Enlightenment of COVID-19 Treated by Botanical Drugs on the Development of Drugs for Rare Diseases in China

Objective To study the feasibility of developing botanical drugs to treat intractable diseases and play an important role in dealing with major public health crises.Methods From January 1990 to May 2021,a bibliographic search was carried out on the use of botanical drugs,rare disease drugs,related registration management policies and regulations in PubMed and CNKI.The following keywords were searched in the database:Rare disease policies and regulations,orphan drugs,botanical drugs for intractable diseases,botanical drugs for the treatment of new coronary pneumonia,traditional Chinese medicine,and emergency guidelines for major public health crisis.Other data were obtained from“Chinese Pharmacopoeia”and relevant Chinese government websites for sorting and analysis.Results and Conclusion Based on 39 Chinese corresponding policies and regulations,challenges and opportunities of developing and researching drugs for treating rare diseases were found out after the analysis and comparison.Based on the study of national policies on drugs for rare diseases,the priority review and approval procedures in the drug registration,as well as China’s emergency guidelines and policies for major public health events,some problems in the use of drugs for rare diseases are found out.Therefore,it is recommended to actively adopt the property rights protection system,explore the folk prescriptions of traditional Chinese medicine and the potential of hospital preparations,and the registration review strategy of giving priority to the use of botanical drugs for rare diseases.Thus,the international status of botanical drugs for rare disease and the influence of responding to major public health events can be enhanced.

EFFECT OF ANTITUMOR DRUGS ON THE ACTIVITY OF DNA TOPOISOMERASE I

The activity of DNA topoisomerase Ⅱ prepared from either normal or tumor tissues were compared. It was found that the unknotting activity of the enzyme in malignant tumor cells was higher than that in normal cells. We selected some antitumor drugs including Chinese traditional medicine, and observed their effects on the unknotting activity of topoisomerase Ⅱ. The results showed that inhibition of the unknotting activity of the enzyme required very low concentrations of drugs, but much higher concentrations were required for other tested. Some antitumor drugs had no effect on the enzyme were also proved. It is interesting that carrageenan, an antiviral drug, strongly blocked the unknotting activity although its antitumor activity has not been reported.

Quality Drugs Only

RECENTWestern media reports blaming China for the flood of counterfeit malar- ia drugs sent to Africa have once again highlighted a major health problem on the continent. Malaria remains the main cause of death for children under five in Sub-Saharan Africa. and costs the continent an estimated $12 billion in lost productivity each year. Counterfeit anti-malaria medicines are contributing to deaths across the world and also leading to drug resistance - putting billions of people at risk. According to a World Health Organization （WHO） study, an estimated one third of the drugs used worldwide to combat malaria are substand- ard. This is a critical problem, particularly serious in Africa. where Tanzania and Uganda have the highest number of malaria cases in the world.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

The use of non-steroidal anti-inflammatory drugs(NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of nonalcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

Combined effects of Cantide and chemotherapeutic drugs on inhibition of tumor cells' growth in vitro and in vivo

AIM: To investigate the combination effect of hTERT antisense oligonucleotide 'Cantide' and three chemotherapeutic drugs (cisplatin, 5-fluorouracil (5-FU) and adriamycin (ADM)) on inhibiting the proliferation of HepG2, BGC and A549 cell lines in vitro, and to investigate the efficacy of Cantide used in combination with cisplatin (DDP) in vivo. METHODS: Cantide was transfected into these tumor cells by Lipofectin, and cell growth activity was calculated by microcytotoxicity assay. In vivo study, cells of HepG2 were implanted in Balb/c nude mice for 4 d. Then Cantide, DDP and Cantide+DDP were given intra peritonea Ily for 24 d respectively. The body weights of the tumor-bearing animals and their tumor mass were measured later to assess the effect of combination therapy in the nude mice. To evaluate the interaction of Cantide and these chemotherapeutic drugs, SAS software and Jin Zhengjun method were used. RESULTS: Combination treatments with 0.1μmol/L Cantide reduced the IC50 of DDP, 5-FU and ADM from 1.07, 4.15 and 0.29 μg/mL to 0.25,1.52 and 0.12 μg/mL respectively. The inhibition ability of DDP, 5-FU and ADM respectively in combination with Cantide in these tumor cells was higher than that of these drugs alone (P<0.0001). And synergism (Q≥1.15)was observed at the lower concentration of DDP (≤1μg/mL) and ADM (≤0.1 μg/mL) with combination of Cantide. In vivo, combination treatment with Cantide and DDP produced the greater growth inhibition of human liver carcinoma cells HepG2 in nude mice (0.65±0.19 g tumor) compared with that when only one of these drugs was used (Cantide group: 1.05±0.16 g tumor, P= 0.0009<0.001; DDP group: 1.13±0.09 g tumor, P= 0.0001<0.001). CONCLUSION: These findings indicate that Cantide may enhance therapeutic effectiveness of chemotherapeutic drugs over a wide range of tumor cells in vitro, and the combination use of Cantide and DDP can produce much higher inhibition rates, as compared with when either of these drugs was used only in vivo.

Effects of antidiabetic drugs on epicardial fat

Epicardial adipose tissue is defined as a deposit of adipocytes with pathophysiological properties similar to those of visceral fat, located in the space between the myocardial muscle and the pericardial sac. When compared with subcutaneous adipose tissue, visceral adipocytes show higher metabolic activity, lipolysis rates, increased insulin resistance along with more steroid hormone receptors. The epicardial adipose tissue interacts with numerous cardiovascular pathways via vasocrine and paracrine signalling comprised of pro-and anti-inflammatory cytokines excretion. Both the physiological differences be-tween the two tissue types, as well as the fact that fat distribution and phenotype, rather than quantity, affect cardiovascular function and metabolic processes, establish epicardial fat as a biomarker for cardiovascular and metabolic syndrome. Numerous studies have underlined an association of altered epicardial fat morphology, type 2 diabetes mellitus(T2 DM) and adverse cardiovascular events. In this review, we explore the prospect of using the epicardial adipose tissue as a therapeutic target in T2 DM and describe the underlying mechanisms by which the antidiabetic drugs affect the pathophysiological processes induced from adipose tissue accumulation and possibly allow for more favourable cardiovascular outcomes though epicardial fat manipulation.

Effects of anti-hypertensive drugs on esophageal body contraction

AIM:To clarify the effects of anti-hypertensive drugs on esophageal contraction and determine their possi-ble relationship with gastro-esophageal reflux disease.METHODS:Thirteen healthy male volunteers were enrolled. Esophageal body peristaltic contractions and lower esophageal sphincter (LES) pressure were measured using high resolution manometry. All subjects were randomly examined on four separate occasions following administrations of nifedipine,losartan,and atenolol,as well as without any drug administration.RESULTS:Peristaltic contractions by the esophageal body were separated into three segments by two troughs. The peak peristaltic pressures in the mid and lower segments of the esophageal body under atenolol administration were signifi cantly higher than those without medication in a supine position. On the other hand,peristaltic pressures under nifedipine administration were lower than those observed without drug ad-ministration. Losartan did not change esophageal body peristalsis. Atenolol elevated LES pressure and slowed peristaltic wave transition,while the effects of nifedip-ine were the opposite. CONCLUSION:Among the anti-hypertensive drugs tested,atenolol enhanced esophageal motor activity,which was in contrast to nifedipine.

Impact of discontinuing non-steroidal antiinflammatory drugs on long-term recurrence in colonic diverticular bleeding

AIM: To determine the effect of discontinuing nonsteroidal antiinflammatory drugs(NSAIDs) on recurrence in long-term follow-up patients with colonic diverticular bleeding(CDB).METHODS: A cohort of 132 patients hospitalized for CDB examined by colonoscopy was prospectively enrolled. Comorbidities, lifestyle, and medications(NSAIDs, low-dose aspirin, antiplatelet agents, anticoagulants, acetaminophen, and corticosteroids) were assessed. After discharge, patients were requested to visit the hospital on scheduled days during the followup period. The Kaplan-Meier method was used to estimate recurrence.RESULTS: Median follow-up was 15 mo. The probability of recurrence at 1, 6, 12, and 24 mo was 3.1%, 19%, 27%, and 38%, respectively. Of the 41 NSAID users on admission, 26(63%) discontinued NSAID use at discharge. Many of the patients who could discontinue NSAIDs were intermittent users, and could be switched to alternative therapies, such as acetaminophen or an antiinflammatory analgesic plaster. The probability of recurrence at 12 mo was 9.4% in discontinuing NSAID users compared with 77% in continuing users(P < 0.01, log-rank test). The hazard ratio for recurrence in the discontinuing NSAIDs users was 0.06 after adjusting for age > 70 years, right-sided diverticula, history of hypertension, and hemodialysis. No patients developed cerebrocardiovascular events during follow-up.CONCLUSION: There is a substantial recurrence rate after discharge among patients hospitalized for diverticular bleeding. Discontinuation of NSAIDs is an effective preventive measure against recurrence. This study provides new information on risk reduction strategies for diverticular bleeding.

Follow-up Efficacy of Integrative Chinese and Western Drugs on Localized Scleroderma with Vitamine B 6 and Xuefu Zhuyu Decoction (血府逐瘀汤)

Objective: To investigate the therapeutic effects of vitamine B 6 (Vit B 6) and Xuefu Zhuyu Decoction (血府逐瘀汤,XFZY, for activating blood circulation to remove stasis) in patients with localized scleroderma(LSD). Methods: Thirty-three patients were treated with XFZY and Vit B 6, with 15 cases taking orally prednisone acetate and 20 healthy volunteers as the control. Their level of soluble interleukin-2 receptor (sIL-2R) and tumor necrosis factor-α (TNF-α) in the patients with LSD before and after treatment were observed. Results: The level of sIL-2R and TNF-α in the serum from the patients with LSD were higher than those of healthy volunteers ( P <0.01). After treatment with Vit B 6 and XFZY, the level of sIL-2R and TNF-α from the patients with LSD decreased significantly ( P <0.01), but there were no difference between the group taking Vit B 6 plus XFZY and the group given prednisone. Conclusion: The activating blood circulation to remove stasis approach in treating LSD with integrative Chinese and Western drugs got better results, and metabolic disorder of tryptophan might be correlated with the etiology of LSD.

Effect of Second-generation Antiepileptic Drugs on Diplopia:A Metaanalysis of Placebo-controlled Studies

Different antiepileptic drugs(AEDs) may cause similar adverse effects,one of which is diplopia.However,the AEDs causing diplopia and the dose-response effect of each drug remains uncertain.In this study,we compared several second-generation AEDs to find out whether they would contribute to the risk of diplopia and their effect-causing dose.A meta-analysis was performed on 19 studies in agreement with our inclusion criteria.The results showed that eight commonly used second-generation AEDs(gabapentin,levetiracetam,oxcarbazepine,lamotrigine,pregabalin,topiramate,vigabatrin and zonisamide) could cause diplopia.The reported odds ratios(ORs) ranged from 1.406 to 7.996.Ranking risks from the highest to the lowest ORs of the eight AEDs of any dose resulted in the following order:use of oxcarbazepine(7.996),levetiracetam(7.472),lamotrigine(5.258),vigabatrin(3.562),pregabalin(3.048),topiramate(2.660),gabapentin(1.966),zonisamide(1.406).Taking into account the ORs above,we can conclude that second-generation AEDs of any dose may cause diplopia.However,the levetiracetam-caused diplopia needs to be further studied according to the data(OR,7.472;95% confidence interval,0.375-148.772).These findings ask for better concerns about patients’ quality of life when giving antiepileptic treatments.

Effects of anti-diabetic drugs on sarcopenia: Best treatment options for elderly patients with type 2 diabetes mellitus and sarcopenia

Human life expectancy increases as society becomes more developed.This increased life expectancy poses challenges associated with the rapid aging of the population.Sarcopenia,an age-related disease,has become a worldwide health issue.Patients with sarcopenia experience decreases in muscle mass and function,becoming frail and eventually bedridden.Type 2 diabetes mellitus(T2DM)is also a major health issue;the incidence of T2DM increases with aging.T2DM is associated with reduced muscle strength and poor muscle quality and may contribute to acceleration of the aging process,augmenting age-related sarcopenia.Recent studies indicate that elderly patients with diabetes are at an increased risk for sarcopenia.Therefore,these older diabetic patients with sarcopenia need specific anti-diabetic therapies targeting not only glycemic control but also sarcopenia,with the goal of preventing sarcopenia in presarcopenic patients.Presently,various types of hypoglycemic drugs are available,but which hypoglycemic drugs are better suited for geriatric T2DM patients with sarcopenia remains undetermined.In this review,we discuss the association between diabetes and sarcopenia in geriatric patients,and how anti-diabetic drugs may influence sarcopenia outcomes.This review will guide clinical workers in the selection of drugs best suited for this patient population.

An Analysis of the Effects of Blood Pressure and Antihypertensive Drugs on Heart Disease

Background: The American College of Cardiology (ACC), American Heart Association (AHA) and other organizations announced a new hypertension guideline (2017 ACA/AHA Guideline) in November 2017. However, other organizations such as the European Society of Cardiology and European Society of Hypertension maintained their diagnostic thresholds. It is necessary to evaluate the effects of blood pressure (BP) and antihypertensive drugs on the probability of having heart disease (HD). Data and Methods: The effects of BP, antihypertensive drugs and other factors on the probability of undergoing HD treatment were analyzed. We used a dataset containing 83,287 medical check-up and treatment records obtained from 35,504 individuals in 5 fiscal years. The probit models were used in the study. Considering the possibility of endogeneity problems, different types of models were used. Results: We could not find evidence that a higher systolic BP increased the probability of undergoing HD treatment. However, diastolic BP increased the probability in most of the models. Taking antihypertensive drugs also increased the probability of undergoing HD treatment. Diabetes was another important risk factor. Conclusion: The results of this study did not support the new 2017 ACC/AHA Guideline. It is necessary to choose proper drugs and methods to reduce the risks of side effects. Limitations: The dataset was observatory, the data were obtained from just one medical society, and sample selection bias might exist.

Effect of non-steroidal anti-inflammatory drugs on fracture healing in children:A systematic review

BACKGROUND Non-steroidal anti-inflammatory drugs(NSAIDs)are among the most commonly prescribed medications in the United States.Although they are safe and effective means of analgesia for children with broken bones,there is considerable variation in their clinical use due to persistent concerns about their potentially adverse effect on fracture healing.AIM To assess whether NSAID exposure is a risk factor for fracture nonunion in children.METHODS We systematically reviewed the literature reporting the effect of NSAIDs on bone healing.We included all clinical studies that reported on adverse bone healing complications in children with respect to NSAID exposure.The outcomes of interest were delayed union or nonunion.Study quality was assessed using the Newcastle-Ottawa scale for non-randomized studies.A final table was constructed summarizing the available evidence.RESULTS A total of 120 articles were identified and screened,of which 6 articles were included for final review.Nonunion in children is extremely rare;among the studies included,there were 2011 nonunions among 238822 fractures(0.84%).None of the included studies documented an increased risk of nonunion or delayed bone healing in those children who are treated with NSAIDs in the immediate post-injury or peri-operative time period.Additionally,children are likely to take these medications for only a few days after injury or surgery,further decreasing their risk of adverse side-effects.CONCLUSION This systematic review suggests that NSAIDS can be safely prescribed to pediatric orthopaedic patients absent other contraindications without concern for increased risk of fracture non-union or delayed bone healing.Additional prospective studies are needed focusing on higher risk fractures and elective orthopaedic procedures such as osteotomies and spinal fusion.

Effects of fi laricidal drugs on longevity and enzyme activities of the microfilariae of Setaria cervi in white rats

Objective: To analyse the efficacy of diethylcarbamazine(DEC), tetramisole and chlorpromazine on the longevity and activity of glucose-6-phosphatase and succinate dehydrogenase in the microi lariae recovered from the peripheral circulation of the rats before and after the treatment.Methods: Setaria cer vi worms were implanted in white rats via laparotomy and microfilaraemic rats were divided into 4 groups. Groups 1, 2 and 3 were treated with DEC, tetramisole and chlorpromazine respectively, while Group 4 served as infected control. Longevity of microi lariae and dif erential leucocyte counts were recorded till the disappearance of microi lariae from peripheral blood. Glucose-6-phosphatase and succinate dehydrogenase enzymes were localized in the microi lariae recovered from normal and treated rats.Results: The microi lariae survived for 48 days in untreated rats while survival was reduced to 15, 21 and 27 days after treatment with DEC, tetramisole and chlorpromazine, respectively. Eosinophils and neutrophils increased during 2nd and 3rd weeks, whereas the lymphocytes increased during 4-7 weeks. DEC treatment resulted in slight decrease in the localization of succinate dehydrogenase but not in glucose-6-phosphatase. Tetramisole and chlorpromazine treatment did not show any appreciable change in the localization of both the above enzymes. Conclusions: DEC proved the most ef ective drug which cleared the microi laraemia within 15 days and reduced the activity of succinate dehydrogenase to some extent followed by tetramisole and chlorpromazine which took more time for the clearance of microi lariae and had no ef ect on the localization of both glucose-6-phosphatase and succinate dehydrogenase.

The Antagonistic Action of Heat-Clearing and Detoxifying Chinese Drugs on Endotoxins

In the recent decade, interest in treatment and prevention of many critical, severe and acute diseases caused by bacterial endotoxins has been aroused along with the advance of the knowledge on the nature of the endotoxin and the conditions involved. In abroad, attention has been mainly payed to raising antisera and monocolonal antibodies against the endotoxin and the induced mediators. However, the allergic reactions and the cost are still the problems. Till now, there is no drug that can antagonize endotoxin with high effectiveness and low toxicity. Clinical treatments are still confined in inhibiting or killing the pathogen, and correcting the internal environmental disturbance. Being less toxic and rich in resources with low cost and less side-effects, screening of effective Chinese drugs for antagonizing endotoxin is of important and practical significance. Endotoxin belongs to the category of toxic evils, or more precisely, the heat toxin in TCM. Therefore the application of heat-clearing and detoxifying Chinese drugs to antagonizing endotoxins is consistent with the theory of TCM. Some achievements in this field are reported as follows.

Effects of chronic therapy with non-steroideal antinflammatory drugs on gastric permeability of sucrose: A study on 71 patients with rheumatoid arthritis

AIM： To evaluate the gastric permeability after both acute and chronic use of non-steroidal anti-inflammatory drugs （NSAIDs） and to assess the clinical usefulness of sucrose test in detecting and following NSAIDs-induced gastric damage mainly in asymptomatic patients and the efficacy of a single pantoprazole dose in chronic users. METHODS： Seventy-one consecutive patients on chronic therapy with NSAIDs were enrolled in the study and divided into groups A and 13 （group A receiving 40 mg pantoprazole daily, group B only receiving NSAIDs）. Sucrose test was performed at baseline and after 2, 4 and 12 wk, respectively. The symptoms in the upper gastrointestinal tract were recorded. RESULTS： The patients treated with pantoprazole had sucrose excretion under the limit during the entire follow-up period. The patients without gastroprotection had sucrose excretion above the limit after 2 wk, with an increasing trend in the following weeks （P = 0.000）. A number of patients in this group revealed a significantly altered gastric permeability although they were asymptomatic during the follow-up period. CONCLUSION： Sucrose test can be proposed as a valid tool for the clinical evaluation of NSAIDs-induced gastric damage in both acute and chronic therapy. This tecnique helps to identify patients with clinically silent gastric damages. Pantoprazole （40 mg daily） is effective and well tolerated in chronic NSAID users .

Advances in the Researches on the Blocking Effect of Chinese Drugs on Tumors

Malignant tumors are caused by multiple carcinogenic factors undergoing several stages. The occurrence and development of tumors may be prevented and blocked if some effective interference factors are brought into play.1 At present, there are two main subjects for the researches, that is, blocking the precancerous lesions and blocking the develop-ment of tumors. The former focuses on the removing of carcinogenic factors and on the chemoprophylaxis of cancer, while the latter on the inhibition of cancer cell infiltration and cancerometastasis. These are summarized as follows.

Effects of anti-TNF biologic drugs on uveitis severity in Behcet patients: systematic review and Meta-analysis

AIM:To investigate effects of anti-TNF biologic drugs on uveitis severity(comparing visual acuity log MAR levels) in Behcet patients.METHODS:Three databases Pub Med, Scopus, and the Web of Science were searched for qualified papers focusing on the anti-TNF-α factors treatment in Behcet’s disease(BD)-associated uveitis. Studies that were designed pre and post anti-TNF drug treatment, were selected. After determining the search strategy for this study, the relevant data were extracted. RESULTS:The initial search was performed in the target databases and a total of about 1458 articles were found. Fifteen articles were selected for systematic review and only 12 of them had inclusion criteria for Meta-analysis(with visual acuity data). The mean dose of prednisolone before and after biological treatments was reported in 5 studies(28.56 and 7.56 mg/kg, respectively). Also, the preliminary results indicate a significant reduction in visual acuity log MAR levels(MD=-1.5 IU/L, 95%CI:-2.1,-0.01).CONCLUSION:Biological drugs significantly reduce the dose of prednisolone and affect visual acuity values.

Preventive Effects of Five Drugs on Mycoplasma Pneumonia of Swine (MPS)

The paper was to explore the preventive effects of five drugs on mycoplasma pneumonia of swine （MPS） and to provide reference for clinical medication of pig farms in Hainan Province. A total of 444 health piglets were randomly divided into 6 groups, including five medication groups （72 piglets in group A, 74 pig- lets in group B, 72 piglets in group C, 76 piglets in group D, 76 piglets in group E） and one control group （74 piglets）. The piglets in experimental groups were treated drugs once a day for successive 5 days at 30, 60, 90, 120 and 150 of age. The piglets in control group were free of medication. At 70 and 140 days of age, 15 piglets of each group were randomly selected to collect their blood sermn. The Mycoplasma hyopneumoniae （M-Hyo） antibodies in serum were measured by en- zyme-linked immunosorbent assay （ELISA）. During the experiment, the incidence rates of respiratory disease, lung lesion, feed conversion rate, average daily gain （ADG）, and mortality rate of pigs were also observed and recorded. The results showed that the five drugs had significant difference in preventative effects. Group C （Zhiyuanjing group） received the best preventive effect and the highest economic benefits. Compared with control group, the ADG and feed conversion rate in group C were increased by 7.53% and 9.09%, respectively; the incidence rate of respiratory disease was reduced by 13.44% and lung lesion was alleviated by 81.43% ; and the earnings of each pig could rise by 132.70 yuan. The preventative effect and economic benefit of the drugs was sequenced by Chansu Kechuanling and Bingchan Kechuanwang. Wante Feilin and amoxicillin had weaker preventive effects against MPS but greatly influenced growth performance of pigs, so they should be used alternatively with other drugs.