ABSTRACT
Radiation enteritis (RE) is a common syndrome in the radiotherapy of abdominal and pelvic malignant tumors, heavy influencing living quality, but no specific clinical regimens are available. Long oil (LO) is composed of the fat components from cuttlebone, safflower, walnut oil and rapeseed oil and has been clinically used for wound healing. In this study, oral LO was applied for the prevention and treatment of RE and the mechanisms were explored. Animal experiments were approved by the Ethics Committee of the Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences, and the experiments were conducted in accordance with relevant guidelines and regulations. An RE mouse model was established after single whole abdominal γ-ray radiation of 13 Gy. LO (8 mL·kg-1) was intragastrically administered to the mice 1 h pre-radiation. Compared to the models, the mice of the LO group had more regenerated intestinal crypts and longer villus on day 3.5, and remarkable increase in the abundance of gut microbiota on day 7, especially the amounts of probiotics including Eubacterium and Lactobacillus. Moreover, the mice of the LO group showed longer total movement distance, shorter immobility time, and higher speed than the model mice on day 7. On day 14, the mice of the LO group showed the high descending of proinflammatory factors including tumor necrosis factor-α and interleukin-6, close to the normal levels. Therefore, oral LO can alleviate the inflamed syndromes of RE and improve the repair of damaged intestinal tissues. Moreover, the mice of the LO group had highly low permeability of intestinal mucosa according to the fluorescence labeling experiment, which was close to the normal level. Oral LO can protect intestine mucosa and prevent RE by modification of the intestinal microenvironment, alleviation of the inflammatory response, and promotion of tissue repair.
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Leech bites usually lead to more bleeding, and dermal tissue is damaged to form lifelong scars. If leeches enter the body cavity, it will be more dangerous. Therefore, there is an urgent need to develop effective repellents. In this study, oil in water (O/W) emulsion of tea tree oil was prepared with tea tree oil as the main ingredient, and konjac glucomannan (KGM), ethyl cellulose (EC) as the main excipients. The filter-paper ring method and repellent test in water were used to evaluate the repellent effects on leeches. The animal experiments were approved by the Ethics Committee of Academy of Military Medical Sciences and were conducted in accordance with relevant guidelines and regulations. The activities of acetylcholinesterase (AchE), glutathione S-transferase (GST) and carboxylesterase (CarE) in vivo were measured to clarify the repellent mechanisms. The results showed that a uniform and stable tea tree oil emulsion was successfully prepared, which has excellent hydrophilicity and can effectively repel leeches. The tea tree oil emulsion has a good repellent effect on leeches, which can avoid the volatilization of tea tree oil and prolong the effective repelling time. The novel formulation of tea tree oil provides a new idea for repelling effects with long time and high efficiency based on similar essential oil.
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Photodynamic therapy (PDT) is a therapeutic strategy by which photosensitizers are excited by specific light irradiation to produce singlet oxygen for killing the surrounding cells. The advantages of PDT include weak invasion, slight side effect, and low resistance. The advantages of nanoscale drug delivery systems (DDS) include tumor-targeting, sustained release, and environmental-sensitivity. The combination of PDT and nanoscale DDS would likely lead to tumor targeting of photosensitizers and enhance their antitumor effectiveness. This review discusses the mechanism of PDT, photosensitizer-loaded nanoscale formulations, the combination of PDT and other antitumor therapies, and summarizes the applications and prospects of anti-tumor nanoscale DDS based on PDT. This review is a useful reference for its clinical application.
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The permeation and pharmacodynamics of ocular drugs are influenced by the corneal barrier. Here, a hard-soluble drug, brinzolamide, was selected as the model drug and used for preparation of minimally invasive dissolving microneedles. Brinzolamide was dissolved in ethanol and polyvinylpyrrolidone (PVP) K90 was added and dissolved. The mixture solution was casted into the dissolving microneedles mold and dried and brinzolamide dissolving microneedles (BMN) were obtained after demolding. The stereoscopic and scanning electron microscopic images showed that BMN were conical needles with the height of 750 μm, the bottom diameter of 300 μm, and the inter-tip distance of 500 μm. The dissolving microneedles patch was composed of 10×10 arrays with the area of 1 cm2 and the high drug load of 7.3 mg·cm-2. BMN showed a rapid in vitro drug release with 93% accumulative release at 2 h and the high drug corneal permeation amount of 877 ± 105 μg. BMN exhibited the high mechanical strength of 0.32 N/needle, leading to easy rat corneal insertion with the depth of 200 μm. Moreover, BMN were rapidly dissolved in the cornea, and more importantly, the damaged cornea were quickly self-healed within 24 h. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical and the experiments were conducted in accordance with relevant guidelines and regulations. Ocular minimally invasive dissolving microneedles have the advantages of corneal minimal wounds and rapid healing, high drug loading, and high permeability, favoring the treatment of ocular diseases.
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Environmentally sensitive hydrogels are a novel formulation that has developed rapidly in recent years. It could form semi-solid with good adhesion in the topical sites based on different physiological environments. Its long local retention time is conducive for sustained drug release, and the preparation process is relatively simple and easy to realize industrialization. This review summarized the categories, commonly used polymer, and different administration routes based on the recently published literatures. According to different response factors, it can be divided into temperature, pH, ion, light, and multiple sensitive hydrogels, among which temperature-sensitive hydrogels are the most common. The most commonly used polymers include chitosan, poly N-isopropyl acrylamide, and poloxamer. There are different administration routes for environmentally sensitive hydrogels, such as transdermal, ophthalmic, nasal, oral, vaginal, rectal, injection, etc. Environmentally sensitive hydrogels have broad prospects in clinical application.
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The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (<32 ℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H&E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.
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Melatonin (MLT) is an endogenous chemical that has antitumor effects at high doses. However, it shows low oral bioavailability and short in vivo half-life, leading to drug resistance. Here, liposomal melatonin dry powder inhalers (LMD) were prepared, and were used for treatment of primary rat lung cancer by pulmonary delivery. Liposomal melatonin (LM) was prepared by the ethanol injection method to achieve an entrapment efficiency of 98.89%. LMD was obtained by freeze-drying after LM was mixed with mannitol. LMD appeared as spherical particles under a scanning electron microscope. The rehydrated liposomes had a small size of 65.15 nm and the zeta potential of -14.2 mV without change inentrapment efficiency. LMD had an aerodynamic particle size of 6.73 ± 0.012 μm and a fine particle fraction (FPF<8.06 μm) of 22.2%, suitable for pulmonary delivery. When administered with the same dose, LMD showed much higher inhibition on A549 lung cancer cells than MLT and gemcitabine. LMD of a large dose had no effect on the growth of normal lung epithelial cells (BEAS-2B). Rat lung cancer models were established after 45 days by instilling 3-methylcholanthrene (MCA) and N,N-dimethylnitrosamine (DEN) into the rat lungs once (the experiments had been approved by the ethics committee and carried out in accordance with relevant guidelines and regulations). Decreases of tumor nodules and inflammatory cells in the tumor-bearing rat lungs were observed after treatment of MLT, gemcitabine and LMD by pulmonary delivery compared with the models, wherein LMD was most effective. The efficiencies of inhibition of NF-κB p65, increase of Tunel detection (indicating enhancement of apoptosis), and decrease of malondialdehyde corresponded to LMD being most effective. Therefore, given the fact that LMD can deliver the drug into the tumor tissues of lungs, and it presents as a promising pulmonary inhalable regiment for treatment of lung cancer.
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Three-dimensional (3D) printing,a type of rapid prototyping technology,is based on a digital model file and prints layer-by-layer using adhesive materials,such as powdered metal or plastic.3D printing has attracted much attention in the pharmaceutical field because of the various advantages,such as simple operation,good flexibility,high repeatability,wide adaptability,and more importantly,customized service.Currently,it is used in formulations of immediate release,sustained release,implants,etc.Recently,the integration of medical devices and drugs with 3D printing has been gaining popularity.This review not only summarizes the latest progress in techniques,materials,and pharmaceutical dosage forms used in drug delivery system with 3D printing,but also analyzes its advantages and limitations,with the hope of providing reference for the development and application of 3D printing technology in drug delivery.This novel drug delivery system will bring new vitality to individualized medication.
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Topically applied traditional Chinese medicines (TCM) generally show low transdermal rates and doses, leading to weak therapeutic efficacy. Here, cataplasm of white mustard seed varnish was prepared. The effects of iontophoresis and sonophoresis on the transdermal delivery of this TCM and its anti-asthma effect were evaluated. Active components of white mustard seed, rhizoma corydalis and Radix Kansui were obtained after alcohol extraction, respectively. The volatile oil in Asarum Heterotropoides were obtained with volatile oil extraction equipment. The drug loading ratio of cataplasms was 17% (w/w). Franz cell diffusion method was used to evaluate the accumulated permeation amount and the steady-state transdermal absorption rate of sodium thiocyanate. The improvement of sonophoresis on transdermal absorption was higher than that of iontophoresis.Asthma model of guinea pigs were established. Cataplasms of white mustard seed varnish were applied on the back of guinea pigs. Iontophoresis and sonophoresis obviously promoted the transdermal absorption and enhanced anti-asthma efficacy of white mustard seed varnish cataplasms. Pathological analysis showed that iontophoresis and sonophoresis significantly alleviated inflammation. Compared with the model group, IL-4 and IgE levels in the cataplasm group, cataplasm/iontophoresis group, cataplasm/sonophoresis group decreased obviously, although the IFN-γ levels markedly increased. Moreover, the therapeutic efficacy of cataplasm/sonophoresis group was the best in all the groups, even leading to levels similar to that of healthy animals. Iontophoresis and sonophoresis are effective methods to promote transdermal absorption of cataplasms. Moreover, the effect of sonophoresis is higher than that of iontophoresis. Physical penetration improvement techniques provide a novel insight for the wide application of transdermal TCM.
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Chitosan,a natural polysaccharide,has attracted increasing attention as an excellent carrier for drug delivery.The advantages of chitosan include its good biocompatibility,biodegradability and non-toxicity.Polyphenol,flavone,coumarin,terpenes,alkaloids are important active natural products for disease treatment.Curcumin,paclitaxel,resveratrol,podophyllotoxin,vincristine,cannabidiol,triptolide are all remarkable molecules of bioactive natural products.However,most of them cannot be made into appropriate formulations due to their poor stability.It is imperative to select an appropriate drug delivery system to improve the stability of natural products.This review summarizes the recent progress related to chitosanbased drug delivery system for natural product,involving nanoparticles,hydrogels,microspheres,films,nanofibers,sponges and liposomes.In addition,this review describes the characteristics of chitosan in promoting wound healing,inhibiting bacterial growth,treating tumors and osteoarthritis.It seems that chitosan will be a promising and important excipient for novel formulations of bioactive natural products.
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Objective To demonstrate the therapeutic effect of curcumin hydrogel combined with photodynamics on acne. Methods Sieving and ultrasound/high pressure homogenization were used to prepare curcumin micropowder.Curcumin-loaded hydro?gel was prepared with Poloxamer 407 and its rheological characteristics were evaluated.The antibacterial activity of curcumin hydrogel irritated with 657 nm laser was assayed by a hole-punching method.Acne model on rabbit ears war established.Fifteen New Zealand white rabbits were randomly divided into five groups:the model group,tretinoin cream group,illumination group,curcumin hydrogel group,and curcumin hydrogel/illumination group.The therapeutic effects on acne were evaluated by the morphological and histopatho?logical examination.Results The micropowdered curcumin prepared with ultrasound/high pressure homogenization had smaller size and more uniform distribution(size range:5-20 μm.)than the sieving-prepared curcumin micro-powders(10-45 μm).The prepared hydrogels being a pseudoplastic fluid had the properties of gelatin.The antibacterial effect of curcumin hydrogel/illumination was bet?ter than that of curcumin hydrogel.The inhibition zone diameters were(9.4±0.92)and(12.57±1.12)mm for the curcumin hydrogel and the curcumin hadrogel/illumination groups,respectively.The therapeutic effect for the treatment of acne on the rabbit ears with ac?ne was better in the curcumin hydrogel/illumination group than in both the illumination and the curcumin hydrogel groups. Conclu?sion Curcumin hydrogel combined with photodynamic therapy showed better therapeutic efficacy on acne treatment.It provides an ideal choice for acne treatment.
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Objective To investigate the therapeutic effect of curcumin in situ hydrogels for treatment of vaginal candidiasis. Methods In situ hydrogels were prepared using poloxamer 407 and 188 as the gel matrix.Gelation temperature,gelation time and rheological characteristics were determined.Mice models with vaginal candidiasis were established.The animals were divided into six groups:the healthy mice group,the model group,the positive control group(ketoconazole cream),curcumin-loaded in situ hydrogels of 0.025,0.10 and 0.20 g/ml.Before treatment and after the fourth and eighth treatments,the vaginal smears were collected and Gram-stained.The vagina washings fluid of mice were collected to determine DNA of Lactobacillus.On 8thday,the mice were sacrificed and the vaginal tissues were excised for pathological detection.Results The gelation temperature and time of in situ hydrogels were 29℃and 2′30″,respectively.Rheological profiles demonstrated that it showed good retention effect in vivo.Compared with the model group, curcumin hydrogels of 0.025,0.10 and 0.20 g/ml could inhibit the growth of Candida albicans,inhibit vaginal mucosal edema,inflam?matory hyperplasia,and decrease the expression of inflammatory factors including TNF-α(P<0.01)and IL-1β(P<0.01).Howev?er,curcumin hydrogels could not influence the growth of lactobacillus in the vagina.It indicated that curcumin hydrogels did not de?pend on lactobacillus to treat fungal vaginitis.Conclusion Curcumin in situ hydrogels could inhibit candidiasis growth,decrease ede?ma of vaginal mucosa and inflammatory hyperplasia,and reduce the expression of inflammatory factors.It provides a novel choice for the treatment of clinical vaginal candidiasis.
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Artesunate is one of artemisinin derivatives with anti-malarial and anti-inflammatory activities though its water solubility and bioavailability are low. Acute lung injury (ALI) is a seriously dispersive lung disease with a high mortality. In this study, artesunate liposomes were prepared with the film dispersion method, and then lyophilized to obtain the liposomal artesunate dry powder inhalers (LADPIs). The LADPIs were pulmonary-delivered into the lung to treat ALI in rats. The artesunate liposomes had the capsulation efficiency of 71.4%, the particle size of 47.3 nm, and the zeta potential of -13.7 mV. The LADPIs had the aerodynamic particle size of 4.2 μm and the fine particle fraction (FPF) of 34.5%. ALI was established in rats by instilling lipopolysaccharide (LPS) into the lungs. The rats quickly showed a reduction in movement and acceleration in breath followed by diarrhea and so on. The LADPIs were directly administrated into the lungs of ALI rats through airways after 1 h of LPS challenge. The treatment induced a reduction in ALI syndromes. Two inflammatory factors, including TNF-α and IL-6, were significantly reduced by the artesunate powder in the LADPI group similarly to the reduction in the positive drug dexamethasone group (P<0.05). Therefore, the anti-inflammatory effect of LADPIs contributed to the anti-ALI activity. Furthermore, the liposomal formulation improved drug bioavailability in the lung and increased therapeutic efficiency. The LADPIs are promising medicines for therapy of ALI through local drug administration.
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Ultrasonic microbubbles were used to open blood-brain barriers (BBB) with a reversed and limited behavior feature in the study, which could improve the brain-targeted delivery of anti-tumor drugs. The glioma rat model was prepared. Low-frequency ultrasound was combined with microbubbles to affect the permeability of BBB compared with the permeability of independently administered Evans blue (EB) crossing BBB. Time point and length of ultrasound were investigated whether they affect the permeability of BBB and the damage of brain tissue. The effect of the growth time of glioma on BBB permeability was explored. Only glioma had a very little impact on BBB permeability. However, ultrasonic microbubbles opened the BBB with the features of temporary, limited and reversed behavior and improved EB and magnetic resonance imaging contrast agent penetrating BBB. A length of 30 s ultrasound is appropriate for opening BBB and no damage of brain tissue. Drugs should be injected before ultrasound so that they enter into brain as BBB opening. Ultrasonic microbubbles can open BBB effectively and safely, which improve drugs penetrating BBB under proper time point and length.
Subject(s)
Animals , Rats , Blood-Brain Barrier , Contrast Media , Drug Delivery Systems , Glioma , Drug Therapy , Magnetic Resonance Imaging , Microbubbles , Permeability , UltrasonicsABSTRACT
Pulmonary drug delivery systems (PDDS) have some advantages, including high drug accumulation in the lungs, no first pass effect, and rapid absorption of drugs. They have become a key way to treat lung diseases and improve the absorption of biomacromolecules. In this review, we analyze lung's physiological features, and discuss the main dosage forms of lung inhalations, their preparation methods, the evaluation methods, and the in vivo experimental methods. The applications of pulmonary drug delivery to lung diseases, including acute lung injury, pulmonary infection, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, and lung cancer, are also discussed.
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The aim of the manuscript was to optimize formulations and preparation technologies of cataplasm of white mustard seed varnish, and to evaluate its anti-asthma effect on rats. The single factor experiments included spreading thickness, types of crosslinking agents, dihydroxyaluminum aminoacetate amount, sodium polyacrylate amount, types of adhesive agents with human sense as the evaluation index. Blank cataplasm matrix was optimized by the orthogonal experiment with the amount of glycerine, citric acid, and sodium carboxymethylcellulose as the major influential factors. Initial adhesive force, peeling strength and human sense were as the evaluation index. The optimized formulation of blank cataplasm were as followings: glycerine-water-ethanol-PEG400-dihydroxyaluminum aminoacetate-citric acid-sodium carboxymethylcellulose-sodium carboxymethylcellulose 2 : 8 : 0.8 : 0.4 : 0.07: 0.15 : 0.1 : 0.5. The active ingredients of white mustard seed, corydalis, and gansui root were extracted by alcohol extraction method. Asiasarum volatile oil was extracted by oil extractor. The optimized drug loading amount was 11% with initial adhesive force, peeling strength and human sense as the evaluation index. Asthma rats model were established by sensitized with ovalbumin and nose-scratching time as the evaluation index. High dose (17%) group of drug-loaded cataplasm had the obvious inhibition effect on nose-scratching time of rats (P = 0.037 < 0.05). In comparison, middle dose (11%), low dose (4%) and positive-control groups had no obvious inhibitive effect on rats. White mustard seed cataplasm supplied a novel choice for anti-asthma therapy. And the overall pharmacodynamics assessment will be carried out on molecular level in near future.
Subject(s)
Animals , Female , Humans , Male , Rats , Anti-Asthmatic Agents , Chemistry , Asthma , Drug Therapy , Chemistry, Pharmaceutical , Drugs, Chinese Herbal , Chemistry , Mustard Plant , Chemistry , Rats, Sprague-Dawley , Seeds , ChemistryABSTRACT
<p><b>AIM</b>To study the action of RMP-7 and its derivative on transporting liposome across the blood brain barrier (BBB) into the brain.</p><p><b>METHODS</b>RMP-7 and DSPE-PEG-NHS [[1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly (ethylene-glycol)]-hydroxy succinamide]] were conjugated together in mild condition and MALDI-TOF-MS (Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry) was used to determine their molecular ratio. An in vitro BBB model was established and used to determine in vitro bioactivity of RMP-7 and its derivative. The fluorescence of brain slices and the Evens Blue (EB) concentration in the brain, liver, spleen, lung and kidney of each group were used to evaluate the in vivo bioactivity of RMP-7 and its derivative on transporting liposome across the BBB.</p><p><b>RESULTS</b>The average molecular weight (MW) of the reaction product was 4,900, while those of DSPE-PEG-NHS and RMP-7 were 3,224 and 1,098. The results demonstrated that RMP-7 was conjugated to DSPE-PEG-NHS at the molecular ratio of 1:1, so the product was DSPE-PEG-RMP-7. RMP-7 and DSPE-PEG-RMP-7 was shown to improve the transporting of peralcohol enzyme across the in vitro BBB model 2-3 times higher than the peralcohol enzyme only. DSPE-PEG-RMP-7 could facilitate the transporting of EB into brain more easily than RMP-7.</p><p><b>CONCLUSION</b>Both RMP-7 and DSPE-PEG-RMP-7 could facilitate the transporting of liposome across the BBB, especially DSPE-PEG-RMP-7.</p>