Stability and compatibility of morphine-clonidine admixtures in an implantable infusion system

Nonopioid analgesics are often coadministered with intrathecal morphine to increase efficacy. The purpose of this study was to evaluate stability and compatibility of morphine-clonidine admixtures with an implantable infusion system that is commonly used to treat pain patients. Infusion systems were filled with admixture and maintained at 37 degrees C for 90 days. Samples were collected monthly. Drug concentrations were determined using stability-indicating, high-performance liquid chromatography. For compatibility testing, individual materials comprising the fluid pathway of the device were immersed in clonidine solution and stored at 37 degrees C for various periods through 64 weeks and mechanical performance evaluated. After 3 months of containment in the infusion system, morphine and clonidine concentrations remained at > or = 94% of the theoretical starting concentrations. All device materials retained acceptable mechanical performance following clonidine exposure. These results demonstrate that morphine and clonidine are stable when combined in aqueous solution maintained at body temperature in an implantable infusion system for at least 3 months.     

Stability of admixture containing morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride in an implantable infusion system

Intrathecal infusion is often performed using drug combinations. This study was conducted to evaluate the stability of the admixture of morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride when used in an implantable pump under simulated clinical use conditions. SynchroMed implantable pumps were filled with an admixture and incubated at 37°C for a period of 90 days. Drug admixture stored in glass vials at 4°C and at 37°C served as controls. Samples which included pump reservoir and catheter delivered aliquots were collected every 30 days and analyzed for drug concentrations using a stability-indicating HPLC method. All drugs contained in the admixture were stable and the original concentrations remained greater than 96%. Over 90 days, and with the pump at the simulated body temperature of 37°C, there were no evident heat catalyzed or device catalyzed reactions.     

Stability and compatibility of ceftazidime administered by continuous infusion to intensive care patients

The stability and compatibility of ceftazidime have been examined in the context of its potential use in concentrated solutions for continuous infusion in patients suffering from severe nosocomial pneumonia and receiving other intravenous medications by the same route. Ceftazidime stability in 4 to 12% solutions was found satisfactory (<10% degradation) for 24 h if kept at a temperature of 25 degrees C (77 degrees F) maximum. Studies mimicking the simultaneous administration of ceftazidime and other drugs as done in clinics showed physical incompatibilities with vancomycin, nicardipine, midazolam, and propofol and a chemical incompatibility with N-acetylcystein. Concentrated solutions (50 mg/ml) of erythromycin or clarithromycin caused the appearance of a precipitate, whereas gentamicin, tobramycin, amikacin, isepamicin, fluconazole, ketamine, sufentanil, valproic acid, furosemide, uradipil, and a standard amino acid solution were physically and chemically compatible.     

Tolerance develops to the effect of lipopolysaccharides on movement-evoked hyperalgesia when administered chronically by a systemic but not an intrathecal route

Single exposures to lipopolysaccharides (LPS) produce deep tissue pain in humans and cutaneous hyperalgesia in rodents. While tolerance develops to many effects of LPS, sensitization to hyperalgesia is documented after a single injection. To determine the effect of long-term exposure to LPS, we explored the chronic effect of LPS on movement-evoked pain using a new assay based on grip force in mice. We found that a single systemic injection of LPS (i.p. or s.c.) induced a dose-related decrease in forelimb grip force responses beginning 6-8 h after injection and peaking between 9 and 24 h. The consequence of LPS is likely hyperalgesia rather than weakness as these decreases were rapidly attenuated by either 10 mg/kg of morphine i.p. or 10 microg of morphine injected intrathecally (i.t.). Complete tolerance to this hyperalgesia developed after repeated injections of LPS at doses of 0.9 mg/kg i.p. or 5 mg/kg s.c. Tolerance began after a single injection and was fully developed after as few as four injections of 5 mg/kg of LPS delivered s.c. The concentration of circulating LPS 5 h after a single parenteral injection was less in LPS-tolerant mice than na?ve controls, suggesting that tolerance may result from a more efficient clearance of LPS from the circulation. Injected i.t., LPS also induced hyperalgesia, however, tolerance did not develop to multiple injections by this route. There was no cross-tolerance between s.c. and i.t. injections of LPS. These data indicate that decreases in grip force are a sensitive measure of LPS-induced movement-evoked hyperalgesia and that tolerance develops to parenteral but not central hyperalgesic effects of LPS.     

Loss of effectiveness with an implanted drug delivery system for intrathecal pain therapy due to corrosion

Introduction

Intrathecal drug delivery is an established invasive treatment option. Most common complication is catheter malfunction, which can lead to overdose or withdrawal.

Case Presentation

A 61-year-old female patient underwent an elective replacement of an intrathecal drug delivery pump. The patient complained about a loss of effectiveness over the past 2 years. Intraoperatively, a white mass corresponding to morphine precipitation in the pump pocket was found, which appeared to be due to corrosion at the pump-catheter connection site.

Conclusions

Recommendations on how to deal with the decreasing effectiveness of intrathecal drug delivery and on intraoperative catheter handling are provided.     

Attachment of an aminoglycoside, amikacin, to implantable collagen for local delivery in wounds.

Cultured skin substitutes consisting of implantable collagen (COL) and cultured human skin cells often fail clinically from destruction by microbial contamination. Hypothetically, addition of selected antimicrobial drugs to the implant may control microbial contamination and increase healing of skin wounds with these materials. As a model for drug delivery, bovine skin COL (1 mg/ml) and amikacin (AM; 46 micrograms/ml) were modified by covalent addition of biotin (B-COL and B-AM, respectively) from B-N-hydroxysuccinimide and bound together noncovalently with avidin (A). B-COL was incubated with A and then with B-peroxidase (B-P) or by serial incubation with B-AM and B-P, before P-dependent chromogen formation. Colorimetric data (n = 12 per condition) from spot tests on nitrocellulose paper were collected by transmission spectrophotometry. Specificity of drug binding in spot tests was determined by (i) serial dilution of B-COL; (ii) reactions with COL, AM, or P that had no B; (iii) removal of A; or (iv) preincubation of B-COL-A with B before incubation with B-P. Binding of B-AM was (i) dependent on the concentration of B-COL; (ii) specific to B-COL, A, and B-P (P < 0.05); and (iii) not eluted by incubation in 0.15 or 1.0 M NaCl. B-AM was found to block binding of B-P to the B-COL-A complex and to retain bacteriocidal activity against 10 clinical isolates of wound bacteria in the wet disc assay. Antimicrobial activity of B-AM was removed from solution by treatment with magnetic A and a permanent magnet. These results suggest that selected antimicrobial drugs can be biotinylated for attachments to COL-cultured cell implants without loss of pharmacologic activity. Because this chemistry utilizes a common ligand, any molar ratio of agents may be administered simultaneously and localized to the site of implantation.     

埋入式给药装置动态监测肝癌术后门静脉压力的护理

经埋入式给药装置(i mplantable drug deliverysystem,IDDS)途径治疗中晚期恶性肿瘤已成为我国肿瘤临床治疗研究的重点和热点[1]。我院2002年10月-2006年2月采用经IDDS对31例肝癌术后患者进行动态监测门静脉压力的变化,现报道如下。临床资料1.一般资料。31例均为原发性肝癌手术     

埋入式给药装置动态监测肝癌术后门静脉压力的护理

目的 探讨经埋入式给药装置动态监测肝癌术后患者门静脉压力的方法及护理措施。方法 对31例肝癌患者术中放置埋入式给药装置，术后经其进行门静脉压的直接动态观察，并给予相应的护理措施。结果 31例患者均顺利完成了251次门静脉压力的测量，无并发症发生。结论 经埋入式给药装置动态监测门静脉压力变化，操作简单，安全，可重复进行，易被患者接受。护士应熟练掌握护理要点，积极防治并发症，对提高监测成功率有着重要作用。     

The safety and efficacy of intrathecal diamorphine

One hundred and seventy-eight patients undergoing total hip replacement and 67 patients undergoing spinal surgery were given diamorphine intrathecally in varying doses. Doses in mg/kg were plotted against duration of analgesia and the absence of retention and emetic symptoms in each type of surgery. Analysis showed that these were not dose dependent within the therapeutic range of 0.005-0.015 mg/kg.     

The spinal pharmacology of acutely and chronically administered opioids.

Systematic studies on the pharmacology of the antinociceptive activity of spinally administered agents have emphasized the action in animal models of mu and delta opioid receptors. Importantly, aside from receptor selectivity, the opioid agonists differ in the property of efficacy. Agents with high efficacy (large receptor reserves) show smaller rightward shifts in their dose-response curves in the face of a given degree of opioid tolerance or when the stimulus intensity is elevated. With regard to loss of drug effect with long-term exposure (tolerance), multiple mechanisms may be considered, including changes in stimulus intensity, change in afferent processing, or changes in receptor number/coupling. Basic studies are providing insights into these several mechanisms.     

Bacteriology, drug stability and exchange of percutaneous delivery systems and antibacterial filters in long-term intrathecal infusion of opioid drugs and bupivacaine in "refractory" pain.

OBJECTIVE: To provide a basis for recommendations on the exchange of containers (syringes and cassettes) and antibacterial filters, and for choice of administration device in patients with "refractory" pain treated with long-term percutaneous intrathecal (IT) infusions of opioid (morphine or buprenorphine) and bupivacaine mixtures. DESIGN: Prospective, cohort, nonrandomized control trial-case series, with consecutive sample, no standard criterion, and cost-benefit analysis. SETTING: Tertiary care center, institutional practice as well as hospitalized and ambulatory care. PATIENTS: Eighty-nine (51 women and 38 men); 81 with malignant pain and 8 with benign "refractory" pain. INTERVENTIONS: (a) The chemical stability of the drugs in the containers during 30 days. (b) The results of bacteriologic culture of the residual volumes of the analgesic mixtures from used and reused (1-16 times) syringes (n = 135) and cassettes (n = 258), and of 5 ml of sterile isotonic saline filtered through the used Millipore filters (n = 149). The bacteriologic samples from the 89 patients were taken after 1-40 (median = 7), 1-86 (median = 20), and 5-78 (median = 31) days of IT treatment, respectively. MAIN OUTCOME MEASURES: Chemical stability: buprenorphine and bupivacaine concentrations-liquid chromatography; morphine concentrations--gas chromatography. Bacteriologic cultures: standard laboratory procedures. The hypothesis (repeated use of the infusion systems and their exchange once a month does not significantly affect drug concentrations or increase the infection risk) was elaborated before data collection began. RESULTS: The bupivacaine-opioid mixtures were found to be chemically stable within 3-10% of the original doses up to 30 days. Seventeen cultures (from five syringes, six cassettes, and six filters) in 13 patients (having no signs of meningeal infection) were found to be colonized with Staphylococcus aureus (n = 4), coagulase negative staphylococci (n = 7), viridans streptococci (n = 3), Neisseria sp (n = 4), Corynebacterium sp (n = 4), Enterobacter sp (n = 2), Klebsiella sp (n = 3), gram-negative bacilli (n = 1), and yeasts (n = 2). The place of IT treatment, its duration, and patient-related infection risk factors (age; malignancy; diabetes; presence of a colostomy, pyelostomy, or indwelling urinary catheter; and the presence and location of infection foci) were not related to the results of the cultures. However, 9 of the 17 positive cultures came from patients with skin ulcers, a notable incidence. The positive cultures had no connection with the cultured item, its in-use duration, the number of times of reuse, the analgesic drugs used, their concentrations or the presence of preservatives (sodium metabisulfite and sodium edetate), or the antiseptic agent (70% ethanol or 0.5% chlorhexidine gluconate) used during bacteriologic sampling. The bacterial growth was sparse in 14 and massive in 3 of the 17 positive cultures. One item (filter) from one patient with meningitis was sterile. CONCLUSIONS: In our population, exchange of the infusion systems when they are empty (within 1 month) and of the antibacterial filters once a month does not appear to affect the concentrations of, or increase the infection risk from, the opioid-bupivacaine mixtures. The risk of bacterial contamination/colonization of the syringes from syringe drivers does not seem to be higher than that of cassettes from external portable pumps.     

老年患者蛛网膜下腔注射左旋布比卡因、罗哌卡因和布比卡因运动阻滞效能的比较

目的:比较老年患者蛛网膜下腔注射左旋布比卡因、罗哌卡因和布比卡因运动阻滞的效能. 方法:拟在腰麻-硬膜外联合麻醉下行下腹部手术的老年患者,随机分成左旋布比卡因组(L组)、罗哌卡因组(R组)和布比卡因组(B组).采用序贯法进行试验,每组第1例患者局麻药剂量均为5 mg,剂量变化梯度为1 mg.运动阻滞有效定义为蛛网膜下腔注药后20 min内任何一侧下肢改良Bromage评分大于或等于1分.计算两种药物运动阻滞的半数有效剂量(ED50)和95%可信区间(95%CI).结果:左旋布比卡因运动阻滞的ED50为5.483 mg;罗哌卡因运动阻滞的ED50为7.516 mg;布比卡因运动阻滞的ED50为4.277 mg.结论:老年患者蛛网膜下腔注射三种局麻药的运动阻滞效能从高到低依次是布比卡因、左旋布比卡因和罗哌卡因,后两者感觉-运动阻滞分离的优势更明显.     

Treatment of ventricular tachyarrhythmias with an implantable cardioverter-defibrillator system

5 patients (3 with coronary artery disease and chronic myocardial infarction, 2 with dilatative cardiomyopathy) with a mean age of 59 years (range 54-69 years) with drug refractory ventricular tachycardia and/or ventricular fibrillation received the automatic implantable cardioverter defibrillator (AICD). Intraoperative testing revealed a mean defibrillation threshold of 13 +/- 2.7 Joule. Over a mean follow-up period of 15.2 months (range 3-25 months) the patients received a total of 117 discharges. 15% of the delivered shocks were recorded during continuous ECG monitoring, 13% were associated with palpitations and 27% were discharged during syncope. 45% of shocks occurred in the absence of symptoms. No patient died suddenly. 1 patient died of intractable heart failure, 1 patient died of septic shock. In carefully selected patients the automatic implantable cardioverter defibrillator is an effective tool in the treatment of life-threatening ventricular tachyarrhythmias. Modifications of the device to incorporate programmability of the cut-off rate, the sensing criteria and the levels of shock energy, as well as the options for different pacing modes combined with memory functions are needed to improve antiarrhythmic strategies.     

植入式人工肛门括约肌系统的实现及动物实验

背景：研制新型的符合人体生理需求的人工肛门括约肌系统具有十分重要的意义。目的：设计一种新型植入式人工肛门括约肌系统。方法：利用无线通讯模块和压力传感器重建排便控制机制,并由经皮能量传输模块供电,采用机电系统模拟人体自然器官的功能,最终实现人体肛门括约肌的控制效果。结果与结论：设计并实现了一种新型的植入式人工肛门括约肌系统,在重建排便机制和模型的基础上,一定程度上恢复肛门失禁患者的生物反馈控制能力,并带有经皮能量传输模块,为体内系统长期无缆式供电提供可能。该系统实现了植入式动物实验,完成了系统植入可行性和基本功能验证。     

The pharmacokinetics, safety, and tolerance of cefepime administered as an intravenous bolus or as a rapid infusion

OBJECTIVE: To evaluate the pharmacokinetics, safety, and tolerability of cefepime administered as an intravenous bolus and short infusion. METHODS: A single-dose, pharmacokinetic study was conducted on 16 healthy men. Fifty milliliters of a 40 mg/mL solution of cefepime was administered by continuous infusion in intervals of three, five, 10, or 15 minutes. Blood was sampled three minutes through 12 hours after the end of the infusion. Analysis of cefepime was performed by reverse-phase HPLC with ultraviolet detection. Cefepime plasma concentrations versus time were evaluated by noncompartmental methods. History and physical examinations were conducted within two weeks of the start of the study, 24 hours before dosing, and at the end of the study. Assessments for adverse events were made throughout the study. RESULTS: Maximum concentration (Cmax) increased with decreasing time of infusion and was similar to reference values of Cmax. Pharmacokinetic characteristics of cefepime were not affected by the time of infusion and were on average: mean residence time was 2.3 hours, half-life 1.9 hours, the AUC extrapolated to infinity 239 microg x h/mL, total body clearance 142 mL/min, and steady-state volume of distribution 19 L. No serious adverse events, local tolerance at injection site, or significant laboratory abnormalities were noted. CONCLUSIONS: Cefepime 2 g was safely administered to healthy subjects as a rapid, single bolus, and its key pharmacokinetic parameters were consistent with those from longer infusions and other studies.     

Simultaneous delivery of tenofovir and acyclovir via an intravaginal ring

Vaginal microbicides may play an important role in protecting women from HIV infection. A strong synergy between HSV and HIV has been observed, and epidemiological studies demonstrate that HSV infection increases the risk of HIV acquisition. Incorporation of the antiretroviral tenofovir (TFV) along with the antiherpetic acyclovir (ACV) into combination intravaginal rings (IVRs) for sustained mucosal delivery of both compounds could lead to increased microbicide product adherence and efficacy compared with conventional vaginal formulations. A novel, dual-protection "pod IVR" platform developed in-house and delivering ACV and TFV was evaluated in rabbit and sheep models. The devices were safe and exhibited sustained release of both drugs independently and at controlled rates over the 28-day studies. Daily release rates were estimated based on residual drug content of the used devices: rabbits, 343 ± 335 μg day(-1) (ACV) and 321 ± 207 μg day(-1) (TFV); sheep, 174 ± 14 μg day(-1) (ACV) and 185 ± 34 μg day(-1) (TFV). Mean drug levels in sheep vaginal samples were as follows: secretions, 5.25 ± 7.31 μg ml(-1) (ACV) and 20.6 ± 16.2 μg ml(-1) (TFV); cervicovaginal lavage fluid, 118 ± 113 ng ml(-1) (ACV) and 191 ± 125 ng ml(-1) (TFV); tissue, 173 ng g(-1) (ACV) and 93 ng g(-1) (TFV). An in vitro-in vivo correlation was established for both drugs and will allow the development of future formulations delivering target levels for prophylaxis and therapy. These data suggest that the IVR based on the pod design has potential in the prevention of transmission of HIV-1 and other sexually transmitted pathogens.