A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

The effectiveness of 'nursing beds': a review of the literature

A literature search was conducted to identify 'nursing led in-patient units' where the nurse is the designated leader of the clinical team. The review concentrates on studies which have attempted to measure the impact of nursing-led in-patient units and reviews both the methodology and outcomes. Three major bodies of work were identified. Lydia Hall's evaluation of the Loeb Center for Nursing and Rehabilitation (USA) is reviewed in some detail. This work was the model for 'nursing beds' at the two Oxfordshire Nursing Development Units (UK) in the 1980s. Studies evaluating these centres are reviewed and reports of similar UK units discussed. A third body of work evaluates a nurse-managed critical care environment. Common features include a case mix based on nursing need with nurses having authority to admit and discharge patients. While results are generally favourable, with improved patient independence, fewer readmissions, lower mortality and cost savings reported in some or all of the studies, all studies reviewed demonstrate the difficulties of applying an experimental model to real life clinical services. Methodological limitations render firm conclusions difficult. Techniques adopted from studies in field settings, the so-called 'quasi-experiment', are advocated as a remedy, as is further study of the process of care in investigating this model of care delivery.     

The use of the rat facial nerve model to assess the effect of differing nerve anastomotic agents on the facial nerve

There are relatively few papers which prove that one nerve anastomotic agent for the facial nerve is superior to any other. Previous experiments on the division and anastomosis of the facial nerve have failed to consider the indeterminate variables involved, i.e. operator variability, controls and the reaction of the materials on normal nerve tissue. In this experiment, a variety of anastomotic agents were tested to see if the anastomotic agents themselves affected the extra-temporal facial nerve function. The absorbable suture, non-absorbable suture, glue and tube wrap used had no effect on normal nerve tissue or on the anastomosis of the sectioned facial nerve of the rat compared with simple laying together of the divided ends of the divided nerve.     

ROMEO: rethink organization to improve education and outcomes.

AIMS: Scarcity of resources, expertise and evidence-based models have so far limited delivery of patient-centred diabetes education. We have developed and validated a group care approach that is applicable to everyday clinical practice and cost-effective in improving metabolic control, knowledge of diabetes, health behaviours, and quality of life in Type 2 diabetes. A clinical trial (ROMEO) was planned to evaluate applicability and reproducibility of group care in other outpatients facilities and assess its impact on a larger patient population. METHODS: Multicentre, randomized, controlled clinical trial of group vs. individual care in the routine management of Type 2 diabetes. Nine hundred patient aged < 80, with diabetes of > or =1 year known duration, treated by either diet alone or diet and oral agents, will be recruited in 15 centres and followed for 4 years. Training of physicians, nurses and dietitians included preparation of operating manual and videos, interactive sessions, and evaluation of local facilities and resources. RESULTS: Primary measurements: 3-monthly HbA1c, fasting blood glucose, body weight, waist-hip ratio, yearly blood lipids, and bi-yearly assessment of knowledge of diabetes, health behaviours and quality of life. Secondary outcomes: systolic and diastolic blood pressure, evaluation of ECG for ischaemia and QT interval, hypoglycaemic and anti-hypertensive medication and cardiovascular events. Analysis will be by intention-to-treat. DISCUSSION: If ROMEO confirms that group care can be successfully implemented in different clinics, a novel clinico-pedagogic tool will have been acquired to support patient-centred education, improve lifestyle and outcomes, support team work, enhance providers' attitudes and competencies and ameliorate diabetes care organization.     

The current status of thrombolytic therapy

Fibrinolytic therapy substantially reduces mortality from acute myocardial infarction. Patient selection is, however, important. The patient must present within 12 hours of the onset ofischaemic symptoms, have definite ECG changes of ST elevation or left bundle branch block and no contraindications. The major contraindications are those for risk of an intracerebral bleed, recent stroke, intracranial tumour or risk of a major systemic bleed. Age and hypertension are not contraindications but may modify the regimen used.
Heparin is required with recombinant tissue plasminogen activator but is optional with streptokinase.
The recent COBALT trial suggests that the accelerated weight related t-PA regimen given over 90 minutes is more satisfactory than double bolus t-PA. However, inpatients under 75 years of age, the two regimens were equivalent.
For patients suffering acute myocardial infarction, practitioners should now individualise choice of therapy, rather than give the same cocktail to all patients. The choice of regimen will depend on the cardiac risk, the stroke risk, the bleeding risk and the cost.     

Open mesh versus non-mesh repair of groin hernia meta-analysis of randomized trials leased on individual patient data

Abstract Background. The EU Hernia Trialists Collaboration was established to provide reliable evaluation of newer methods of groin hernia repair. It involved 70 investigators in 20 countries. Materials and methods. Twenty eligible trials (5016 participants) of open mesh vs. non-mesh groin hernia repair were identified. Meta-analysis was performed using raw individual patient data where possible. Results. Fewer hernia recurrences were reported after mesh repair. There were no clear differences between mesh and non-mesh groups in complications. Overall, those in the mesh groups had a shorter hospital stay, quicker return to usual activities and less frequent persisting pain, but individual trial results varied. Conclusions. The review provides strong evidence that open mesh repair is associated with a reduction in the risk of recurrence of between 50% and 75%. There is also some evidence of quicker recovery and of lower rates of persisting pain following open mesh repair. Electronic Publication     

Fusion and failure following anterior cervical plating with dynamic or rigid plates: 6-months results of a multi-centric, prospective, randomized, controlled study

Anterior cervical plate fixation is an approved surgical technique for cervical spine stabilization in the presence of anterior cervical instability. Rigid plate design with screws rigidly locked to the plate is widely used and is thought to provide a better fixation for the treated spinal segment than a dynamic design in which the screws may slide when the graft is settling. Recent biomechanical studies showed that dynamic anterior plates provide a better graft loading possibly leading to accelerated spinal fusion with a lower incidence of implant complications. This, however, was investigated in vitro and does not necessarily mean to be the case in vivo, as well. Thus, the two major aspects of this study were to compare the speed of bone fusion and the rate of implant complications using either rigid- or dynamic plates. The study design is prospective, randomized, controlled, and multi-centric, having been approved by respective ethic committees of all participating sites. One hundred and thirty-two patients were included in this study and randomly assigned to one of the two groups, both undergoing routine level-1- or level-2 anterior cervical discectomy with autograft fusion receiving either a dynamic plate with screws being locked in ap - position (ABC, Aesculap, Germany), or a rigid plate (CSLP, Synthes, Switzerland). Segmental mobility and implant complications were compared after 3- and 6 months, respectively. All measurements were performed by an independent radiologist. Mobility results after 6 months were available for 77 patients (43 ABC/34 CSLP). Mean segmental mobility for the ABC group was 1.7 mm at the time of discharge, 1.4 mm after 3 months, and 0.8 mm after 6 months. For the CSLP- group the measurements were 1.0, 1.8, and 1.7 mm, respectively. The differences of mean segmental mobility were statistically significant between both groups after 6 months (P = 0.02). Four patients of the CSLP-group demonstrated surgical hardware complications, whereas no implant complications were observed within the ABC-group (P = 0.0375). Dynamic plate designs provided a faster fusion of the cervical spine compared with rigid plate designs after prior spinal surgery. Moreover, the rate of implant complications was lower within the group of patients receiving a dynamic plate. These interim results refer to a follow-up period of 6 months after prior spinal surgery. Further investigations will be performed 2 years postoperatively.     

异丙酚复合麻醉下髋关节置换术患者瑞芬太尼控制性降压的效果

目的探讨异丙酚复合麻醉下髋关节置换术患者瑞芬太尼控制性降压的效果。方法择期行髋关节置换术患者30例,ASA分级Ⅱ级或Ⅲ级,随机分为2组(n=15):瑞芬太尼组(R组)和硝普钠组(N组)。2组麻醉诱导气管插管后在30min内静脉输注6%羟乙基淀粉200/0.5 15ml/kg行急性高容量血液稀释,桡动脉穿刺置管监测平均动脉压(MAP)和心率(HR),颈内静脉穿刺置管监测中心静脉压,术中维持脑电双频谱指数45～55。2组于切皮前开始降压,R组和N组分别持续静脉输注瑞芬太尼0.3～0.7μg·kg~(-1)·min~(-1)、硝普钠0.5～6.0μg·kg~(-1)·min~(-1),使MAP降低到术前基础值的70%左右(60～70mm Hg)并维持至术毕。分别于急性高容量血液稀释后控制性降压前即刻(T_0)、控制性降压20min(T_1)、40min(T_2)、术毕(T_3)时抽取静脉血,测定血红蛋白(Hb)、红细胞压积(Hct)、乳酸(Lac)浓度,同时抽取动脉血,行动脉血气分析,记录开始降压至目标血压所需的时间(降压诱导时间)、停降压药后MAP恢复至基础值的时间(MAP恢复时间)及术中出血量、输血量。结果与N组比较,R组降压诱导时间、MAP恢复时间、血气分析指标及Lae水平差异无统计学意义(P>0.05),T_(1,2)时HR降低,出血量减少(P<0.05或0.01);N组有5例患者发生反射性心动过速,需使用艾司洛尔,T_3时有2例患者发生反跳性高血压,2组术后均未见并发症。结论异丙酚复合麻醉下髋关节置换术患者持续静脉输注瑞芬太尼0.3～0.7μg·kg~(-1)·min~(-1)控制性降压可控性好,降压及恢复平稳,且血液保护作用优于硝普钠。     

Application of Animal Toxicology Data to Clinical Study of Experimental Drugs

The pharmaceutical industry performs safety studies in animals to underwrite administration of new chemical entities to man. Early clinical evaluation of drugs in volunteers is performed, generally, using highdose acute studies in rodents and 1-month repeat dose studies in one rodent species and one non-rodent species as a basis for risk assessment. Results from the 1-month toxicology studies enable a ceiling for initial clinical doses to be set and give some indication of the major target organs for toxicity. Extrapolation of these results to man helps determine the preliminary safety endpoints, including clinical chemistry parameters, for use in early clinical studies in man.Originally presented at ECCP 93.