Free radical pathways in CNS injury

Free radicals are highly reactive molecules implicated in the pathology of traumatic brain injury and cerebral ischemia, through a mechanism known as oxidative stress. After brain injury, reactive oxygen and reactive nitrogen species may be generated through several different cellular pathways, including calcium activation of phospholipases, nitric oxide synthase, xanthine oxidase, the Fenton and Haber-Weiss reactions, by inflammatory cells. If cellular defense systems are weakened, increased production of free radicals will lead to oxidation of lipids, proteins, and nucleic acids, which may alter cellular function in a critical way. The study of each of these pathways may be complex and laborious since free radicals are extremely short-lived. Recently, genetic manipulation of wild-type animals has yielded species that over- or under-express genes such as, copper-zinc superoxide dismutase, manganese superoxide dismutase, nitric oxide synthase, and the Bcl-2 protein. The introduction of the species has improved the understanding of oxidative stress. We conclude here that substantial experimental data links oxidative stress with other pathogenic mechanisms such as excitotoxicity, calcium overload, mitochondrial cytochrome c release, caspase activation, and apoptosis in central nervous system (CNS) trauma and ischemia, and that utilization of genetically manipulated animals offers a unique possibility to elucidate the role of free radicals in CNS injury in a molecular fashion.     

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS: After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.     

Peripheral progesterone (P) levels and endometrial response to various dosages of vaginally administered P in estrogen-primed women

Objective: To compare the pharmacokinetics and pharmacodynamics of 100 mg/d, 200 mg/d, and 400 mg/d (200 mg two times per day) of P administered vaginally for 14 days to estrogen-primed postmenopausal women.Design: Randomized, open-label, three-way crossover study.Setting: Two university-based investigative sites.Patient(s): Twenty healthy postmenopausal women with histologically normal endometria.Intervention(s): Oral 17,β-E₂ was given each day of a 28-day cycle; a P vaginal suppository was inserted daily according to the randomization schedule during days 15–28 of each cycle; blood samples were collected; an endometrial biopsy was obtained on day 25; and patients were crossed over to the next treatment cycle after a washout period of at least 30 days.Main Outcome Measure(s): Mean P blood levels, endometrial dating/conversion.Result(s): There was good vaginal absorption of P for all dosages. Endometrial conversion occurred in all 200- and 400-mg/d P-dosed cycles, whereas the 100-mg/d dosage failed to convert primed endometria consistently. There also was a significantly increased tendency for earlier bleeding and spotting with the 100-mg/d dosage.Conclusion(s): Both the 200- and 400-mg/d dosage regimens consistently convert an estrogen-primed endometrium, and yield appropriate endometrial dating and bleeding patterns. However, the 400-mg/d dosage attains the highest sustained blood levels and may be the best dosage regimen for further study.     

Factors associated with osteoarthritis of the hip and knee in Hong Kong Chinese: obesity, joint injury, and occupational activities

In 1998, a case-control study was conducted in Hong Kong on hospital patients with osteoarthritis of the hip (n = 138) and osteoarthritis of the knee (n = 658). Age- and sex-matched controls were recruited consecutively from general practice clinics in the same region. The following three risk factors were found to be associated with osteoarthritis of both the hip and the knee: first, a history of joint injury: for osteoarthritis of the hip, the odds ratio = 25.1 (95% confidence interval (CI): 3.5, 181) in men and 43.3 (95% CI: 11.7, 161) in women; for osteoarthritis of the knee, the odds ratio = 12.1 (95% CI: 3.4, 42.5) in men and 7.6 (95% CI: 3.8, 15.2) in women; second, climbing stairs frequently: for osteoarthritis of the hip, the odds ratio = 12.5 (95% CI: 1.5, 104.3) in men and 2.3 (95% CI: 0.6, 8.1) in women; for osteoarthritis of the knee, the odds ratio = 2.5 (95% CI: 1.0, 6.4) in men and 5.1 (95% CI: 2.5, 10.2) in women; third, lifting heavy weight frequently: for osteoarthritis of the hip, the odds ratio = 3.1 (95% CI: 0.7, 14.3) in men and 2.4 (95% CI: 1.1, 5.3) in women; for osteoarthritis of the knee, the odds ratio = 5.4 (95% CI: 2.4, 12.4) in men and 2.0 (95% CI: 1.2, 3.1) in women. In addition, subjects whose height and weight were in the highest quartile were at increased risk of osteoarthritis of the hip and knee, respectively (p < 0.05).     

Dose-Volume Histograms for bladder and rectum

: A careful examination of the foundation upon which the concept of the Dose-Volume Histogram (DVH) is built, and the implications of this set of parameters on the clinical application and interpretation of the DVH concept has not been conducted since the introduction of DVHs as a tool for the quantitative evaluation of treatment plans. The purpose of the work presented herein is to illustrate problems with current methods of implementing and interpreting DVHs when applied to hollow anatomic structures such as the bladder and rectum.

: A typical treatment plan for external beam irradiation of a patient with prostate cancer was chosen to provide a data set from which DVH curves for both the bladder and rectum were calculated. The two organs share the property of being shells with contents that are of no clinical importance. DVHs for both organs were computed using a solid model and using a shell model. Typical treatment plans for prostate cancer were used to generate DVH curves for both models. The Normal Tissue Complication Probability (NTCP) for these organs is discussed in this context.

: For an eight-field conformal treatment plan of the prostate, a bladder DVH curve generated using the shell model is higher than the corresponding curve generated using the solid model. The shell model also has a higher NTCP. A six-field conformal treatment plan slo results in a higher DVH curve for the shell model. A treatment plan consisting of bilateral 120-degree arcs, results in a higher DVH curve for the shell model, as well as a higher NTCP.

: The DVH concept currently used in evaluation of treatment plans is problematic because current practices of defining exactly what constitutes “bladder” and “rectum.” Commonly used methods of tracing the bladder and rectum imply use of a solid structure model for DVHs. In reality, these organs are shells and the critical structure associated with NTCP is obviously and indisputably the shell, as opposed to its contents. Treatment planning algorithms for DVH computation should thus be modified to utilize the shell model for these organs.     

Contraindicated use of cisapride: impact of food and drug administration regulatory action

Context  Cisapride, a gastrointestinal tract promotility agent, can cause life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or prolong the QT interval or because of the presence of other diseases that predispose to such arrhythmias. In June 1998, the US Food and Drug Administration (FDA) determined that use of cisapride was contraindicated in such patients and informed practitioners through additions to the boxed warning in the label and a "Dear Health Care Professional" letter sent by the drug's manufacturer. Objective  To evaluate the impact of the FDA's 1998 regulatory action regarding contraindicated use of cisapride. Design and Setting  Analysis of data for the 1-year periods before (July 1997-June 1998) and after (July 1998-June 1999) the regulatory action from the population-based, pharmacoepidemiology research databases of 2 managed care organizations (sites A and B) and a state Medicaid program (site C). Participants  Patients with at least 180 days of prior enrollment in 1 of the 3 sites who were prescribed cisapride at least once in the period before (n = 24 840) or after (n = 22 459) regulatory action. Patients could be included in both cohorts. Main Outcome Measures  Proportion of cisapride users in each period for whom cisapride use was contraindicated by the product label, based on computerized patient medical encounter records. Results  In the year prior to regulatory action, cisapride use was contraindicated for 26%, 30%, and 60% of users in study sites A, B, and C, respectively. In the year after regulatory action, use was contraindicated for 24%, 28%, and 58% of users, a reduction in contraindicated use of approximately 2 per 100 cisapride users at each site. When the analysis was restricted to new users of cisapride after regulatory action, only minor reductions in contraindicated use were found. Conclusion  The FDA's 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.      

Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia: a single-centre experience.

Between 1990 and 1997, we performed 29 allogeneic BMTs for acute lymphoblastic leukemia (ALL) patients with HLA-identical sibs. Their median age was 31 years (range 15 to 43); there were 15 males and 14 females. The conditioning protocol was Cy-TBI (n = 15), VP16-Cy-TBI(n = 12), CBV (n = 1) and Bu-Cy (n = 1). Cyclosporin and methotrexate were used for GVHD prophylaxis. The median disease-free survival (DFS) was 12 months (range 1 to 92) with an actuarial 4-years DFS of 42.3 per cent. Three patients died of transplant-related complications before 100 days. Relapse occurred in 11 cases at a median time of 5 months (range 3 to 14). All nine patients relapsing within one year died form resistant leukemia. Three patients died of late treatment-related complications. There were 13 survivors (median follow-up 38 months, range 12-98), with 12 in remission. Only four had limited cGVHD, and all had 100 per cent performance scores. One patient also cleared her chronic hepatitis B carrier status due to acquired immunity. The DFS rates amongst CR1 cases and R1/CR2 cases were comparable (p = 0.39). No long-term DFS is obtained from patients with resistant disease (n = 4). The survival results for BMT at CR1 were superior to those using intensive chemotherapy consolidation (p = 0.29), mainly due to poor late results in the chemotherapy arm. For young ALL patients with HLA-matched siblings, the option of BMT should be considered in light of local consolidation survival results.     

Phase II study of Temodal in the treatment of patients with advanced nasopharyngeal carcinoma

Purpose: A single-institution phase II trial of Temodal (temozolomide, SCH52365) in Chinese patients with advance nasopharyngeal carcinoma was undertaken to determine the efficacy and safety of the drug in this population. Methods: A total of 14 patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma were entered into the study. One patient was unevaluable. Temodal was given at doses of 150 or 200 mg/m² daily on days 1–5 every 28 days. Results: In all, 30 cycles of Temodal were given with no significant toxicity. All 13 (100%) evaluable patients had progressive disease after 2 (84.6%) or 4 (15.4%) courses. Conclusion: Temodal given on this schedule has no activity in advanced nasopharyngeal carcinoma. Received: 9 January 1998 / Accepted: 4 February 1998