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OBJECTIVE To prepare progesterone-2-chloro-4-nitroaniline cocrystal （CNA） so as to improve the solubility of progesterone and primarily evaluate the safety of the progesterone cocrystal in vivo. METHODS Using progesterone as the main body and CNA as the ligand， progesterone-CNA cocrystal was prepared with solvent evaporation method. The cocrystal was characterized by X-ray single crystal diffraction， X-ray powder diffraction （XRPD）， differential scanning calorimetry （DSC） and Fourier transform infrared spectroscopy （IR）. The dissolution rate of cocrystal was compared with those of progesterone and physical mixture. Forty-eight female KM mice were randomly divided into normal group （phosphate buffer containing 0.1% dimethyl sulfoxide）， progesterone group （16 mg/kg）， CNA group （9 mg/kg）， progesterone-CNA cocrystal low-dose， medium- dose and high-dose groups （6， 12.5， 25 mg/kg）， with 8 mice in each group. They were given relevant medicine/solvent intramuscularly， once a day， for consecutive 14 d. The safety of cocrystal was evaluated primarily by determining/observing the changes in body weight， organ index， tissue morphology， blood routine indicators， and liver and kidney function indicators. RESULTS The new crystal structure in the X-ray single crystal diffraction results， the new characteristic peak in the XRPD pattern， the change of melting point in the DSC results， and the change of the characteristic peak position in the range of 3 500- 2 750 cm－1 and 1 700-1 250 cm－1 in the infrared spectrum all Δ 基金项目国家重点研发计划项目（No.2022YFC3502100） indicated that progesterone-CNA cocrystal was successfully ＊第一作者 硕士研究生 。研究方向 ：药物制备技术与工艺 。 prepared， and the dissolution rate of cocrystal was more than E-mail：SWB_1221@163.com # 通信作者教授，硕士生导师，博士。研究方向：药物制备技术与 twice that of the progesterone raw material drug. The results of 工艺。E-mail：wuxx-415@126.com in vivo safety experiments showed that the mortality rate of all 中国药房 2023年第34卷第13期 China Pharmacy 2023 Vol. 34 No. 13 · 1567 · groups was zero. Compared with normal group， uterine indexes of mice in progesterone group and progesterone-CNA cocrystal groups were significantly increased （P＞0.05）， and endometrium was also thickened； there was no statistical difference in the changes of body mass， liver and kidney function， liver index， kidney index， the number of leukocyte， lymphocyte and neutrophil in routine blood test among those groups （P＞0.05）， and the morphology of liver and kidney tissue has also no significant difference. However， the number of plasma red blood cells in the progesterone group decreased significantly （P＜0.05）， and there was no statistical significance in the number difference of red blood cells among progesterone-CNA cocrystal groups （P＞0.05）. CONCLUSIONS The progesterone-CNA cocrystal is successfully prepared with good safety in vivo， which significantly improve the solubility of progesterone.
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OBJECTIVE：To study the prot ective effects of crocin （CR）against triptolide （TP）-induced visceral organ injury in mice，and to provide reference for the studying TP compatibility and detoxification. METHODS ：Fifty mice were randomly divided into normal group ，TP low-dose and high-dose groups （i.e. TP-L group ，TP-H group ，with 300，600 μg/kg），TP low-dose and high dose combined with CR groups （i.e. TP-L+CR group ，TP-H+CR group ，with 300 μg/kg TP+100 mg/kg CR ，600 μg/kg TP+ 100 mg/kg CR ），with 10 mice in each group. Except for normal group ，other groups were given relevant medicine intragastrically ， once a day ，for consecutive 7 d. The body weight of mice was weighted every day ，and their death was recorded. After last administration，the mice were sacrificed ，and the heart ，liver，kidney and testis were taken ，and the organ index was calculated ； serum levels of ALT ，AST，BUN and Scr ，the activity of T-SOD and the contents of MDA were all determined. The pathological changes of heart ，liver，kidney and testis were observed ；mRNA expression of Bcl- 2，Bax and caspase- 3 in liver tissue were determined. RESULTS ：Three，five，two and three mice in TP-L group ，TP-H group ，TP-L+CR group and TP-H+CR group died respectively，and the survival rates were 70％，50％，80％ and 70％，respectively. Compared with normal group ，the body weight （7th day of experiment ），heart index ，liver index ，kidney index （except for TP-L group ），testicular index ，T-SOD activity and mRNA expression of Bcl- 2 in liver tissue ，serum levels of ALT （except for TP-L group ），AST（except for TP-L group ），BUN and Scr，MDA content and mRNA expression of Bax ，mRNA expression of caspase- 3 in liver tissue were increased significantly （P＜ 0.05 or P＜0.01）. There were obvious pathological changes in heart ，liver，kidney and testis tissue. Compared with the same dose of TP alone group ，the above indexes of TP combined with CR group were improved in varying degrees. Except for the renal index and serum ALT level of TP-L+CR group ，there was statistical significance for all indexes （P＜0.05 or P＜0.01）；the pathological injuries of heart ，liver，kidney and testis were significantly improved. CONCLUSIONS ：CR can relieve the damage of heart ， liver，kidney and testis induced by TP ，which may be related to the antioxidant stress of CR.
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@#Objective To investigate the validity and reliability of Item Erectile Function Scale (I-EF) for neurogenic erectile dysfunc-tion (ED). Methods 104 patients with spinal cord injury were assessed with I-EF. They were measured with pudendal somatosensory ner-vous evoked potential (SEP), bulbocavernosus reflex potential time (BCR) and nocturnal penile tumescence (NPT) detection. 34 patients ac-cepted medicine for ED, and were assessed with I-EF after treatment. 21 patients with medium ED were assessed by 2 testers, and retested 2-4 weeks later. Results The patients who recorded their potential of SEP and BCR got the scores of Q1, Q2 above 7, and the absence with the scores of 3. Those found NPT 1-3 times got the score of Q3 above 7, and the absence with the scores of 3. The incidence of reflex erec-tions and NPT were more in complete suprasacral ones than in complete sacral ones (P<0.05). There was significant improvement after med-ication in patients with mild to medium ED (P<0.05). The interclass correlation coefficient (ICC) was 0.93 between testers and 0.90 between test-retest. Conclusion I-EF can be used to assess neurogenic erectile dysfunction for rehabilitation.
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@#Objective To explore the technique, efficacy and complications of transurethral sphincterotomy with Holmium laser for the treatment of male patients with neurogenic bladder and examine its long-term outcome. Methods 20 male cases who received transurethral sphincterotomy with Holmium laser were included in this retrospective analysis, in which 7 cases injuried at cervical spinal cord, 6 at thoracic spinal cord, 3 at cauda equine; 1 was spinal meningocele, 1 was sacral crack, 1 was ependymoma, and 1 was myelitis sequel. The age was 20~64 years, averaged 45.1 years. They were followed up for 3~95 months (averaged 43.6 months) since the last sphincterotomy. Results The 20 patients significantly improved in symptoms, laboratory examination, imaging demonstration and urodynamic index after the operation.There were 3 patients who required repeated laser surgery during the follow- up. 17 patients were stable. Conclusion Transurethral sphincterotomy with Holmium laser is effective on neurogenic bladder with less bleeding for the appropriately selected patients.
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Objective To assess clinical and urodynamic results of augmentation enterocystoplasty (AE) in patients with ncurogcnic hladdcr dysfunction (NBD).Methods Retrospectively reviewed our database between 2005-2011 to identify 77 patients who underwent AE ( sigmoid 74 patients,ileum 3 patients).Postoperativc complications,renal function,urodynamics parameters and quality of daily life were evaluated.Results The mean follow-up length was 24 months.Compared with pre-operative condition,the mean bladder capacity significantly increased from (160.6 ± 128.3) to (468.5 ± 60.6) ml (P ＜0.001 ) and the maximum detrusor pressure decreased from ( 31.1 ± 26.4) to ( 10.9 ± 4.5 ) cm H2O ( P =0.002 ).Serum creatinine level decreased from (270.3 ± 113.6 ) to ( 174.4 ± 81.3 ) μmol/(l) ( P =0.00 1 ).There were significant decrease on mean number of incontinence episodes and pads used per day ( P ＜0.01 ).Post-operative complications included metabolic acidosis in two patients (2.6％),adhesive intestinal obstruction in four patients (5.2％),deteriorating renal function in one patients ( 1.2％ ) and recurrence of vesicoureteral reflux in three patients (3.9％).Conclusions The results suggest that AE is safe and effective in treating patients with NBD.Concomitant URI is considerèd on patients with long illness history,vesicoureteral reflux at low intravesical pressures and upper urinary tract dilation.Patients with moderate and severe upper urinary tract deteriorations benefit from this procedure and the benefit can maintain a long time.
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Objective To evaluate the long-term outcome of reconstruction for urinary conti-nence function by using implantation of artificial urinary sphincter (AUS). Methods From 2002 to 2005,15 incontinent patients (14 men and 1 woman) with age range of 19-75 years treated with im-plantation of AUS were followed up. In 15 eases, there were 5 cases with traumatic urinary inconti-nence, 1 with neurogenic stress incontinence, 1 with neurogenic urgent incontinence,6 with postpros-tatectomy incontinence and 2 with neurogenie voiding dysfunction. Three eases had taken urethro-stenotomy, 3 had sphineterotomy and 1 had enterocystoplasty and ureterovesieostomy before the im-plantation for AUS. The patients were followed up for 13-55 months with mean of 37 months. The information about the continence status and pads usage, also the complications were collected. Results After implantation, 13 cases(87%)used AUS device normally, 12(92%)beeame dry and 1 (8%) got social continence. Eleven cases (85%) got continence depending on the original implanted AUS and 15% did continence by reoperation. There were 4 cases(27%) with complications including erosion of skin and urethral in 1, graft rejection in 1, urethral atrophy in 1, and voiding dysfunction in 1. Durability of 11 cases with original implanted devices was 13-55 months with mean of 38 months.Conclusion The implantation of AUS is a long-term reliable method in reconstruction for lower uri-nary tract function.
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@#Objective To investigate the effect of Holmium laser urethrotomy under ureteroscopy on urethral stricture.Methods 30 men with urethral stricture who accepted urethrotomy with Holmium laser under ureteroscopy were observed.Results Operation was performed successfully in 21 cases;7 cases underwent 2～3 endoscopic surgical treatments.Endoscopic surgical treatment failed in 2 cases,and open surgery were performed on them.21 cases were followed up for 3～37 months,and 8 of them need urethral dilatation termly.Conclusion Endoscopic surgery with ureteroscopy and Holmium laser may be effective on urethral stricture with slight trauma.
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Objective To evaluate the effectiveness and safety of Botulinum toxin-A (BTX-A) injection into detrusor to treat neurogenic detrusor overactivity in patients with spinal cord injury (SCI).Methods A total of 78 patients with SCI were treated with transurethral injection of BTX-A (300 IU dissolved in 15 ml of saline) into 30 different points of detrusor with 15 ml in every patients. Urodynamic parameters and voiding diary were assessed at baseline and 3 weeks and 3 months after the injections. Adverse events were recorded after the injection if present.Results After the first injection, 78 patients showed that the mean frequencies of incontinence decreased from 13.5 to 2.7 times per day, the mean volume of intermittent catheterization (IC) increased from 131 ml to 389 ml per time, the mean volume of incontinence decreased from 1 690 ml to 281 ml per day, the mean getting effect time was 7.6 days. 10 patients received second injection at 8.9 months after first injection, the results showed that the mean frequencies of incontinence decreased from 9.7 to 3.7 times per day, the mean IC volume increased from 108 ml to 387 ml. 6 patients received third injection at 5.8 months after second injection, the results showed that the mean frequencies of incontinence decreased from 9.2 to 3.9 times per day, the mean IC volume increased from 116 ml to 364 ml. No side effects were observed during the follow-up.Conclusion BTX-A injection into detrusor to treat neurogenic detrusor overactivity in patients with SCI seems to be an effective, safe and miniinvasive solution.
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@# Objective To explore the technique,efficacy and complications of external sphincterotomy with Holmium laser for the treatment of detrusor external sphincter dyssynergia (DSD). Methods 7 male cases with neurogenic DSD who received the procedure were reported. Results All patients got significant improvement after the operation in symptoms,laboratory,imaging and urodynamic index. No one required transfusion. 1 case lost the erection. There was no need of re-operation during the follow-up. Conclusion External sphincterotomy with Holmium laser for the treatment of DSD shows the advantages of less bleeding,safety and good effectiveness for the well selected patients.
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@#ObjectiveTo investigate the safety and efficiency of transurethral holmium laser enucleation of the prostate(HoLEP) for the aged.Methods50 old patients(above 70) with benign prostatic hyperplasia(BPH) accepted HoLEP.All patients were assessed with IPSS,QOL,Qmax and PVR before and 3 months after operation.ResultsBefore the treatment,the mean IPSS was 22.9 and was 9.7 3 months after operation,while the mean QOL was 5.3 and 2.1,Qmax was 7.2 ml/s and 14.3 ml/s,PVR was 127.5 ml and 19.3 ml.ConclusionHoLEP is a safe,effective procedures for treating BPH.
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@#ObjectiveTo explore the efficacy and safety of sacral neuromodulation(SNM) for the treatment to neurogenic bladder.MethodsOne patient with neurogenic bladder after spinal bifida underwent the therapy of SNM 42 months ago.The therapeutic efficacy was evaluated and followed up by means of the symptom improvement and voiding diaries.ResultsDuring the test stimulation period,there were significant improvements(>50%) in the objective findings and subjective symptoms.This patient received permanent electrode and neurostimulator implantation and lower urinary tract symptoms were improved continuously until 42 months.ConclusionSNM may be effective for some neurogenic dysfunctions of the bladder.
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@#ObjectiveTo explore the effects of sacral neuromodulation using a new tined-lead electrode on neurogenic bladder.MethodsThe use of a new tined-lead electrode for sacral neuromodulation was evaluated in a study including 5 consecutive patients with neurogenic bladder.The tined leads were implanted at the S3 foramen under the X-ray screening.Subjects completed the recording of detailed voiding diary pre-and post-operation including fluid intake,voided volume,leaked volume,catheterized volume,frequency,accompanying symptoms and sensation.Vesicourethral function was assessed by video-urodynamics.ResultsUrinary frequency and voided volume were improved 22% and 49% respectively in one patient with spinal bifida.Urinary frequency,voided volume and residual volume were improved 0.7%,11% and 46% respectively in another one.Urinary frequency,voided volume and residual volume were improved 0.4%,18% and 44% respectively in the third one.Frequency of leakage and leaked volume were improved 36% and 54% respectively in the patient with brain trauma.Frequency of CIC and catheterized volume were improved 42% and 54% respectively,and indexes of urodynamics were improved 37%～45% in the patient with spinal cord injury.ConclusionA new tined-lead electrode for sacral neuromodulation provide a new alterative and minimally invasive procedure to treat neurogenic bladder.
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@#ObjectiveTo evaluate the effects of Botulinum toxin type A(BTX-A) repeated injection into detrusor to treat detrusor hyperreflexia and neurogenic incontinence in spinal cord injury(SCI) patients.Methods6 patients with SCI were included into the study.300 U of BTX-A was dissolved in saline 15 ml,and injected into 30 different sites in detrusor using a flexible cystoscopic needle.BTX-A injection was repeated 3 times for all the patients.Urodynamic examination,voiding diary and toxic effects were recorded.ResultsThe improvement for symptoms was observed within 5 to 21 days.The effects of injections lasted averagely 8.9 and 5.8 months for each injection.After the first injection,the mean frequency of incontinence decreased from 10.1 /d to 3.3 /d.The mean volume of intermittent catheterization(IC) increased from 98.5 ml to 404.2 ml each time.Mean cystometric volume increased from 95.4 ml to 385.6 ml,mean maximum storage detrusor pressure decreased from 105.8 cmH2O to 31 cmH2O.After the second injection,the mean frequency of incontinence decreased from 9.7/d to 3.7/d.The mean volume of IC increased from 108.3 ml to 387.2 ml each time.Mean cystometric bladder storage volume increased from 105.4 ml to 375.6 ml.Mean maximum storage detrusor pressure decreased from 97.8 cmH2O to 33 cmH2O.After the third injection,the mean frequency of incontinence decreased from 9.2/d to 3.9/d.The mean volume of IC increased from 115.7 ml to 363.9 ml each time.Mean cystometric volume increased from 102 ml to 357.6 ml.Mean maximum storage detrusor pressure decreased from 98.1 cmH2O to 36.9 cmH2O.The patients were followed up for 6 months.No adverse and toxic effect was observed.ConclusionBotulinum toxin type A repeated injection into detrusor is effective,safe,feasible and mini-invasive to treat detrusor hyperreflexia and neurogenic incontinence in patients with SCI.Botulinum toxin type A repeated injection into detrusor is effective,safe,feasible and mini-invasive to treat detrusor hyperreflexia and neurogenic incontinence in patients with SCI.