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.     

Auditing paediatric diabetes care and the impact of a specialist nurse trained in paediatric diabetes

AIMS: To define outcome measures for auditing the clinical care of children and adolescents with insulin dependent diabetes mellitus (IDDM) and to assess the benefit of appointing a dedicated paediatric trained diabetes specialist nurse (PDSN). METHODS: Retrospective analysis of medical notes and hospital records. Glycaemic control, growth, weight gain, microvascular complications, school absence, and the proportion of children undergoing an annual clinical review and diabetes education session were assessed. The effect of the appointment of a PDSN on the frequency of hospital admission, length of inpatient stay, and outpatient attendance was evaluated. RESULTS: Children with IDDM were of normal height and grew well for three years after diagnosis, but grew suboptimally thereafter. Weight gain was above average every year after diagnosis. Glycaemic control was poor at all ages with only 16% of children having an acceptable glycated haemoglobin. Eighty five per cent of patients underwent a formal annual clinical review, of whom 16% had background retinopathy and 20% microalbuminuria in one or more samples. After appointing the PDSN the median length of hospital stay for newly diagnosed patients decreased from five days to one day, with 10 of 24 children not admitted. None of the latter was admitted during the next year. There was no evidence of the PDSN affecting the frequency of readmission or length of stay of children with established IDDM. Non-attendance at the outpatient clinic was reduced from a median of 19 to 10%. CONCLUSIONS: Outcome measures for evaluating the care of children with IDDM can be defined and evaluated. Specialist nursing support markedly reduces the length of hospital stay of newly diagnosed patients without sacrificing the quality of care.     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

Expression and Significance of Coxsackie and Adenovirus Receptor in Renal-Cell Carcinoma

OBJECTIVE To investigate the expression of Coxsackie and Adenovirus receptor (CAR) in renal-cell carcinoma and the relationship of the CAR to the biological behavior of the carcinomas.METHODS The immunohistochemical SP method was used to detect the expression of Coxsaekie and Adenovirus receptor in 48 cases of renalcell carcinoma and in 12 cases of normal renal tissue 2 cm away from the tumor tissue.RESULTS The positive rates of CAR were 100% in 12 cases of para-tumcr normal renal tissue and 35.4% in 48 cases of renal-cell carcinoma respectively. The difference of CAR expression between them was significant (P＜0.05). The grades of the tumor were as follows: 22 in Grade Ⅰ, 17in Grade Ⅱ and 9 in Grade Ⅲ with the CAR positive rate being 54.5%,23.5% and 11.1%, respectively. There was a negative correlation between CAR expression and tumor grading (P＜0.05). In addition, the number of the cases in stages Ⅰ to ⅣV were 19, 13, 11 and 5 respectively, with the respective positive rates being 57.9%, 30.8%, 18.2% and 0.0%, i.e. there also was a negative relationship between CAR expression and the stage (P＜0.05).CONCLUSION CAR expression is down-regulated in renal-cell carcinoma compared with normal tissue. The level of CAR may be a sensitive predictor of differentiation, invasion and metastasis. Loss of CAR expression correlates with the invasive phenotype in our analysis of renal-cell carcinoma.     

The Role of Streptococcal Cell-Envelope Proteases in Bacterial Evasion of the Innate Immune System

Bacteria possess the ability to evolve varied and ingenious strategies to outwit the host immune system, instigating an evolutionary arms race. Proteases are amongst the many weapons employed by bacteria, which specifically cleave and neutralize key signalling molecules required for a coordinated immune response. In this article, we focus on a family of S8 subtilisin-like serine proteases expressed as cell-envelope proteases (CEPs) by group A and group B streptococci. Two of these proteases known as Streptococcus pyogenes CEP (SpyCEP) and C5a peptidase cleave the chemokine CXCL8 and the complement fragment C5a, respectively. Both CXCL8 and C5a are potent neutrophil-recruiting chemokines, and by neutralizing their activity, streptococci evade a key defence mechanism of innate immunity. We review the mechanisms by which CXCL8 and C5a recruit neutrophils and the characterization of SpyCEP and C5a peptidase, including both in vitro and in vivo studies. Recently described structural insights into the function of this CEP family are also discussed. We conclude by examining the progress of prototypic vaccines incorporating SpyCEP and C5a peptidase in their preparation. Since streptococci-producing SpyCEP and C5a peptidase are responsible for a considerable global disease burden, targeting these proteases by vaccination strategies or by small-molecule antagonists should provide protection from and promote the resolution of streptococcal infections.     

催产素对妊娠末期大鼠蜕膜细胞内游离钙的刺激作用

妊娠末期催产素刺激子宫蜕膜细胞产生与分娩有关的前列腺素,但其作用方式仍未知。本实验分离妊娠19d大鼠蜕膜细胞,测定了催产素作用后蜕膜细胞内游离钙的变化,结果加入0.001～1μmol·L^-1催产素后,蜕膜细胞内[Ca²⁺]i出现瞬息增加,其峰值与催产素浓度呈剂量依赖关系,且此作用有自身钝化现象。说明催产素可能激活妊娠末期大鼠蜕膜细胞内的肌醇磷酯蛋白激酶C系统。给妊娠末期大鼠ip硫酸去氢表雄酮钠盐后分离的蜕膜细胞,催产素作用引起[Ca²⁺]i瞬息增加峰值较对照升高。