oral delivery of insulin: preparation, characterization, and in vitro evaluation.

Chitosan phthalate polymer was synthesized and its microspheres were prepared by emulsion phase separation technique. The characterization of microspheres was determined by means of FTIR spectroscopy, electron microscopy, particle size, and zeta potential. The insulin was loaded to the microspheres by passive absorption technique. The peptic and tryptic enzymes degradation of insulin in microspheres was investigated. The in vitro release behavior of the microspheres was investigated under different pH conditions (pH 2.0 and pH 7.4). The degree of phthalate substitution in the synthesized polymer was 20%. The prepared microspheres were spherical with an average diameter 46.34 micro m. The insulin-loading capacity was 62%. Chitosan phthalate microspheres protect the insulin from gastric enzymes degradation that may enhance the oral stability of insulin. The encapsulated insulin was quickly released in a phosphate buffer saline (pH 7.4), whereas a small amount of insulin was released under acidic condition (0.1N HCl; pH 2.0) because under acidic conditions, carboxylic groups present in the system exist in nonionized form and are poorly hydrophilic. However, in alkaline conditions, it exists in ionized form and is considerably hydrophilic. The results suggest that chitosan phthalate microspheres may be used as a potential carrier for oral insulin delivery.

Alginate microspheres of isoniazid for oral sustained drug delivery.

In the present study, spherical microspheres able to prolong the release of INH were produced by a modified emulsification method, using sodium alginate as the hydrophilic carrier. The shape and surface characteristics were determined by scanning electron microscopy using gold sputter technique. Particle sizes of both placebo and drug-loaded formulations were measured by SEM and the particle size distribution was determined by an optical microscope. The physical state of the drug in the formulation was determined by differential scanning calorimetry (DSC). The release profiles of INH from microspheres were examined in simulated gastric fluid (SGF pH 1.2) and simulated intestinal fluid (SIF pH 7.4). Gamma-scintigraphic studies were carried out to determine the location of microspheres on oral administration and the extent of transit through the gastrointestinal tract (GIT). The microspheres had a smoother surface and were found to be discreet and spherical in shape. The particles were heterogeneous with the maximum particles of an average size of 3.719mum. Results indicated that the mean particle size of the microspheres increased with an increase in the concentration of polymer and the cross-linker as well as the cross-linking time. The entrapment efficiency was found to be in the range of 40-91%. Concentration of the cross-linker up to 7.5% caused increase in the entrapment efficiency and the extent of drug release. Optimized isoniazid-alginate microspheres were found to possess good bioadhesion (72.25+/-1.015%). The bioadhesive property of the particles resulted in prolonged retention in the small intestine. Microspheres could be observed in the intestinal lumen at 4h and were detectable in the intestine 24h post-oral administration, although the percent radioactivity had significantly decreased (t(1/2) of (99m)Tc=4-5h). Increased drug loading (91%) was observed for the optimized formulation suggesting the efficiency of the method. Nearly 26% of INH was released in SGF pH 1.2 in 6h and 71.25% in SIF pH 7.4 in 30h. No significant drug-polymer interactions were observed in FT-IR studies. Dissolution and gamma-scintigraphy studies have shown promising results proving the utility of the formulation for enteric drug delivery.

Fabrication and evaluation of polymeric films for transdermal delivery of pinacidil.

The objective of the present work was to fabricate Eudragit RL 100-polyvinyl acetate films and evaluate their potential for transdermal drug delivery in a quest to develop a suitable transdermal therapeutic system for pinacidil. The polymeric films (composed of Eudragit RL100 and polyvinyl acetate in 2:8, 4:6, 6:4, 8:2 ratios in films P-1, P-2, P-3, P-4 respectively, together with 5% w/w of pinacidil and 5% w/w of dibutylphthalate in all the films) were cast on a glass substrate and evaluated for physicochemical parameters viz. thickness, weight, folding endurance (a measure of fragility), percent elongation at break (a measure of flexibility), drug content uniformity, water absorption capacity, moisture vapour transmission, drug-polymer interaction, in vitro drug release and skin permeation profiles. The films were also evaluated for appearance, smoothness and transparency. The film finally selected was assessed for its skin irritation potential, and its stability on storage under accelerated temperature and humidity conditions. The values of thickness, weight, folding endurance, percent elongation at break, percentage water absorbed, moisture vapour transmission, cumulative amount of drug released and permeated for different films were in the following order: P-1 < P-2 < P-3 < P-4. The results suggest that Eudragit RL 100, a freely permeable polymer, has a major influence on the physicochemical profile of the films. The higher the quantity of Eudragit RL100 in the film, the better its strength and flexibility as well as its higher drug release and skin permeation potential. The final optimized film (with a composition of Eudragit RL 100: polyvinyl acetate: pinacidil monohydrate: dibutylphthalate in 8.0:2.0:0.5:0.5 ratio) was found to be the best in terms of drug release (cumulative amount of drug released in 48 h was 96.09%) and skin permeation (permeability coefficient, 0.0164 cm/h). There was no apparent drug-polymer interaction in the films. The optimized film was seemingly free of potentially hazardous skin irritation. The film was found to be stable and intact at ambient temperature and humidity conditions. The films hold promise for the development of a matrix type transdermal therapeutic system for pinacidil.