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The National Health Commission of the People′s Republic of China and six other departments jointly released the Second Catalog of Rare Diseases, which expanded the definition of rare diseases in China. The expansion of the catalog means greater attention to rare diseases at the national level, and is also expected to accelerate the launch of relevant rare disease drugs and benefit more rare disease patients. When the new rare disease catalog released, it is necessary to quickly sort out the availability of drugs and find out the base number for the advancement of subsequent relevant measures. This paper searched official medical information websites and medical databases such as the National Medical Products Administration (NMPA), the Center for Drug Evaluation (CDE), and foreign drug regulatory agencies, and sorted out and summarized the subject categories of diseases included in the Second Catalog of Rare Diseases, the corresponding global research and development and implementation of drugs, as well as the medical insurance access situation in China, elaborates on the differences in the accessibility of orphan drugs at home and abroad. As China′s prevention, treatment and protection of rare diseases has reached a new point, plans and prospects are made for the introduction of relevant policies in the future, as well as the promotion of research and development and protection and other key tasks.
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Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.
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Objective:To evaluate the effect of intravenous infusion of lidocaine on the efficacy of conventional treatment for rheumatoid arthritis.Methods:Forty-four patients with rheumatoid arthritis of either sex, aged 32-85 yr, weighing 40-76 kg, who were admitted to the Department of Pain and Nephrology in our hospital from September 2019 to September 2020, were divided into 2 groups ( n=22 each) according to the random number table method: control group (C group) and lidocaine group (L group). Both groups received conventional treatment.When visual analogue scale (VAS) score ≥5, glucocorticoid (GC) and non-steroidal anti-inflammatory drugs (NSAIDs) were taken orally to maintain the VAS score ≤4.In group L, 0.2% lidocaine hydrochloride injection 3 mg/kg (diluted with 0.9% sodium chloride injection 500 ml) was intravenously infused at a rate of 25 ml/h for 2 h, once a day, for 5 consecutive days, based on the conventional treatment.The VAS score, 28-joint Disease Activity Score (DAS28 score), simplified disease activity index score (SDAI score), consumption of GC and NSAIDs and adverse reactions were recorded before treatment (T 1) and at 1, 4 and 8 weeks after treatment (T 2-4). The temperature of the pain area of the affected joint was evaluated through infrared thermal imaging at T 1 and T 2. Results:Compared with the baseline at T 1, VAS score, DAS28 score and SDAI score were significantly decreased at each time point, and the temperature of the pain area of the affected joint at T 2 was decreased in the two groups ( P<0.05). There were no significant differences in VAS score, DAS28 score and SDAI score at each time point between two groups ( P>0.05). Compared with group C, the consumption of GC and NSAIDs was significantly decreased, and the temperature of the pain area of the dorsum of both hands and the dorsum of right foot at T 2 and incidence of adverse reactions were decreased in group L ( P<0.05). Conclusions:Intravenous infusion of lidocaine can optimize the efficacy of conventional treatment for rheumatoid arthritis.
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@#Objective To explore the risk of venous thromboembolism (VTE), especially lower-extremity deep vein thrombosis (DVT) and pulmonary embolism (PE), for stroke patients in rehabilitating, and the functional outcome. Methods A total of 3 557 stroke patients in the neurological rehabilitation center of Beijing Bo'ai Hospital for stroke rehabilitation from January, 2015 to October, 2020 were reviewed through the electronic medical record system. Demographic characteristics, stroke characteristics (type and location), laboratory data (D-dimer polymer and arterial partial pressure of oxygen), motor function (Brunnstrom stage, Fugl-Meyer Assessment of motor and balance, modified Ashworth Scale score of triceps crus, and Holden Walking Ability Classification), activities of daily living (Barthel Index), and anticoagulant/antiplatelet treatment data were collected and analyzed. Results The incidence of DVT and PE was 28.5% and 1.29%, respectively. Most were found 30 days later after onset. The incidence of PE was higher after ischemic stroke (χ2 = 12.49, P < 0.001) rather than hemorrhagic stroke. The patients with hemispheric stroke, severe lower-extremity paralysis, and poor activities of daily living were more prone to complications associated with VTE. After rehabilitation, the function of stroke patients with PE could be improved (|t| > 4.302, P < 0.001). Conclusion The risk of DVT and PE in patients during stroke convalescence may not be negligible, and those with older age, previous history of thrombosis, severe stroke, and severe limb paralysis may be stratified in high-risk. Following anticoagulation treatment, early individualized comprehensive rehabilitation can be done for patients with PE to improve their function and activities of daily living.
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@#Objective To investigate the incidence of Holmes tremor (HT) after stroke and its outcome after medication and rehabilitation. Methods Patients diagnosed as HT after stroke in the ward of neurorehabilitation department from October, 2019 to September, 2021 were reviewed the clinical features, imaging manifestations, drug treatment plan, rehabilitation evaluation scales scores, rehabilitation plan and outcome. Results There were five inpatients with HT (0.7%, 5/715), and all were hemorrhagic stroke, accounting for 1.7% of hemorrhagic stroke. The lesions were located in the midbrain and pons in three cases, cerebellum in one case and thalamus in one case. The tremor appeared 1.5 to seven months after stroke, limited on head and limbs, with other neurological dysfunction. After the comprehensive treatment of drugs and rehabilitation, tremor improved in four cases, and ineffective in one case. The motor and balance function improved less, and the activities of daily living improved somehow. Conclusion The incidence of Holmes tremor is low in stroke patients. The tremor might respond to the treatment, but motor function would not.
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@#Objective To observe the clinical effect of Mirabegron combined with Silodosin on detrusor hyperactivity with impaired contractile (DHIC).Methods From September, 2019 to December, 2021, 40 patients with DHIC in the Department of Urology of Beijing Bo'ai Hospital were selected and randomly divided into control group and experimental group, with 20 cases in each group. The control group took Silodosin only, and the experimental group took Mirabegron in addition, for four weeks. The urinary diary, residual urine volume, Overactive Bladder Symptom Score (OABSS) and quality of life (QOL) score were compared before and after treatment.Results A total of 18 patients in the control group and 19 in the experimental group finished the trial. After treatment, the number of night urination per day, the residual urine volume and QOL score improved in the control group (P<0.01); the number of urination per 24 hours, the number of night urination per day, the volume per urination, the residual urine volume, the daily urgency score, the OABSS score and QOL score improved in the experimental group (P<0.01). The number decrease of urination per 24 hours, the volume decrease of per urination, the daily urgency score decrease, the OABSS score decrease and QOL score decrease were more in the experimental group than in the control group (P<0.01). The adverse reactions included palpitations, increased heart rate, dyspareunia, increased blood pressure, gastric discomfort, postural hypotension, and retrograde ejaculation, and there was no significant difference between two groups (P > 0.05).Conclusion The efficacy of Mirabellone combined with Silodosin on DHIC is better than Silodosin only, and there was no significant increase in drug-related adverse effects.
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Objective:To explore the value of Neoseq in screening and diagnosis of neonatal fatty acid oxidation disorders (FAOD).Methods:A retrospective case-control study was conducted on 163 500 live births in Changzhou city from April 2015 to April 2021. The following two models were adopted for FAOD screening and diagnosis. (1) Traditional mode: Heel blood samples were obtained from all subjects for initial screening using tandem mass spectrum (TMS), followed by next-generation sequencing (NGS) and other differential diagnostic testings for those with positive results. (2) Neoseq: Neoseq was performed on the true positive, negative and false positive cases according to the traditional mode screening results. The detection rate, additional discovery, reporting period, and other parameters of the two models for FAOD were described and compared.Results:(1) Detection and diagnosis of FAOD: A total of 18 confirmed cases of FAOD were detected through the traditional model, with an incidence of 1/9 083 in Changzhou city. The positive rate was 0.55% (907/163 500) for initial TMS and 0.04% (73/163 500) for the second. The positive predictive value was 2.0%(18/907), with a false positive rate of 98%(889/907) in the initial screening. (2) The results of Neoseq: ①Pathogenic mutations were detected in 16 of the 18 confirmed cases, and the coincidence rate of mutation sites between the two methods was 16/18. The other two confirmed cases were missed diagnosed by Neoseq, including one β-ketothiolase deficiency with only one detected pathogenic mutation and one medium-chain acyl-CoA dehydrogenase deficiency without any detected pathogenic mutation. ②No pathogenic mutations were detected in the 57 false-positive cases by Neoseq. ③Among the 100 negative cases in initial screening, DUOX2 heterozygous mutation, and MTTL1 hemizygous mutation were detected in one case each. ④The median period of results reporting was 43.5 d (28-104 d) for the traditional mode and 12 d (10-15 d) for the Neoseq mode. Conclusions:Neoseq has a high detection rate for FAOD. Combined with TMS screening, Neoseq reduces the false-positive rate of biochemical screening, rapidly identifies genetic causes by shortening the results waiting time and covers diseases that couldn't be detected by traditional biochemical methods.
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Objective:To explore the association between platelet/lymphocyte ratio (PLR) and frequent peritoneal dialysis (PD) - associated peritonitis (PDAP) in PD patients.Methods:The data of PD patients with PDAP from Guizhou Provincial People's Hospital between January 2015 and June 2019 were analyzed retrospectively. The patients were divided into mono group (only once PDAP occurred in one year) and frequent group (2 or more PDAP occurred in one year) according to the frequency of PDAP. The demographic data including gender, age, height and weight, the clinical data including blood pressure, duration of PD, causes of peritonitis, the laboratory data at the first time of PDAP and the prognosis of PDAP were compared between two groups. Logistic regression analysis method was applied to analyze the relationship between PLR and frequent PDAP. The predictive power of PLR was evaluated by receiver operating characteristic curve (ROC).Results:A total of 78 PD patients with PDAP were enrolled, including 53 males and 25 females, with average age of 45.2 years. The total person-year was 765.1 person-years and the incidence of peritonitis was 0.10 case/person-year during the median follow-up of 16 months. All patients were divided into two groups: 53 patients in mono group and 25 patients in frequent group. Compared with mono group, the patients in frequent group had lower body mass index, longer dialysis duration, higher systolic blood pressure level, higher PLR level, lower uric acid level, and higher rate of drug-resistant bacteria in peritoneal effusion (all P<0.05). The extubation rate of the frequent group was 44.0%(11/25), which was significantly higher than that [15.1%(8/53)] of mono group ( P<0.05). Multivariate logistic regression analysis showed that higher PLR level was an independent related factor for frequent PDAP( OR=1.006, 95% CI 1.002-1.010, P=0.003), and the area under the ROC curve of PLR was 0.783(95% CI 0.663-0.904, P<0.001). Conclusions:High PLR level is an independent related factor of frequent PDAP for PD patients, and PLR can be a potential predictor of frequent PDAP.
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Objective:To evaluate the relationship between transforming growth factor beta-3 (TGF-β 3)/mammalian homologs of the drosophila mad gene 3 (Smad3) signaling pathway and neuronal apoptosis during reduction of focal cerebral ischemia-reperfusion (I/R) injury by isoflurane postconditioning (ISO) in rats. Methods:Sixty clean-grade healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 210-230 g, were randomly divided into 5 groups ( n=12 each): sham operation group (group S), cerebral I/R group (group I/R), cerebral I/R plus isoflurane postconditioning group (group I/R+ ISO), cerebral I/R plus pirfenidone group (group I/R+ P), and cerebral I/R plus isoflurane postconditioning plus pirfenidone group (group I/R+ ISO+ P). Local cerebral I/R was produced by middle cerebral artery occlusion for 1.5 h followed by 24-h reperfusion in anesthetized rats.Pirfenidone 5 μg/kg was injected into the lateral ventricle at 30 min before ischemia in I/R+ P and I/R+ ISO+ P groups.In I/R+ ISO and I/R+ ISO+ P groups, 1.5% isoflurane was inhaled for 1 h starting from the time point immediately after onset of reperfusion.Neuro-functional deficit was assessed using neurologic deficit scores (NDS) at the end of reperfusion.Then the animals were sacrificed, and brain tissues were removed for determination of the neuronal damage rate (by Nissl staining), neuronal apoptosis rate (by TUNEL), expression of TGF-β 3 (using immunofluorescence), and expression of TGF-β 3, phosphorylated Smad3 (p-Smad3), caspase-3, Bax and Bcl-2 (by Western blot). Results:Compared with group S, the NDS, neuronal damage rate and apoptosis rate of neurons were significantly increased, the expression of TGF-β 3, caspase-3 and Bax was up-regulated, and the expression of p-Smad3 and Bcl-2 was down-regulated in group I/R ( P<0.05). Compared with group I/R, the NDS, neuronal damage rate and apoptosis rate of neurons were significantly decreased, the expression of TGF-β 3, p-Smad3 and Bcl-2 was up-regulated, and the expression of caspase-3 and Bax was down-regulated in group I/R+ ISO, and the NDS, neuronal damage rate and apoptosis rate of neurons were significantly increased, the expression of TGF-β 3 and p-Smad3 was down-regulated, and the expression of caspase-3 was up-regulated in group I/R+ P ( P<0.05). Compared with group I/R+ ISO, the NDS, neuronal damage rate and apoptosis rate of neurons were significantly increased, the expression of TGF-β 3, p-Smad3 and Bcl-2 was down-regulated, and the expression of caspase-3 and Bax was up-regulated in group I/R+ ISO+ P ( P<0.05). Conclusion:Isoflurane postconditioning can inhibit neuronal apoptosis by activating the TGF-β 3/Smad3 signaling pathway, thus reducing focal I/R injury in rats.
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Objective:To report a rare case of paroxysmal nocturnal hemoglobinuria (PNH) complicated with chronic tubulointerstitial nephropathy, combined with literature review, and discuss the clinical, imaging and pathological characteristics of the disease and the diagnosis and treatment ideas.Methods:The patient's clinical data, magnetic resonance imaging (MRI) and kidney pathological examination results, treatment measures and effects were collected and reported. Through systematic review of relevant literature, the clinical manifestations and pathogenesis of chronic tubular interstitial nephropathy complicated by PNH were summarized and discussed.Results:In this case, PNH was diagnosed for more than 30 years, the peripheral blood PNH clone was positive, urine specific gravity was 1.012, urine pH 6.0-7.0, urine protein (+), urine sugar (3+), serum creatinine 259 μmol/L, serum lactic acid dehydrogenase 800 U/L. MRI showed bilateral renal cortical signal was low intensity on both T1- and T2- weighted images. Kidney biopsy revealed remarkable chronic tubulointerstitial nephropathy with massive hemosiderin deposition in proximal tubular cells demonstrated by Prussian blue staining and electron microscopy. By using low-dose prednisone to control hemolytic attack and other supportive treatments, the patient's renal function has been stabilized for a long time.Conclusions:PNH complicated with chronic tubulointerstitial nephritis is easy to be misdiagnosed due to insidious onset. MRI and kidney histopathological examination are helpful to clarify the diagnosis. Early diagnosis and treatment are helpful to improve the prognosis of such patients.