Therapeutic Efficacy of Great Plantain (Plantago major L.) in the Treatment of Second-Degree Burn Wounds: A Case-Control Study.

Background: Great plantain (Plantago major L. or P.major) is a medicinal plant that is available all around the world. The whole plant has several bioactive compounds including terpenoids, flavonoids, phenolic compounds, alkaloids, fatty acids, iridoid glycosides, polysaccharides, and vitamins. Scientific studies have recognized several medical benefits like wound healing, anti-inflammatory, antimicrobial, antiulcerative, and antioxidative agents. The wound-healing capacity of this plant has been investigated under in vivo and ex vivo conditions. In the current study, we aim to compare the therapeutic effect of the P.major extract with 1% sulfadiazine on the healing of second-degree burn wounds. Method: Second-degree burn victims were included in our study. The investigation and control group, respectively, received P. major ointment 10% and silver sulfadiazine ointment 1%. The bacterial culture from the wound site was taken on days 3, 7, 10, 13, and last day of hospitalization. Patients' subjective complaints were obtained through the visual analog scale (VAS). All patients were treated and evaluated in the hospital. Result: Among the 15 patients, 11 were male, and the mean age was 33.3 years. The average complete healing duration was 11.73 vs. 13 days in the P. major and control group, respectively (P=0.166). On the third day, infection control was similar between the two groups, and on the seventh day, all bacterial cultures were negative. Although there was a significant reduction in pain scores during the recovery time, no significant differences in pain reduction were noted between the two groups (P=0.849). Conclusion: We showed that P.major ointment is a safe and suitable herbal compound in the treatment of second-degree burn wounds that not only has wound-healing properties but also is an analgesic and antimicrobial compound.

Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer's disease animal model by reducing Tau hyperphosphorylation.

BACKGROUND: Nicotinamide is considered to be effective in halting the Alzheimer's disease progression. The body could absorb a limited amount of nicotinamide at a time, requiring multiple doses through a day. To overcome such an obstacle which reduces the patient compliance, a sustained/controlled delivery system could be useful. METHOD: Nicotinamide loaded solid lipid nanoparticles (SLN) were prepared and functionalized with polysorbate 80 (S80), phosphatidylserine (PS) or phosphatidic acid (PA). The acquired particles were characterized and evaluated in respect of their cytotoxicity, biodistribution, and in vivo effectiveness through the different routes of administration. RESULTS: The optimum sizes of 112 ± 1.6 nm, 124 ± 0.8 nm, and 137 ± 1.05 nm were acquired for S80-, PS-, and PA-functionalized SLNs, respectively. The in vitro cytotoxicity on SH-SY5Y cell line showed the safety of formulations except for S80-functionalized SLNs. Biodistribution study of SLNs has proved the benefits of functionalization in improving the brain delivery. The results of spatial and memory test, i.e. Morris water maze, and also histopathology and biochemical tests demonstrated the effectiveness of i.p. injection of PS -functionalized SLNs in improving the cognition, preserving the neuronal cells and reducing tau hyperphosphorylation in a rat model of Alzheimer's disease. CONCLUSION: The acquired PS-functionalized SLN could be a potential brain delivery system. Loaded with nicotinamide, an HDAC inhibitor, it could ameliorate the cognition impairment of rats more effectively than the conventional administration of nicotinamide, i.e. oral, in the early stage of Alzheimer's disease. Graphical abstract ᅟ.

Application of Response Surface Method for Preparation, Optimization, and Characterization of Nicotinamide Loaded Solid Lipid Nanoparticles.

Purpose: Solid lipid nanoparticles (SLNs) have been proven to possess pharmaceutical advantages. They have the ability to deliver hydrophilic drugs through lipid membranes of the body. However, the loading of such drugs into SLNs is challenging. Hydrophilic nicotinamide, a histone deacetylase inhibitor, is used to establish SLNs with enhanced encapsulation efficiency by using statistical design. Methods: The possible effective parameters of these particles' characteristics were determined using pre-formulation studies and preliminary tests. Afterwards, the Response Surface Method (RSM) was utilized to optimize the preparation condition of SLNs. The effect of the amount of lipid, drug, surfactant, and the mixing apparatus were studied on particle size, zeta potential, and encapsulation efficiency of the obtained particles. The acquired particles were characterized in respect of their morphology, in vitro release profile, and cytotoxicity. Results: According to this study, all the dependant variables could be fitted into quadratic models. Particles of 107 nm with zeta potential of about -40.9 and encapsulation efficiency of about 36% were obtained under optimized preparation conditions; i.e. with stearic acid to phospholipon® 90G ratio of 7.5 and nicotinamide to sodium taurocholate ratio of 14.74 using probe sonication. The validation test confirmed the model's suitability. The release profile demonstrated the controlled release profile following the initial burst release. Neither the nicotinamide nor the SLNs showed toxicity under the evaluated concentrations. Conclusion: The acquired results suggested the suitability of the model for designing the delivery system with a highly encapsulated water soluble drug for controlling its delivery.

Nanoparticles of Chitosan Loaded Ciprofloxacin: Fabrication and Antimicrobial Activity.

Purpose: Chitosan is a natural mucoadhesive polymer with antibacterial activity. In the present study, chitosan (CS) nanoparticles were investigated as a vehicle for delivery of antibiotic, ciprofloxacin hydrochloride. Methods: Ionotropic gelation method was used for preparation chitosan nanoparticles. The effects of various factors including concentration of CS, concentration of tripolyphosphate (TPP), and homogenization rate on the size of nanoparticles were studied. The effects of various mass ratios of CS to ciprofloxacin hydrochloride on the encapsulation efficiency of nanoparticles were assessed. Results: The particles prepared under optimal condition of 0.45% CS concentration, 0.45% TPP concentration and homogenizer rate at 6000 rpm, had 72 nm diameter. In these particles with 1:0.5 mass ratio of CS to ciprofloxacin hydrochloride, the encapsulation efficiency was 23%. The antibacterial activity of chitosan nanoparticles and ciprofloxacin-loaded nanoparticles against E.coli and S.aureus was evaluated by calculation of minimum inhibitory concentration (MIC). Results showed that MIC of ciprofloxacin loaded chitosan nanoparticles was 50% lower than that of ciprofloxacin hydrochloride alone in both of microorganism species. Nanoparticles without drug exhibited antibacterial activity at higher concentrations and MIC of them against E.coli and S.aureus was 177 and 277 µg/ml, respectively. Conclusion: Therefore chitosan nanoparticles could be applied as carrier for decreasing the dose of antibacterial agents in the infections.

Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.

The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and voriconazole trough levels were quantified by a validated high-performance liquid chromatography method. Cytochrome P450 genotypes for CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable, and possible invasive fungal infections were reported for 8/104 (7.7%), 42/104 (40.4%), and 54/104 (51.9%) patients, respectively. Receiver operating characteristic (ROC) curve analysis indicated that trough concentrations of ≥1.3 µg/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 µg/ml) (P < 0.001) and that those of <5.3 µg/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 µg/ml) (P < 0.001). Voriconazole trough levels were significantly higher for heterozygous extensive metabolizers, poor metabolizers, and individuals receiving coadministration with proton pump inhibitors. For ultrarapid metabolizers, oral administration of voriconazole, and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patient age, weight, or gender or coadministration of tacrolimus and cyclosporine with the voriconazole trough level. In conclusion, the results of our analysis indicate large inter- and intraindividual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations of ≥1.3 µg/ml and <5.3 µg/ml are optimal for treatment and for minimization of adverse events. Optimization of drug efficacy and safety requires the use of rational doses for voriconazole therapy.

Development, evaluation and optimization of superparamagnetite nanoparticles prepared by co-precipitation method.

Magnetic nanoparticles (MNPs) are of high interest due to their application in medical fields, in particular for theranostics. Specific properties required for such particles include high magnetization, appropriate size and stability. Biocompatible magnetically soft magnetite particles (Fe3O4) have been investigated for biological purposes. The intrinsic instability of these nanoparticles and their susceptibility to the oxidization in air, are limitations for their applications. Various methods have been described for synthesis of these nanoparticles among which co-precipitation method is widely experimented. In order to illustrate the synthesis of MNPs elaborately, the effect of different factors on particle formation were studied. The particles morphology, stability, paramagnetic effect, chemical structure and cytotoxicity were evaluated. Particles of 58 and 60 nm obtained by oleic acid coated (OMNPs) and citric acid coated (CMNPs) magnetite nanoparticles respectively. Transmission electron microscopy images exhibited the real sizes are 15 and 13 nm. Magnetic saturations of these nanoparticles were 72 and 68 emu/g which is suitable for medical applications. Both OMNPs and CMNPs were non-toxic to the SK-Br-3 and MCF-7 cells in the concentrations of <2.5 µg/mL. Since these particles exhibit relatively high magnetic saturation, low dose of such material would be required; therefore, these NPs seem to be suitable for theranostics.

An Evidence-Based Review on Medicinal Value of Clays in Traditional Persian Medicine.

The use of earths and clays for medical purposes dates back to antiquity. In recent years, there has been an increasing interest in researches on traditional remedies in the hope of discovering new drug. Iran is an ancient country with a medical backbone acquired from the experiences of ancient Persian scholars, who had made a great contribution to the development of the medical sciences. Many medical and pharmaceutical books by early Persian scientists still exist and may have the potential of leading researchers to new drug discoveries. Owing to the emergence of new and antimicrobial-resistant infections, present-day medicine has recently begun focusing on medicinal earths and clays especially as mineral antimicrobials. The current study is, therefore, aimed at gathering information regarding medicinal clays in traditional Persian medicine (TPM). Five main Persian materia medica with the key word 'tin' (clay) and current databases such as PubMed, Scopus, ScienceDirect, and Google Scholar were searched by key words 'white, green, red, maroon, violet, black, grey and pink clays' and 'pharmacological effects'. Twenty three clays were found in Persian manuscripts. Although their mineralogical compositions are unknown, different pharmacological properties have been attributed to these mineral medicaments. Clay's properties were widely used in medieval times for the treatment of infections to poisoning. They were also used in compound formulations, possibly for their pharmaceutical formulation modifying effects. Modern scientific proofs have also been found in many of the medicinal clays reported in Persian manuscripts. Although many of the reported clays are still unknown, their characterization may lead to new medicinal developments. Novel analytical methods available today make it possible to elucidate the chemical compositions of these minerals as parameters responsible for their medicinal effects.

Non-invasive endotracheal delivery of paclitaxel-loaded alginate microparticles.

Aerosolized chemotherapeutics leads to higher, localized and continuous concentrations of active agents in lung tissue with lower side effects for other organs. The present study was performed on jugular vein cannulated rats which endothracheally received 4 mg/kg of free paclitaxel powder (Free-PTX), paclitaxel-loaded alginate microparticles (PTX-ALG-MPs) and i.v. paclitaxel (Anzatax(®)). Pharmacokinetic parameters for Free-PTX and PTX-ALG-MPs contain higher AUC, mean residence time (MRT),half-life and bioavailability, with lower elimination constant (ke). Statistical analysis showed that the amount of paclitaxel per gram of lung tissue after 0.5, 6 and 24 h after administration of Free-PTX was lower than PTX-ALG-MPs. Lung tissue AUC for Free-PTX was lower than PTX-ALG-MPs. According to the obvious advantages obtained, such as dose lowering and increasing paclitaxel residence time and half-life. It should be noted that cell cytotoxicity test on normal airway cell lines was not examined in this study but due to previous reports on safety of inhaled paclitaxel, it can be suggested that pulmonary delivery of paclitaxel can be a useful non-invasive route of administration compared with i.v administration.

Inhalable, large porous PLGA microparticles loaded with paclitaxel: preparation, in vitro and in vivo characterization.

Large porous particles (LPPs) could be used as a useful carrier for non-invasive delivery to the deep lung. Pulmonary delivery of paclitaxel-loaded LPPs (PTX-LPPs) can help to eliminate the highly complicated and harmful solvent used in PTX parenteral formulations. PTX-LPPs with mass median aerodynamic diameter (MMAD) of 5.74 ± 0.09 µm, high encapsulation efficiency and good aerosolisation properties were produced using ammonium bicarbonate as porogen. Cytotoxicity of PTX-LPPs on A549 and Calu-6 cell lines was comparable with Free-PTX. Endotracheal administration of PTX-LPPs in rats exhibited PTX plasma concentration in the therapeutic range which lasted 4-fold longer than i.v. injection. The bioavailability was measured as 51 ± 7.1%. The lung targeting efficiency (Te) of PTX-LPPs was 11.9-fold higher than i.v. administration. PTX-LPPs could deliver a higher PTX to lung with a non-toxic plasma level in a longer duration which shows their pulmonary delivery suitability.

A Randomized Double Blind Clinical Trial on a Sabgh Formulation for Patients With Vitiligo.

BACKGROUND: The cosmetic problem that vitiligo produces affects patients psychologically. Many patients with vitiligo are suggested to cover their white skin patches with cosmetic products. There are formulations in traditional Iranian pharmacy to color these white skin patches. In this study, one of these formulations was compared with a cosmetic formulation. METHODS: Two groups of patients were selected. One group used a marketed formulation and other group used a traditional Iranian Pharmacy formulation. The quality of life of the patients was compared based on the Dermatology Life Quality Index Questionnaire. RESULTS: Both interventions were associated with statistically improved Dermatology Life Quality Index scores over the 8-week intervention (P < .05), although the difference between the 2 was not statistically significant (P = .436). CONCLUSION: Traditional Iranian Pharmacy formulation is effective in increasing the quality of life in vitiligo patients.

Armenian bole: a historical medicinal clay.

The medical use of earths and minerals is probably as old as the history of mankind. Particular types of clays and earths are still being used worldwide as therapeutic agents in the folk medicine of different countries. From the 19th century, the medicaments included in countries' pharmacopeias whose exact pharmacological activity or the chemistry of their active components was not known gradually decreased in number, despite their popularity among patients. With today's analytical armamentarium it may be time to reconsider returning some of those compounds to pharmacopeias. By using modern techniques in the past two decades, researchers have studied the active components of healing clays and their pharmacological properties. Many of them possess valuable therapeutic properties which could be used in modern medicine in pharmaceutical dosage forms. Our knowledge about the medical substances that our ancestors used through centuries could be used today as an evidence base for further clinical and pharmacological research. One of these substances is Armenian bole. In this work we studied the historical perspective of its therapeutic use in different countries. Also a sample sold in the market in Iran was purchased and X-ray diffraction analysis was performed on it to find out its chemical composition.

Enhanced oral bioavailability of paclitaxel by concomitant use of absorption enhancers and P-glycoprotein inhibitors in rats.

Paclitaxel (PCT) is a cytotoxic agent with a broad antineoplastic activity. IV formulation of PCT causes hypersensitivity reactions in some patients and oral administration is an alternative to decrease the side effects. PCT is not orally available because of low solubility, lack of intestinal permeability, and efflux by pumps in intestinal wall. PCT solution in cremophor EL: ethanol (100 mg/kg) was administered orally to rats after pre-treatment by mefenamic acid, ibuprofen, verapamil, cyclosporine, and verapamil+ibuprofen in individual groups. Ibuprofen presented positive effect on intestinal permeation of PCT. C(max) and area under the serum concentration versus time curve (AUC) after pre-treatment by ibuprofen was decreased when the oral dose of PCT was decreased to 50 and 25 mg/kg, while dose-blood concentration relationship was nonlinear. Rise in oral bioavailability of PCT after pre-treatment by cyclosporine was lower than ibuprofen. It seems that by using ibuprofen in concomitant with potent P-gp inhibitors before PCT solution, oral delivery of PCT could be promising.

Olfactory stimulation by vanillin prevents apnea in premature newborn infants.

OBJECTIVE: Apnea is one of the most common problems in premature newborns. The present study aimed to determine the effect of olfactory stimulation by vanillin on prevention of apnea in premature newborns. METHODS: In this randomized controlled trial, 36 premature newborns with the postnatal age of 2 days and weight under 2500 grams referred to the hospitals affiliated to Shiraz University of Medical Sciences, were selected through simple random sampling and allocated into control and experimental groups. The experimental group received olfactory stimulation by saturated vanillin solution, while the control group received no interventions. The newborns of both groups were continuously monitored for presence/absence of apnea and number of episodes of apnea as well as arterial blood oxygen saturation and heart rate for 5 days. The data were analyzed by independent Student t-test and repeat measure ANCOVA. FINDINGS: The presence of apnea revealed to be significantly different between the two groups in the first, second, and fourth day of the study (P<0.05). The number of episodes of apnea during five days was also significantly different between the study groups (t=8.32, P<0.05). Using olfactory stimulation by vanillin caused a 3.1-fold decrease in apnea and the effect size was 0.72. Moreover, the two groups were significantly different regarding the arterial blood oxygen and heart rate during the study period (P<0.05). CONCLUSION: This study indicated the beneficial effect of saturated vanillin solution on apnea; therefore, it may be used for prevention and treatment of apnea in premature infants. Further studies are needed to improve evidence-based practice in this regard.

Preparation and in-vitro characterization of tramadol-loaded carrier erythrocytes for long-term intravenous delivery.

OBJECTIVES: The hypo-osmotic dialysis method was used for preparation of tramadol-loaded human intact erythrocytes. In response to rapid drug escape from the erythrocytes, a membrane cross-linker, glutaraldehyde, was used successfully. METHODS: The resulting carrier cells were validated in terms of the accuracy and precision of the whole drug loading procedure. KEY FINDINGS: The average loaded amount, entrapment efficiency and cell recovery were 1.9041 mg, 95.98% and 85.13%, respectively. The effects of different drug concentrations on loading parameters were studied with the concentration of 10 mg/ml selected as optimal. A series of in-vitro characteristics of carrier erythrocytes, including tramadol release behaviour, haematological indices, particle size distribution, scanning electron microscopy, and osmotic/turbulence fragilities were determined compared with the sham-entrapped and unloaded cells. The results of these in-vitro tests indicated that the erythrocytes did not undergo remarkable irreversible size and shape/topology changes, but the fragility of the membranes of the processed cells were increased. CONCLUSIONS: The collective results of this study showed that the optimized method of entrapment was suitable for the encapsulation of tramadol in erythrocytes with the final carrier cells ready to enter the in-vivo animal studies as a promising long-circulating carrier for tramadol.

Preparation and characterization of biodegradable paclitaxel loaded alginate microparticles for pulmonary delivery.

In primary or metastatic lung cancer, administration of chemotherapeutic agents via inhalation could increase exposure of lung tumor to the drug, while minimizing systemic side effects. In addition, mucosal drug delivery system may reduce the toxicity and increase the site specific efficacy of drugs. Sodium alginate is a biodegradable, biocompatible and mucoadhesive polymer which is used for site specific drug delivery to mucosal tissues. At the present study alginate microparticles were fabricated by an emulsification technique and characterized. Selection of appropriate parameters enabled the preparation of microparticles with a mean volume diameter of 3±0.7 µm, mass median aerodynamic diameter of 5.9±0.33 µm, fine particle fraction of 13.9±0.57% and encapsulation efficiency of 61±4%. The in vitro release profile showed a slower release rate for microparticles compare to pure paclitaxel. Physiochemical characterization of paclitaxel via FT-IR, DSC and XRD techniques revealed information of solid state of paclitaxel loaded microparticles. The in vitro cytotoxicity activity of paclitaxel loaded microparticles was assessed using human non-small cell lung cancer cell lines (A549 and Calu-6). Results showed that exposure of cells to pure paclitaxel and paclitaxel loaded microparticles effectively inhibited the growth of A549 and Calu-6 cells similarly in a concentration- and time-dependent manner.

The effects of some permeability enhancers on the percutaneous absorption of lidocaine.

Local anesthesia of the intact skin is difficult because of the barrier properties of skin to epicutaneous penetration of local anesthetic drugs. Using local anesthetics with combination of penetration enhancers could overcome this problem. The main objective of this study was to assess the effects of some permeability enhancers on the percutaneous permeation of lidocaine. The effect of polysorbate 80, polysorbate 20, dimethylsulfoxide (DMSO), tert-butyl cyclohexanol (TBCH), and alpha-terpinol in different concentrations and various ratios of lidocaine to enhancers was evaluated. The results showed that polysorbate 80 and polysorbate 20 has no detectable penetration enhancing effects in guinea pig skin mounted to diffusion cells. The same results were obtained to water/oil ratio and the type of oil phase (liquid paraffin vs. castor oil). Addition of DMSO to the previous formulations had a considerable enhancing effect. According to the data, the extent of lidocaine permeation was proportional to the concentration of DMSO in these formulations. The best results belonged to the addition of terpenes but interestingly there wasn't any linear relationship between the concentrations of alpha- terpinol/ or TBCH and the duration of antinociceptive effects of lidocaine. Based on the results of this study the ratio of 1: 4 from alpha- terpinol or TBCH to lidocaine results in a better antinociceptive effect and alpha- terpinol was the best one among of these compounds. This effect was proven with in vivo tail- immersion test to assess the antinociceptive effect of formulations which have shown more penetration.

Aqueous concentration of tranexamic acid after 5% and 10% eyedrop administration.

PURPOSE: To determine whether topical tranexamic acid can provide acceptable therapeutic concentration in the aqueous humor. METHODS: A total of 47 patients with cataract as the sole eye disease who have been scheduled for cataract operation received one drop of tranexamic acid 5% solution at various time intervals prior to operation (from 15 minutes to 9 hours). Two patients received 10% solution of the drug. Paracentesis of the anterior chamber was done and the aqueous humor was aspirated in the operation room. The aqueous samples were analyzed using high-performance liquid chromatography method with the limit of quantification around 0.1 microg/mL. Systemic and ocular side effects were evaluated. RESULTS: Aqueous concentrations of tranexamic acid was higher than 1.5 microg/mL up to 160 minutes after administration of a single drop of 5% solution of the drug and then declined to an average concentration of 1 microg/mL at 300 minutes which persisted up to 9 hours after administration.In two patients for whom a single drop of 10% tranexamic acid solution was used, aqueous concentrations of 2.72 and 2.90 microg/mL were detected 60 minutes after administration. None of the patients experienced ocular or systemic side effects. CONCLUSIONS: Topical administration of tranexamic acid is effective in yielding therapeutic intraocular concentrations of drug without any ocular or systemic toxicity.

The effect of polymer blends on release profiles of diclofenac sodium from matrices.

The purpose of this study was to evaluate the effect of polymer blends on the in vitro release profile of diclofenac sodium. Several controlled release matrices of diclofenac sodium with different proportions of hydroxypropyl methylcellulose (HPMC; viscosity grade 60 and 500 mPa.s), carbopol 940 and lactose as a water soluble filler were prepared. The results showed that when HPMC (viscosity grade 60 mPa.s) alone was used as matrix former, diclofenac sodium was released fast but the release rate became slower with HPMC (viscosity grade 500 mPa.s) at higher polymer/drug ratios (more than 0.8:1). However in lower polymer/drug ratios (lower than 0.7:1) the release rate still was fast. The results showed that carbopol can extend the release time appreciably but the release profiles had considerable fluctuations, and drug release in first hours was slow but increased appreciably with time at the end of profiles. When an appropriate blend of HPMC (viscosity grade 60 or 500 mPa.s) and carbopol 940 was used, the drug release became more uniform and its kinetic approached to zero order and release fluctuations were diminished. The results with these polymer blends showed that it is possible to reduce the total amounts of polymer in each formulation. According to kinetic analysis data, drug release from these matrix tablets did not follow Fick's law of diffusion and the results were in agreement with the earlier reports.