Advanced Pharmaceutical Bulletin
Volume:9 Issue: 2, Jun 2019

Microalgae are a source material in food, pharmacy, and cosmetics industries for producing various products including high-protein nutritional supplements, synthetic pharmaceuticals, and natural colors. A promising algal source for such productions is Chlorella vulgaris which contains a considerable protein content. Similar to other microalgae, its desirability is minimal nutrient requirements since they are unicellular, photosynthetic, and fast-growing microorganisms. Another propitious option to be produced by C. vulgaris is biodiesel, since it is rich in oil too. Besides, algal well thriving in presence of increased amount of carbon dioxide makes them a practicable alternative biofuel resource without some problems of the traditional ones. At the same time, C. vulgaris is also a promising source for nutraceuticals such as amino acids, vitamins, and antioxidants. This review aims to discuss the conditions need to be observed for achieving a favorable growth efficiency of the C. vulgaris, as well as targeted productions such as biomass, antioxidant, and biofuel. Additionally, different approaches to induce any specific production are also considered comprehensively.

Nanoparticles (NPs) have been found to be potential targeted and controlled release drug delivery systems. Various drugs can be loaded in the NPs to achieve targeted delivery. Chitosan NPs being biodegradable, biocompatible, less toxic and easy to prepare, are an effective and potential tool for drug delivery. Chitosan is natural biopolymer which can be easily functionalized to obtain the desired targeted results and is also approved by GRAS (Generally Recognized as Safe by the United States Food and Drug Administration [US FDA]). Various methods for preparation of chitosan NPs include, ionic cross-linking, covalent cross-linking, reverse micellar method, precipitation and emulsion-droplet coalescence method. Chitosan NPs are found to have plethora of applications in drug delivery diagnosis and other biological applications. The key applications include ocular drug delivery, per-oral delivery, pulmonary drug delivery, nasal drug delivery, mucosal drug delivery, gene delivery, buccal drug delivery, vaccine delivery, vaginal drug delivery and cancer therapy. The present review describes the formation of chitosan, synthesis of chitosan NPs and their various applications in drug delivery.

Various physiological processes involve appropriate tissue developmental process and homeostasis - the pathogenesis of several diseases connected with deregulatory apoptosis process. Apoptosis plays a crucial role in maintaining a balance between cell death and division, evasion of apoptosis results in the uncontrolled multiplication of cells leading to different diseases such as cancer. Currently, the development of apoptosis targeting anticancer drugs has gained much interest since cell death induced by apoptosis causes minimal inflammation. The understanding of complexities of apoptosis mechanism and how apoptosis is evolved by tumor cells to oppose cell death has focused research into the new strategies designed to induce apoptosis in cancer cells. This review focused on the underlying mechanism of apoptosis and the dysregulation of apoptosis modulators involved in the extrinsic and intrinsic apoptotic pathway, which include death receptors (DRs) proteins, cellular FLICE inhibitory proteins (c-FLIP), anti-apoptotic Bcl-2 proteins, inhibitors of apoptosis proteins (IAPs), tumor suppressor (p53) in cancer cells along with various current clinical approaches aimed to selectively induce apoptosis in cancer cells.

Cancer remains a complex disease with increasing global mortality and morbidity. Numerous theories have been established to understand the biological mechanism underlying cancer. One of the most renowned frameworks is the hallmark of cancer proposed by Hanahan and Weinberg that covers ten eminent characteristics of cancer: (i) genome instability and mutation, (ii) sustaining proliferative signaling, (iii) evading growth suppressor, (iv) enabling replicative immortality, (v) resisting cell death, (vi) inducing angiogenesis, (vii) activating invasion and metastasis, (viii) avoiding immune destruction, (ix) tumor-promoting inflammation, and (x) deregulating cellular energetics. These hallmarks provide a rational approach to design an anticancer therapy. In the current review, we summarized specific target molecules on each hallmark of cancer. Further, we evaluated the biological activity of several Indonesia medicinal plants against those specific targets. We explicated the anticancer and chemopreventive activities of some medicinal plants that have been used for centuries by local communities in Indonesia, including Curcuma genus, Brucea javanica, Boesenbergia pandurata, Caesalpinia sappan, and Nigella sativa. Interestingly, these medicinal plants target several hallmarks of cancer, and even Curcuma genus exhibited biological activities that target all hallmarks of cancer. Further, we also discuss several strategies to develop those medicinal plants and/or their active compounds as anticancer and chemopreventive agents.

In the current study, electrospraying was directed as a novel alternative approach to improve the physicochemical attributes of gliclazide (GLC), as a poorly water-soluble drug, by creating nanocrystalline/amorphous solid dispersions (ESSs). ESSs were formulated using Eudragit® RS100 and polyethylene glycol (PEG) 6000 as polymeric carriers at various drug: polymer ratios (i.e. 1:5 and 1:10) with different total solution concentrations of 10, 15, and 20% w/v. Morphological, physicochemical, and in-vitro release characteristics of the developed formulations were assessed. Furthermore, GLC dissolution behaviors from ESSs were fitted to various models in order to realize the drug release mechanism. Field emission scanning electron microscopy analyses revealed that the size and morphology of the ESSs were affected by the drug: polymer ratios and solution concentrations. The polymer ratio augmentation led to increase in the particle size while the solution concentration enhancement yielded in a fiber establishment. Differential scanning calorimetry and powder X-ray diffraction investigations demonstrated that the ESSs were present in an amorphous state. Furthermore, the in vitro drug release studies depicted that the samples prepared employing PEG 6000 as carrier enhanced the dissolution rate and the model that appropriately fitted the release behavior of ESSs was Weibull model, where demonstrating a Fickian diffusion as the leading release mechanism. Fourier-transform infrared spectroscopy results showed a probability of complexation or hydrogen bonding, development between GLC and the polymers in the solid state. Hence the electrospraying system avails the both nanosizing and amorphization advantages, therefore, it can be efficiently applied to formulating of ESSs of BCS Class II drugs.

We aimed to evaluate the effect of blueberry extract and microparticles (MPs) on sunscreen performance of multifunctional cosmetics. Octocrylene (OCT), benzophenone-3 (BENZ-3) and Tinosorb® M (MBBT) were employed as UV filters. An in-silico modeling was used to determine the UV filters concentrations to obtain high values of sunscreen protection factor (SPF) and UVA protection factor (UVA-PF). MBBT and blueberryloaded microparticles (MPMB+B) and MBBT-loaded microparticles (MPMBBT) were prepared by spraydrying. OCT and BENZ-3 were added in the oil phase of cosmetics. Cosmetics A and B contained MPMB+B and MPMBBT, respectively, and cosmetic C was prepared without MP. Characterization, physicochemical stability and in vitro SPF was performed. UV filters distribution in human stratum corneum (SC) for each cosmetic was performed. Anti-oxidant activity of blueberry extract was evaluated. Sunscreen combination with the highest SPF was selected for formulations. Formulations A and B maintained their rheological behavior over time, unlike formulation C. In-vitro SPFs for formulations A, B and C were 51.0, 33.7 and 49.6, respectively. We also developed and validated a method for analysis of the UV filters by HPLC/ PDA suitable for the in-vivo assay. In Tape stripping test, MBBT showed SC distribution similar for all cosmetic formulations. OCT and BENZ-3 distribution to formulation A and C was also similar. Blueberry extract showed antioxidant capacity of 16.71 μg/mL equivalent to vitamin C. Cosmetics containing MPs presented better physical stability. Blueberry increased the photoprotective capacity of the formulations and added extra benefits due to its anti-oxidant and anti-aging properties.

The objective of this study was to improve the permeability and water solubility rate of a poor water soluble drug, cyclosporine A (CsA). In order to improve the drug dissolution rate and oral bioavailability, electrospinning method was used as an approach to prepare. The fibers were evaluated for surface morphology, thermal characterizations, drug crystallinity, in vitro drug release and in vivo bioavailability studies. Scanning electron microscope (SEM) results confirmed that the fibers were in microsize range and the size of the fibers was in the rang of 0.2 to 2 micron. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (XRPD) analysis ensured that the crystalline lattice of drug were weakened or destroyed in the fibers. The drug release was 15.28%, 20.67%, and 32.84% from pure drug, fibers of formulation B, and formulation A, respectively. In vivo study results indicated that the bioavailability parameters of the optimized fiber formulation were improved and the maximum concentration (Cmax) were significantly higher for fibers (3001 ng/mL) than for pure drug (2550 ng/mL). The dissolution rate of the formulations was dependent on the nature and ratio of drug to carriers. The physicochemical properties showed that the optimized mixture of polyethylene glycol (PEG) and povidone (PVP) fibers could be an effective carrier for CsA delivery. PEG and PVP fibers improved the absolute bioavailability and drug dissolution rate with appropriate physicochemical properties.

Direct delivery of aminoglycosides to the lungs was under extensive evaluations during the last decades. Because of large particle size, low density and porous structure, large porous particles (LPPs) are versatile carriers for this purpose. In this study, poly (lactic-co-glycolic acid) (PLGA) LPPs encapsulating gentamicin sulfate were prepared and in vitro characteristics of their freeze-dried powder as a dry powder inhaler (DPI) were evaluated. To prepare PLGA LPPs, a double emulsification-solvent evaporation method was optimized and gentamicin sulfate was post-loaded in the LPPs. In vitro characteristics including morphological features, thermal behavior, aerodynamic profile and cumulative drug release were evaluated by the scanning electron microscope (SEM), differential scanning calorimetry (DSC), next-generation cascade impactor (NGI) and Franz diffusion cell respectively. The obtained results revealed that the preparation method was capable to produce spherical large homogenous highly porous particles. 94% of gentamicin sulfate released from LPPs up to 30 minutes. Mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) were 4.9 µm and 39% respectively. In this study, dry powder formulation composed of PLGA LPPs encapsulating gentamicin sulfate showed a promising in vitro behavior as a pulmonary delivery carrier. Improvements on the aerodynamic behavior and in vivo evaluations recommended for further developments.

Hydrophobic nutraceuticals are suffering from water solubility and physicochemical stabilities once administered to the body or food matrixes. The present study depicts the successful formulation of a zein-carboxymethyl cellulose (CMC) complex to stabilize a water in oil (W/O) emulsion to protect them from environmental and gastrointestinal conditions. The formulated water in oil in water (W/O/W) system was used for nanoencapsulating of hydrophobic nutraceutical, rutin, via protein-polysaccharide complexes. Zein nano particles smaller than 100 nm were produced using poly ethylene glycol (PEG 400) and Tween 80, which eliminates the use of ethanolic solutions in preparation of zein nanoparticles (ZN). CMC was then added to the ZN under magnetic stirrer to provide zein-CMC complex. A concentration of 20% CMC showed the smallest particle size (<100 nm). Rutin was dispersed in water in oil in water (W/O/W) emulsion stabilized by zein-CMC complex. A set of experiments such as encapsulation efficiency (EE%), encapsulation stability (ES%), and releasing rate of rutin were measured during 30 days of storage at 4°C. Results showed that, produced multiple emulsion prepared with lower concentrations of Tween 80 (0.5%), ethanol: PEG: water ratio of 0:80:20 showed smaller size (89.8±4.2 nm). ES% at pH values of 1.2, 6.8, and 7.4 were 86.63±6.19, 91.54±3.89, and 97.13±2.39 respectively, indicating high pH tolerability of formulated W/O/W emulsions. These findings could pave a new approach in stabilizing W/O/W emulsions for encapsulating and controlling the release of water insoluble nutraceuticals/drugs.

In the current study, attempts have been made to formulate an omega-3 fatty acid based nanostructured lipid carriers of atorvastatin (AT), for treating hyperlipidemia; and to evaluate their antihyperlipidemic activity using in vitro and in vivo studies. Omega-3 fatty acid based AT-loaded nanolipid carriers (NLC) were formulated by the melt emulsification ultrasonication technology. The prepared NLC consist of stearic acid (as solid lipid), omega-3 fatty acid (as liquid lipid), Tween 80, poloxamer 188 (surfactants) and soya-lecithin (co-surfactant). AT loaded NLCs have a particle size of 74.76 ± 4.266 nm, a zeta potential value of -36.03 ± 1.504 mV and a high drug entrapment efficiency (EE) of 86.70 % ± 0.155. The release of AT from NLCs exhibited a sustained behaviour, which made it an ideal vehicle for drug delivery. MTT assay results indicated that NLCs are compatible with L929 (mouse fibroblast) cell lines. Anti-hyperlipidemic study showed a significant reduction in LDL and TG levels in serum with the orally administered Omega-3 fatty acid based AT loaded NLCs when compared to marketed formulation. The results demonstrated that the omega-3 fatty acid based NLC has the potential to be a promising nanomedicine for the treatment of hyperlipidemia.

The purpose of the study was to develop and optimize rosiglitazone maleate mucoadhesive extended-release tablets by quality by design (QbD) approach. Based on QTPP (quality target product profile) CQAs (critical quality attributes) were identified. Failure mode and effects analysis (FMEA) method were adopted for risk assessment. Risk analysis by the evaluation of formulation and process parameters showed that the optimizing the levels of polymers could reduce high risk to achieve target profile. Drug-excipient compatibility studies by Fourier transforms infra-red and DSC studies showed that the drug was compatible with the polymers used. Design of experiment (DoE) performed by Sigma tech software, Carbopol 934P and sodium carboxymethyl cellulose (SCMC) were identified as independent variables and hardness, drug release at 12 hours and ex vivo mucoadhesion time were adopted as responses. Contour plots generated from the software were used for identification of design space. Carbopol 934P and SCMC had positive and negative effects respectively on the selected responses. Higher the concentration of Carbopol 934P and lower the concentration of SCMC mucoadhesive extended release criteria could be achieved. Drug release kinetics followed first order release with Higuchi diffusion and Fickian diffusion. Ex vivo mucoadhesion test on goat stomach mucosa indicated that adhesion time increased at higher concentrations of Carbopol 934P. Optimized formula satisfying all the required parameters was selected and evaluated. The predicted response values were in close agreement with experimental response values, confirmed by calculating standard error. It has been concluded that the application of QbD in the optimization reduced the number of trials to produce a cost-effective formula.

Evaluation of drug-excipients compatibility is an important stage during preformulation studies. In the present research, differential scanning calorimetry (DSC) at different heating rates (2.5, 10, 15°C/min) was applied for the kinetic evaluation of fluvoxamine (FLM), sertraline (SER) and doxepin (DOX) binary mixtures with lactose. Solid state kinetic parameters of the mixtures were calculated using two different thermal methods including ASTM E698 and Starink and the effect of amine type (pKa value) was investigated based on the calculated activation energies. Based on obtained results mean activation energy calculated for FLM, SER and DOX with lactose using ASTM E698 and Starink methods are equal to 335.23, 132.02 and 270.99 kJ/ mol respectively. Results showed that the probability of drug-lactose interaction is higher in the SERlactose mixture in comparison with other two antidepressant drugs which is consistent with their pKa values.

Manganese (Mn) is a neurotoxic chemical which induces a wide range of complications in the brain tissue. Impaired locomotor activity and cognitive dysfunction are associated with high brain Mn content. At the cellular level, mitochondria are potential targets for Mn toxicity. Carnosine is a dipeptide abundantly found in human brain. Several pharmacological properties including mitochondrial protecting and antioxidative effects have been attributed to carnosine. The current study aimed to evaluate the effect of carnosine treatment on Mn-induced mitochondrial dysfunction in isolated brain mitochondria. Mice brain mitochondria were isolated based on the differential centrifugation method and exposed to increasing concentrations of Mn (10 µM-10 mM). Carnosine (1 mM) was added as the protective agent. Mitochondrial indices including mitochondrial depolarization, reactive oxygen species (ROS) formation, mitochondrial dehydrogenases activity, ATP content, and mitochondrial swelling and permeabilization were assessed. Significant deterioration in mitochondrial indices were evident in Mn-exposed brain mitochondria. On the other hand, it was found that carnosine (1 mM) treatment efficiently prevented Mn-induced mitochondrial impairment. These data propose mitochondrial protection as a fundamental mechanism for the effects of carnosine against Mn toxicity. Hence, this peptide might be applicable against Mn neurotoxicity with different etiologies (e.g., in cirrhotic patients).

Aim of present work was to study cytoprotective properties of lithium pyruvate, as a prospective pharmacological agent. Pyruvate has a lot of potential benefits due to positive influence on cell metabolism. Lithium is "gold-standard" mood-stabilizer. Combination of both may lead advantages. Lithium pyruvate was tested as cytoprotector on human blood mononuclears under induced oxidative stress. Cells were obtained from healthy donors and patients with alcoholism. The detection of cell viability, apoptosis and determination of oxidative stress level were conducted by flow cytometry. Lithium pyruvate showed excellent cytoprotective properties in normal and oxidation conditions. This effect was independent from cell donor health status. It was shown on cells from healthy donors and alcoholics patients. Obtained results allow considering lithium pyruvate as potential normothymic agents (mood stabilizer) with excellent cytoprotective properties.

Contrast-induced nephropathy (CIN) is the third cause of hospital-acquired renal failure and is associated with significant morbidity and mortality. Several studies have revealed the protective role of omega-3 in prevention and treatment of some kidney injuries. This study was conducted to examine the effect of omega-3 supplementation on the markers of renal function and to evaluate its potential in the prevention of CIN in patients undergoing elective percutaneous coronary intervention (PCI). In this double-blind, randomized clinical trial, 85 eligible patients scheduled for PCI was randomly divided into omega-3 (a single 3750 mg dose of omega-3 as well as routine hydration therapy within 12 hours before PCI) or control (placebo plus routine hydration therapy) groups. Serum creatinine (SCr) and cystatin C levels were measured at baseline and 24 hours after PCI. Our results indicated that post- PCI cystatin C levels were significantly decreased in the omega-3 group compared to the control group (P < 0.001). Although less upward manner was seen in the level of 24-hour creatinine in the omega-3 group, it did not reach the significance level (P = 0.008). The positive effect of omega-3 on cystatin C levels showed that it may have a protective role in the prevention of CIN in post-PCI patients with normal kidney function. However, to better assess this effect, it is highly recommended to design future studies with higher doses and longer duration of therapy with omega-3 plus long-term follow up.

Malnutrition is highly prevalent in critically ill patients and is associated with the increased healthcare-related cost and poor patient outcomes. Identifying the factors associated with undernutrition may assist nutritional care. Therefore, this study was designed to identify factors associated with malnutrition and inadequate energy intake to improve nutritional support in intensive care unit (ICU). This prospective study was conducted on 285 random samples of ICU patients. We reported time to initiate the enteral nutrition, percent of the adequately received nutrition, and development of malnutrition during the follow-up period. Moreover, variables and clinical outcomes associated with calories underfeeding and malnutrition were reported. In 28.6% of samples, enteral feeding was initiated greater than 48 hours after ICU admission. During follow-up, 87.4% and 83.3% of patients failed to receive at least 80% of protein and energy target, and malnutrition developed in 84% of study population. Moreover, surgical and medical patients compared to trauma patients were associated with underfeeding. However, only nutrition risk in the critically ill score (NUTRIC) score ≥5 could predict malnutrition development in our study. Finally, underfeeding contributed significantly to a more mortality rate both in ICU and hospital. Our findings revealed that the majority of nutritionally high-risk patients failed to receive adequate calories and subsequently developed malnutrition. The present study added valuable information to the small body of literature about the factors affecting nutritional decline and malnutrition during the ICU stay.

The present study aimed to assess the effect of ginger (Zingiber officinale) powder supplementation on Helicobacter pylori eradication and improvement of dyspeptic symptoms in patients with H. pylori positive functional dyspepsia (FD). During this pilot study 15 patients with H. pylori positive FD received 3 g/d ginger powder as three 1-g tablets for 4-weeks. Dyspepsia symptoms were asked before and after the intervention using a questionnaire based on the Rome III criteria. H. pylori eradication was also assessed by a non-invasive stool antigen (HpSAg) test. Ginger consumption accompanied by significant H. pylori eradication rate of 53.3% (P = 0.019) and the odds ratio (95% CI) was 8 (1.07 to 357.14). Moreover, our results showed significant changes in most of the dyspepsia symptoms after ginger supplementation. According to our findings, Z. officinale can be considered as a useful complementary therapy for FD. However, due to the small number of clinical trials in this area, further welldesigned clinical trials are needed to explicitly talk about its effectiveness especially about the eradication of H. pylori.

Basically insulin is known to be secreted by β cells of the pancreas. Recently, it has also been found to be produced and expressed by intestinal epithelial cells with the help of L cells secreting glucagon like peptide 1 (GLP 1). Here, we have studied the same intestinal insulin expression property in T2D rats. Following 2 weeks of high fat diet (HFD) consumption, we have been given a single dose of streptozotocin (STZ) (35 mg/kg bw). Rats were then sacrificed after 1, 7 and 21 days. The GLP 1 analogue, liraglutide was also given to one group of diabetic rats, upto their respective durations. Intestinal cells apoptosis were checked by tunnel assay, Incretin hormones secretion and dipeptidyl peptidase 4 (DPP-IV) activity were analyzed through ELISA and immunohistochemistry was used to determine the insulin expression of intestine at different time interval during diabetes progression. As compared to 1 and 21 days, we have found minor cells apoptosis in 7 days group along with high level of GLP 1 in diabetic model. Further, these effects were enhanced by liraglutide. In response to these we have found, decreased insulin expression after 21 days and with no significant effect upto 7 days in diabetic control groups. In contrast to this, GLP-1 level and insulin expression enhances prominently after 7 days of liraglutide treatment. These results explain the self-adapting approach of intestinal cells against diabetes onset and insulin expression enhancing property of liraglutide under stressful conditions. This study should be continued in future for the development of intestinal insulin producing drugs, to control diabetes under irreversible β cells damage.

Simple and cheap diagnostic kit development is one of the important aims of pharmaceutical developers and companies focused on public health improvement. The Bacillus subtilis spore surface-display technique is a genetic engineering method that is used to develop new-generation diagnostic kits applicable for the early detection of various types of diseases. In this study, we developed a novel simple, rapid, and inexpensive diagnostic paper-based kit to detect tyrosine in urine samples of humans and animals that is applicable for home or laboratory use. The B. subtilis spore-displayed tyrosinase system developed by genetic engineering methods was used to prepare a paper-based kit to detect tyrosine in urine samples of different groups of patients (i.e., patients with diabetes, diabetes with chronic kidney disease (CKD), and chronic kidney disease) for the detection of tyrosine during the acute disease phase. To confirm the sensitivity and specificity of the kit, tyrosine was also detected in urine samples using conventional liquid chromatography/mass spectroscopy. Different concentrations of tyrosine (0.1–1 mM) were detected in urine samples based on visible changes of color from bright brownish-gray to dark brownish-gray within 1 hour. The kit could screen samples to distinguish the three groups of patients based on formation of a broad spectrum of colors reflecting the concentration of tyrosine. To the best of our knowledge, this is the first diagnostic kit with potential to rapidly diagnose various diseases related to the production of tyrosine in biological samples. This kit is not only widely applicable, including for personal use in the home, but is also appropriate as a part of standard screening tests and health protection programs in countries with limited resources.