Clinical research progress of oral administration of traditional Chinese medicine in the treatment of dry eyes

Dry eye is a common and frequently occurring ophthalmology disease with complex etiology and easy recurrence.Oral administration of traditional Chinese medicine has the characteristicsof high curative effect and little toxic and side effect in the treatment of dry eye.This paper collates the domestic reported clinical studies on the oral administration of traditional Chinese medicine in the treatment of dry eye,which are discussed from four aspects:special prescription for specific disease,addition and subtraction of main prescription,treatment based on syndrome differentiation and proprietary Chinese medicine.The curative effect and advantages of traditional Chinese medicine in the treatment of dry eye are demonstrated,providing a reference for the treatment of dry eye in the future.

Pharmacokinetics of Milbemycin Oxime in Dogs Following Its Intravenous and Oral Administration

The pharmacokinetics of milbemycin oxime was investigated in dogs following oral(per os, PO) and intravenous(IV) administration. Three groups of dogs received milbemycin oxime tablets as a single PO dose equal to 0.25, 0.5 and 1.0 mg · kg-1 of milbemycin oxime, respectively, another group received a single IV dose of 0.5 mg · kg-1. Blood samples were collected at predetermined times after drug administration and the milbemycin oxime concentrations in plasma were determined by LC-MS/MS. The drug protein binding in dog plasma in vitro was determined by equilibrium dialysis at concentrations spanning the range of values observed in vivo in dog plasma. After PO administration at doses of 0.25, 0.5 and 1.0 mg · kg-1, milbemycin oxime was slowly absorbed and eliminated, the time to reach the maximum plasma concentration(Tmax) was 4.14±0.20, 4.27±0.14 and 4.06±0.13 h, the mean absorption time(MAT) was 19.06, 13.67 and 11.77 h, the terminal rate half-life(t1/2λz) was 15.06±0.37, 11.09±0.54 and 9.76±0.89 h and the total body clearance(Cl) was 1.15±0.05, 1.18±0.03 and 1.17±0.07 m L · min-1 · kg-1, respectively. The maximum plasma concentration(Cmax, 36.50±1.40, 76.11±2.77 and 182.05±7.20 ng · m L-1, respectively) and the area under the first-moment curve(AUC-10→∞, 985.83±49.46, 1 663.12±51.42 and 3 558.04±197.88 mg · h · L, respectively) increased accordingly to the administered dose rates; the oral bioavailabilities were estimated to be 88.61%, 74.75% and 79.96%, respectively. The values of fu were 0.12%, 0.14% and 0.13% in dog plasma, respectively. In conclusion, the pharmacokinetics of milbemycin oxime in dogs following oral administration revealed its higher oral bioavailability and advantageous pharmacokinetic properties, such as its lower total body clearance and longer elimination half-life, and indicated that the single oral dose of 0.50 mg · kg-1 of milbemycin oxime which was recommended in all the parasitological efficacy studies allowed an adequate concentration of the drug.

Acute Toxicity of Aluminium Phosphide Following Oral Administration in Rats

Aluminium phosphide (AlP) is used as a fumigant and also sometimes misused for suicidal attempts in India, due to its easy availability. The effect of phosphine, the gas that is liberated when AlP comes in contact with moisture, is well documented in the literature. However, the effect of AlP in its native form on animal models is not well cited. In this study we examined the acute toxic effect of AlP in rats. Oral LD50 of AlP for male and female rats were found to be 14. 13 and 11. 89mg/kg, respectively. Oral administration of an AlP dose of 0. 80 LD50 resulted in significant increases in the level of plasma glutamic oxaloacetic transaminase,alkaline phosphatase, glucose and urea in rats of both sexes. Hemoglobin level and packed cell volume also increased significantly 6h after administration. Body weight was reduced but the organ to body weight ratio of lung, liver, spleen, kidney and testes remained unchanged.Histopathological changes induced by AlP during 24-48h induced hemorrhage, congestion and mild to moderate atrophy of various cellular components of visceral organs. The study showed that the acute toxic effect of AlP may be due to hypovolemic shock. Female rats were found to be more susceptible than were males.

Treatment of Irritable Bowel Syndrome by Oral Administration of Chinese Medicines and Retention-Enema——A Report of 50 Cases

Irritable bowel syndrome (IBS), a common disease of intestinal dysfunction, is also called emotional enteritis, mucous enteritis, irritable colon and so on1. It is often lingering with a long disease course and is easy to recur. The author has in recent years treated 50 cases of the disease by oral administration of Chinese medicines and retention-enema, with satisfactory results reported as follows.

Oral administration of the herbal oligonucleotide XKC-sRNA-h3 prevents angiotensinⅡ-induced hypertension in mice

Hypertension has become a growing public health concern worldwide.In fact,hypertension is commonly associated with increased morbidity and mortality.Currently,oligonucleotide drugs have proven to be promising therapeutic agents for various diseases.In the present study,we aimed to demonstrate that a herbal small RNA(s RNA),XKC-sRNA-h3(B55710460,F221.I000082.B11),exhibits potent antihypertensive effects by targeting angiotensin-converting enzyme(ACE)in mice.When compared with captopril,oral administration of the sphingosine(d18:1)-XKC-s RNA-h3 bencaosome more effectively prevented angiotensin II-induced hypertensive cardiac damage and alleviated kidney injury in mice.Such findings indicated that XKC-sRNA-h3 may be a novel orally available ACE inhibitor type oligonucleotide drug for hypertension.

A Study on Early Biological Effects of Oral Administration of Terephthalic Acid in Rats

Rats were fed with foods containing various doses of terephthalic (TPA) for 8 weeks. General status was observed and biological indices(including urine,serum and bone) were determined after 1, 3 and 8 week administration.Differences in urine calcium, ammonia, PH and serum albumin between the treat groups and the control were significant. Marked correlation was found in these indices. No Change in N-acetyl-β-D-glucosaminidase (NAG),serum calcium,bone calcium, alkaline phosphatase and alanine transaminase was noted in the treat groups.It suggests that change of urine ammonium concentration may serve as a protective level in setting the TPA exposure limit.

The Method of Combining Internal and External Treatment of Ulcerative Colitis in Chinese Medicine

Traditional Chinese medicine(TCM)believes that the main pathogenesis of ulcerative colitis is spleen deficiency;damp heat in the large intestine as the symptom,the treatment must be warming,clearing,eliminating,tonifying,astringing concurrently.From the concept of combining holism and the local treatment in TCM,idea of combining internal and external treatment is adopted.That is,the external treatment follows the therapeutic principle of using herbs with a bitter and cold nature to eliminate stagnation,and the seven carbon decoction,which can clear heat and dampness,cool the blood,and stop dysentery,is used as a rectal drip to retain the enema.Internal treatment follows the therapeutic principle of warmly tonifying and cultivating vital qi,with oral Chinese herbal medicine named Maodie Tang to strengthen the spleen and tonify the kidney,clearing heat and inducing dampness.

Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia

Microglia,which are tissue-resident macrophages in the brain,play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis.Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria,and activates immune cells including microglia via Toll-like receptor 4 signaling.Lipopolysaccharide is generally known as an endotoxin,as administration of highdose lipopolysaccharide induces potent systemic inflammation.Also,it has long been recognized that lipopolysaccharide exacerbates neuroinflammation.In contrast,our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer’s disease pathology and suggested that neuroprotective microglia are involved in this phenomenon.Additionally,other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype.Therefore,lipopolysaccharide may not a mere inflammatory inducer,but an immunomodulator that can lead to neuroprotective effects in the brain.In this review,we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide.We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators,but instead must be described by their complex profile comprising various molecules related to inflammatory regulation,phagocytosis,neuroprotection,anti-apoptosis,and antioxidation.In addition,microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training.Immune training of neuroprotective microglia using lowdose lipopolysaccharide,especially through oral lipopolysaccharide administration,may represent an innovative prevention or treatment for neurological diseases;however more vigorous studies are still required to properly modulate these treatments.

Optimal dosing time of Dachengqi decoction for protection of extrapancreatic organs in rats with experimental acute pancreatitis

BACKGROUND Acute pancreatitis(AP)is a pancreatic inflammatory disorder that is commonly complicated by extrapancreatic organ dysfunction.Dachengqi decoction(DCQD)has a potential role in protecting the extrapancreatic organs,but the optimal oral administration time remains unclear.AIM To screen the appropriate oral administration time of DCQD for the protection of extrapancreatic organs based on the pharmacokinetics and pharmacodynamics of AP rats.METHODS This study consisted of two parts.In the first part,24 rats were divided into a sham-operated group and three model groups.The four groups were intragastrically administered with DCQD(10 g/kg)at 4 h,4 h,12 h,and 24 h postoperatively,respectively.Tail vein blood was taken at nine time points after administration,and then the rats were euthanized and the extrapancreatic organ tissues were immediately collected.Finally,the concentrations of the major DCQD components in all samples were detected.In the second part,84 rats were divided into a sham-operated group,as well as 4 h,12 h,and 24 h treatment groups and corresponding control groups(4 h,12 h,and 24 h control groups).Rats in the treatment groups were intragastrically administered with DCQD(10 g/kg)at 4 h,12 h,and 24 h postoperatively,respectively,and rats in the control groups were administered with normal saline at the same time points.Then,six rats from each group were euthanized at 4 h and 24 h after administration.Serum amylase and inflammatory mediators,and pathological scores of extrapancreatic organ tissues were evaluated.RESULTS For part one,the pharmacokinetic parameters(C max,T max,T 1/2,and AUC 0→t)of the major DCQD components and the tissue distribution of most DCQD components were better when administering DCQD at the later(12 h and 24 h)time points.For part two,delayed administration of DCQD resulted in lower IL-6 and amylase levels and relatively higher IL-10 levels,and pathological injury of extrapancreatic organ tissues was slightly less at 4 h after administration,while the results were similar between the treatment and corresponding control groups at 24 h after administration.CONCLUSION Delayed administration of DCQD might reduce pancreatic exocrine secretions and ameliorate pathological injury in the extrapancreatic organs of AP rats,demonstrating that the late time is the optimal dosing time.

Arsenic toxicity in mice and its possible amelioration

Oral administration of arsenic trioxide(3 and 6 mg/kg body weight/d) for 30 d caused, as compared with vehicle control, dose dependent significant reductions in body weight, absolute weight, protein, glycogen, as well as, total, dehydro and reduced ascorbic acid contents both in the liver and kidney of arsenic treated mice. Succinic dehydrogenase(SDH) and phosphorylase only in the liver activities were significantly reduced in a dose dependent manner. Acid phosphatase activity was significantly decreased in the liver of low dose arsenic treated animals; however, significant rise in its activity was observed in high dose group. As compared with vehicle control, treatment also caused significant dose dependent reductions in SDH, alkaline phosphatase and acid phosphatase activities in the kidney of mice. Vitamin E cotreatment as well as, 30 d withdrawal of arsenic trioxide treatment with or without vitamin E caused significant amelioration in arsenic induced toxicity in mice. Administration of vitamin E during withdrawal of treatment also caused significant amelioration as compared from only withdrawal of the treatment. It is concluded that vitamin E ameliorates arsenic induced toxicities in the liver and kidney of mice.

A meta-analysis of the efficacy of traditional Chinese medicine alone in the treatment of refractory gastroesophageal reflux disease

Background:To systematically evaluate the efficacy and safety of traditional Chinese medicine in the treatment of refractory gastroesophageal reflux.Methods:PubMed,The Cochrane Library,Embase,Web of Science,China National Knowledge Infrastructure,Wanfang Database,China Science and Technology Journal Database and Chinese BioMedical Literature Database were searched for randomized controlled trials of traditional Chinese medicine in the treatment of refractory gastroesophageal reflux from database establishment time to December 2020.After two researchers independently screened the literature,extracted data and evaluated the bias risk included in the study,RevMan5.3 software was used for meta-analysis.Results:A total of 12 randomized controlled trials,were included,including 893 patients.The results of meta-analysis showed that the total effective rate of the treatment group(relative risk=1.28,95%confidence interval(CI)(1.19,1.38),P<0.00001),RGERDQ(refractory gastroesophageal reflux disease)score(mean difference(MD)=−3.35,95%CI(−4.13,−2.57),P<0.00001],acid reflux(acid in the stomach comes out of the mouth)[MD=−0.30,95%CI(−0.45,−0.15),P<0.00001],heartburn(the feeling that the heart is burned)(MD=−0.44,95%CI(−0.60,−0.29),P<0.00001,and retrosternal pain(MD=−0.27,95%CI(−0.44,−0.10),P<0.00001,belching(MD=−0.40,95%CI(−0.57,−0.24),P<0.00001],endoscopic mucosal score(MD=−0.62,95%CI(−0.78,−0.46),P<0.00001],the differences were statistically significant,and the effective rate of mucosal improvement under endoscopy was P=0.93>0.05,with no statistically significant difference.Conclusion:The current evidence shows that traditional Chinese medicine in the treatment of refractory gastroesophageal reflux disease is better than that of western medicine in the total effective rate,relieving acid reflux,heartburn,retrosternal pain and belching symptoms,but it is impossible to judge the improvement of mucosa under endoscope.Due to the limitations of the quality and quantity of included studies,more high-quality studies are needed to confirm the above conclusions.

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Urea transporters(UT)play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics.Thus,UT inhibitors are promising for development as novel diuretics.In the present study,a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening.Optimization of the inhibitor led to the identifi-cation of a promising preclinical candidate,N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide(1 H),with excellent in vitro UT inhibitory activity at the submicromolar level.The half maximal inhibitory concentrations of 1 H against UT-B in mouse,rat,and human erythrocyte were 1.60,0.64,and0.13 mmol/L,respectively.Further investigation suggested that 8 mmol/L 1 H more powerfully inhibited UT-A1 at a rate of 86.8%than UT-B at a rate of 73.9%in MDCK cell models.Most interestingly,we found for the first time that oral administration of 1 H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats.Additionally,1 H did not exhibit apparent toxicity in vivo and in vitro,and possessed favorable pharmacokinetic characteristics.1 H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

The application of biomacromolecules to improve oral absorption by enhanced intestinal permeability:A mini-review

Oral administration has been widely regarded as the most conve nient,quick and safe approach compared to other routes of drug delivery.However,oral absorption of drugs is often limited due to rigorous environments and complex obstacles in gastrointestinal tract.Having received considerable attention,biomacromolecules have been applied for oral drug delivery to improve the bioavailability,which could be attributed to its stability and unique bioactivities,including intestinal adhesion,opening of epithelial tight junctions,inhibiting cell efflux and regulating relative protein expression.Specifically,enhancing intestinal permeability has been regarded as a promising strategy for improving bioavailability of oral drug delivery.In this review,a series of biomacromolecules and the related mechanisms of increasing intestinal permeability for enhanced oral bioavailability are comprehensively classified and elucidated.In addition,recent advances in biomacromolecules based oral delivery and related future directions are mentioned and predicted in this review article.

Fabrication of ulcer-adhesive oral keratin hydrogel for gastric ulcer healing in a rat

Hydrogel has been used for in suit gastric ulcer therapy by stopping bleeding,separating from ulcer from gastric fluids and providing extracellular matrix scaffold for tissue regeneration,however,this treatment guided with endoscopic catheter in most cases.Here,we developed an oral keratin hydrogel to accelerate the ulcer healing without endoscopic guidance,which can specially adhere to the ulcer because of the high-viscosity gel formation on the wound surface in vivo.Approximately 50%of the ulcer-adhesive keratin hydrogel can resident in ethanol-treated rat stomach within 12 h,while approximately 18%of them maintained in health rat stomach in the same amount of time.Furthermore,Keratin hydrogels accelerated the ethanol-induced gastric ulcer healing by stopping the bleeding,preventing the epithelium cells from gastric acid damage,suppressing inflammation and promoting re-epithelization.The oral administration of keratin hydrogel in gastric ulcer treatment can enhance the patient compliance and reduce the gastroscopy complications.Our research findings reveal a promising biomaterial-based approach for treating gastrointestinal ulcers.

Functionality of dietary antimicrobial peptides in aquatic animal health:Multiple meta-analyses

Effects of antimicrobial peptides(AMP)added to diets on aquatic animal health and body function are influenced by multiple factors such as animal species,initial body weight,the dosage of AMP and feeding duration.However,there is limited knowledge on the relationship between these factors and the body function of aquatic animals.Here,we aimed to perform multiple meta-analyses to investigate the effects of dietary AMP on growth performance(feed conversion ratio[FCR],specific growth rate[SGR]),enzyme activity(superoxide dismutase activity[SOD],lysozyme activity[LSA]),disease resistance(cumulative survival rate[CSR],the expression of immune-related genes[GENE])and the abundance of gut microbiota(MICRO)from a pool of empirical studies.Additionally,the dose-effect model was applied to determine the optimal AMP dose,initial body weight and feeding duration to maximize body function.To conduct the meta-analyses,we included 34 publications that estimated 705 effect sizes across 21 fish,2 shrimp and 2 shellfish species.The results confirmed that the inclusion of AMP in the diet can significantly improve SGR,SOD,LSA,CSR and GENE and decrease FCR for aquatic animals.Interestingly,our findings implied a slight positive effect of AMP on MICRO albeit with a limited number of studies available on fish gut microbial communities.Although no significant linear or quadratic relationship was predicted by meta-regression,the dose-effect indicated that the optimal AMP doses for FCR,SGR,SOD and LSA were 707.5,750.0,1,050.0 and 937.5 mg/kg,respectively.Taken together,fish with an initial body weight of 30 g could be fed with a dose of 600 to 800 mg/kg for 2 mo when AMP-supplemented diets were applied in aquaculture,which can effectively improve body function and health while lowering aquafeed costs.In addition,more studies should address fish gut microbiota to delimitate the influence of dietary AMP on MICRO in the future.

Expression of phenylalanine ammonia lyase as an intracellularly free and extracellularly cell surface-immobilized enzyme on a gut microbe as a live biotherapeutic for phenylketonuria

Phenylketonuria(PKU),a disease resulting in the disability to degrade phenylalanine(Phe)is an inborn error with a 1 in 10,000 morbidity rate on average around the world which leads to neurotoxicity.As an potential alternative to a protein-restricted diet,oral intake of engineered probiotics degrading Phe inside the body is a promising treatment,currently at clinical stage II(Isabella,et al.,2018).However,limited transmembrane transport of Phe is a bottleneck to further improvement of the probiotic’s activity.Here,we achieved simultaneous degradation of Phe both intracellularly and extracellularly by expressing genes encoding the Phe-metabolizing enzyme phenylalanine ammonia lyase(PAL)as an intracellularly free and a cell surface-immobilized enzyme in Escherichia coli Nissle 1917(EcN)which overcomes the transportation problem.The metabolic engineering strategy was also combined with strengthening of Phe transportation,transportation of PAL-catalyzed trans-cinnamic acid and fixation of released ammonia.Administration of our final synthetic strain TYS8500 with PAL both displayed on the cell surface and expressed inside the cell to the Pah^(F263S)PKU mouse model reduced blood Phe concentration by 44.4%compared to the control Ec N,independent of dietary protein intake.TYS8500 shows great potential in future applications for PKU therapy.

Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancer via ROS generation and microbiota modulation

Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer,their inefficient therapeutic outcomes,serious adverse effects,and high cost of mass production remain crucial challenges.Herein,we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers(TFENs).These nanovehicles had desirable particle sizes(131 nm),exosome-like morphology,and negative zeta potentials.Furthermore,TFENs were found to contain large amounts of polyphenols,flavonoids,functional proteins,and lipids.Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species(ROS)amplification.The increased intracellular ROS amounts could not only trigger mitochondrial damage,but also arrest cell cycle,resulting in the in vitro anti-proliferation,anti-migration,and anti-invasion activities against breast cancer cells.Further mice investigations demonstrated that TFENs after intravenous(i.v.)injection or oral administration could accumulate in breast tumors and lung metastatic sites,inhibit the growth and metastasis of breast cancer,and modulate gut microbiota.This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v.and oral routes.

变应性鼻炎治疗中口服抗组胺药物的地位

变应性鼻炎（AR）已成为了一个全球性的健康问题,发病率呈逐年增长趋势,其发病时可以影响患者的日常工作、生活及学习效率,WHO组织全球鼻科和变态反应科的学者编写了＂变应性鼻炎及其对哮喘的影响（Allergic rhinitis and its impact on asthma,ARIA）＂指南,