Long-term efficacy and safety of ritonavir/indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as first line antiretroviral therapy

Objective To determine the long‐term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs).
Design and methods In an open‐label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients ( n  = 93) with a high median baseline HIV‐1 RNA level of 210 000 copies/mL (range 17 000–2 943 000) and a median CD4 cell count of 195 copies/µL (range 4–656 copies/µL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4‐week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures.
Results HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks.
Conclusions Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load.     

The long-term pharmacokinetics and safety of adding low-dose ritonavir to a nelfinavir 1,250 mg twice-daily regimen in HIV-infected patients

OBJECTIVES: To evaluate the long-term pharmacokinetics and safety of adding ritonavir 100 mg twice-daily to a nelfinavir 1250 mg twice-daily regimen in HIV-infected patients. METHODS: This was a prospective, randomized, open-label, controlled 24-week study. Sixteen patients receiving a nelfinavir 1250 mg twice-daily regimen with plasma viral load <1000 HIV-1 RNA copies/mL were randomized to continue treatment or to have ritonavir 100 mg twice-daily added. Safety, including fasting lipid levels, was evaluated at weeks 4, 12 and 24. Patients who were randomized to have ritonavir added (n=9) participated in three 12-h pharmacokinetic evaluations at baseline, week 4 and week 24. RESULTS: Increases in median nelfinavir steady-state plasma concentrations at 12 h (C(12)) from 512 to 773 ng/mL [median difference 450 ng/mL; 95% confidence interval (CI) 116--1510 ng/mL] and in median active nelfinavir metabolite M 8 C(12) from 107 to 603 ng/mL (median difference 545 ng/mL; 95% CI 370--891) were seen after the addition of low-dose ritonavir (baseline to week 24). There were no differences between the nelfinavir or M 8 pharmacokinetic parameters at weeks 4 and 24. No significant changes or differences in the concentration of fasting total cholesterol, low-density lipoprotein (LDL) cholesterol or total triglycerides or in the occurrence of adverse events were observed within or between the two groups. CONCLUSIONS: Nelfinavir and especially M 8 concentrations are increased when low-dose ritonavir is added to a nelfinavir-containing regimen. The combination seems to be safe and the nelfinavir/ritonavir regimen could be an option in patients with low nelfinavir+M 8 concentrations.     

The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.

OBJECTIVE: To explore the steady-state plasma pharmacokinetics of indinavir in twice daily dosing regimens with and without the co-administration of 100 mg ritonavir. DESIGN: Observational pharmacokinetic study. PATIENTS: HIV-1-infected individuals who use indinavir alone (1200 mg twice daily, n = 6), or the combination of 100 mg ritonavir twice daily plus either 800 mg (n = 6), or 1200 mg indinavir twice daily (n = 2). METHODS: Steady-state pharmacokinetics of indinavir and ritonavir were assessed by drawing 12 blood samples during an 8-h period after ingestion of the medication. RESULTS: Significant differences were observed for indinavir pharmacokinetics between the dosing regimens indinavir 1200 mg twice daily alone and indinavir/ ritonavir 800/100 mg twice daily with respect to the mean trough concentration (0.21 and 0.99 microg/ml, respectively, P = 0.002), the mean maximum concentration (13.79 and 8.74 microg/ml, respectively, P = 0.028), and for the mean plasma elimination half-life (1.6 and 3.2 h, respectively, P = 0.001). The combination indinavir/ritonavir 1200/100 mg twice daily led to very high exposure to indinavir and was not well tolerated. However, the combination indinavir/ritonavir 800/100 mg twice daily was well tolerated and resulted in therapeutic concentrations of indinavir with improved trough concentrations and similar maximum concentrations as observed with the licensed dosage of 800 mg three times daily. CONCLUSION: Combination of indinavir and 100 mg ritonavir in twice daily dosing regimens significantly affects the pharmacokinetic profile of indinavir. The results of this observational study provide a pharmacologic basis for the combination of indinavir (800 mg) and ritonavir (100 mg) in twice daily dosing regimens.     

综合疗法对非小细胞肺癌的临床疗效观察

目的 探讨综合疗法在非小细胞癌治疗中的临床疗效及对患者生活质量的影响.方法 将我院收治的75例非小细胞肺癌患者随机分为观察组和对照组,对照组给予单纯化疗,观察组在此基础上给予参附注射液,观察两组患者的临床疗效及预后.结果 观察组临床有效率为78.0%（32/41）,临床受益率（CBR）为82.9%（34/41）,疾病进展时间为（5.7±2.7）月,肺癌患者生存质量评价量表（FACT-L）评分为（89.3±1.8）分;对照组临床有效率为44.1%（15/34）,临床受益率（CBR）为52.9%（18/34）,疾病进展时间为（4.6±2.2）月,肺癌患者生存质量评价量表（FACT-L）评分为（72.5±2.4）分;两组间差异有统计学意义（P＜0.05）.结论 综合疗法能显著缓解非小细胞肺癌患者临床症状,提高临床疗效.     

Determination of indinavir and nelfinavir trough plasma concentration efficacy thresholds according to virological response in HIV-infected patients

BACKGROUND: There is evidence to suggest a pharmacokinetic-pharmacodynamic relationship in HIV-infected patients receiving protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART); however, the effective trough PI plasma concentrations achieved have not been precisely determined. METHODS: The relationship between HIV viral load and concomitant PI trough plasma concentration (C(trough)) was evaluated in 101 patients receiving at least 4 months of thrice daily indinavir (IDV)-containing (n=68) or nelfinavir (NFV)-containing (n=33) HAART. The more discriminating C(trough) efficacy thresholds were determined statistically for each PI by using the raw C(trough) and the time-corrected C(trough), using the precise delay since the last PI intake and the half-life of each PI. RESULTS: For IDV (P=0.002) and NFV (P=0.019) median C(trough) levels were higher in patients with undetectable viral load [0.23 mg/L (n=30) and 2.3 mg/L (n=16) respectively] than in patients with detectable viral load [0.11 mg/L (n=38) and 0.6 mg/L (n=17) respectively]. C(trough) levels of IDV (r=-0.45; P<0.0001) and NFV (r=-0.43; P=0.011) were correlated with the concomitant viral load. The more discriminating C(trough) efficacy thresholds were estimated statistically as 0.12 mg/L for IDV and 0.5 mg/L for NFV. When C(trough) values were time-corrected, the C(trough) efficacy thresholds, 8 h after the last intake, were 0.15 mg/L for IDV and 0.65 mg/L for NFV. CONCLUSIONS: These results support the importance of achieving minimal effective C(trough) to improve the virological efficacy of PI-containing HAART, and specify the target concentrations for IDV and NFV.     

The efficacy and safety of fixed-dose combination of amlodipine/benazepril in Chinese essential hypertensive patients not adequately controlled with benazepril monotherapy: a multicenter,randomized, double-blind,double-dummy,parallel-group clinical trial

This double-blind, double-dummy clinical trial evaluated the efficacy and safety of two strengths of fixed-dose combination of amlodipine/benazepril in Chinese hypertensive patients not adequately controlled with benazepril. Of 442 patients who received treatment with benazepril 10?mg for 4 weeks, 341 patients failed to achieve to diastolic blood pressure (DBP) <90?mmHg. These non-responders were randomized to receive amlodipine/benazepril 2.5/10?mg, or amlodipine/benazepril 5/10?mg, or benazepril 10?mg for 8 weeks. BP reductions with amodipinel/benazepril 2.5/10?mg (15.2/11.8?mmHg) or amlodipine/benazepril 5/10?mg (15.4/12.4?mmHg) were significantly greater than that with benazepril 10?mg (9.88/9.46?mmHg) at study end (p?p?0.01, combination versus benazepril). Three groups were generally well tolerated. Our study indicated that amlodipine/benazepril fixed-dose combination offered significant additional BP reductions and BP control rate compared with the continuation of benazepril monotherapy. No significant differences were observed in both BP reductions and BP control rate between amlodipine/benazepril 2.5/10?mg and amlodipine/benazepril 5/10?mg.     

Effect of the combination of low-dose mexiletine and metoprolol on ventricular arrhythmia.

Antiarrhythmic drug therapy is often ineffective or poorly tolerated. Combining antiarrhythmic agents with different electrophysiologic properties may have a synergistic antiarrhythmic effect when compared with each drug alone. If a lower dose of each drug can be used, combination therapy may also result in lower incidence of side effects. The goal of our study was to assess the complementary effect of low-dose mexiletine and metoprolol, when compared with either drug alone. Ten patients with frequent ventricular arrhythmias including 7 patients with nonsustained ventricular tachycardia were evaluated in an open-label sequential study. The response to drug therapy was evaluated by 24-h continuous EKG monitoring, exercise stress testing, and echocardiogram after each treatment. Combination therapy effectively reduced ventricular arrhythmias in 8 patients (80%) in contrast to only 1 patient (10%) on metoprolol alone and 4 patients (40%) on mexiletine alone. In 5 patients (71%) ventricular tachycardia was abolished. The number of couplets was reduced from 51 +/- 39 to 1.9 +/- 2.4 (p less than 0.01) and total premature ventricular beats from 7790 +/- 9047 to 597 +/- 515 (p = 0.06). Combination therapy was well tolerated without proarrhythmia or precipitation of congestive heart failure. It is concluded that low-dose mexiletine combined with metoprolol is effective in suppressing ventricular arrhythmias in selected patients, and enhances the antiarrhythmic effect of either drug alone without significant side effects.     

Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia

Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10·5 years, range 7·3–12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m² and the area under the plasma concentration-time curve (AUC) was 4·49 and 5·40 mg/l × min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5·2; P  = 0·036), or AUC values below median (RR 5·8; P  = 0·025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies.     

Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia

BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.     

Translating science into clinical practice: focus on vildagliptin in combination with metformin

Vildagliptin is a potent and selective oral dipeptidyl peptidase-4 inhibitor that improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by increasing both α- and β-cell responsiveness to glucose. The efficacy, tolerability and safety of the combination of vildagliptin and metformin in the treatment of T2DM have been established in numerous trials in the extensive vildagliptin clinical programme. As add-on therapy in patients with inadequate glycaemic control on metformin, vildagliptin produces clinically significant reductions in glycated haemoglobin (HbA1c) and fasting plasma glucose, is well tolerated, and is associated with absence of weight gain and minimal risk of hypoglycaemia. Compared with thiazolidinedione add-on treatment, vildagliptin is associated with similar significant reductions in HbA1c without the weight gain seen with the former. Compared with sulfonylurea add-on treatment, vildagliptin is associated with similar efficacy in controlling glycaemia but absence of weight gain and a markedly lower risk of hypoglycaemia. In drug-naïve patients, single-tablet combinations of vildagliptin/metformin 50/500 and 50/1000 mg bid produced significantly greater reductions in HbA1c than monotherapy with either agent and were well tolerated, with no weight gain and minimal risk of hypoglycaemia. The combination of vildagliptin and metformin poses numerous advantages in the treatment of T2DM.     

Translating science into clinical practice: focus on vildagliptin in combination with metformin

Vildagliptin is a potent and selective oral dipeptidyl peptidase‐4 inhibitor that improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by increasing both α‐ and β‐cell responsiveness to glucose. The efficacy, tolerability and safety of the combination of vildagliptin and metformin in the treatment of T2DM have been established in numerous trials in the extensive vildagliptin clinical programme. As add‐on therapy in patients with inadequate glycaemic control on metformin, vildagliptin produces clinically significant reductions in glycated haemoglobin (HbA1c) and fasting plasma glucose, is well tolerated, and is associated with absence of weight gain and minimal risk of hypoglycaemia. Compared with thiazolidinedione add‐on treatment, vildagliptin is associated with similar significant reductions in HbA1c without the weight gain seen with the former. Compared with sulfonylurea add‐on treatment, vildagliptin is associated with similar efficacy in controlling glycaemia but absence of weight gain and a markedly lower risk of hypoglycaemia. In drug‐naïve patients, single‐tablet combinations of vildagliptin/metformin 50/500 and 50/1000 mg bid produced significantly greater reductions in HbA1c than monotherapy with either agent and were well tolerated, with no weight gain and minimal risk of hypoglycaemia. The combination of vildagliptin and metformin poses numerous advantages in the treatment of T2DM.     

Steady-state pharmacokinetics of once-daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteers

OBJECTIVES: Use of proton pump inhibitors in HIV-infected patients is common. The purpose of this study was to determine the steady-state pharmacokinetics of once-daily (qd) fosamprenavir/ritonavir (FPV/r) and atazanavir/ritonavir (ATV/r) alone and in combination with 20 mg qd omeprazole (OMP) in healthy volunteers. DESIGN AND METHODS: A prospective, open-label, single-site, two-period, crossover pharmacokinetic study was carried out in healthy volunteers. Subjects received either qd FPV/r 1400 mg/200 mg or ATV/r 300 mg/100 mg in the morning for 14 days and then 20 mg OMP in the evening for an additional 7 days. The pharmacokinetics were assessed over 24 h on days 14 and 21. Following a 2-week washout, subjects repeated the process with the other regimen. Trough protease inhibitor (PI) concentrations were taken on day 16 of each period to assess the impact of a single dose of OMP on ATV and amprenavir (APV) concentrations. Plasma ATV and APV pharmacokinetic parameters were assessed by noncompartmental analysis; geometric mean ratios (GMRs; PI+OMP/PI; 90% confidence interval) were calculated between days 14 and 21. RESULTS: Nineteen healthy, non-HIV-infected volunteers were evaluated. OMP reduced ATV exposure [area under the concentration curve at 0-24 h (AUC0-24 h)] and the minimum drug concentration (Cmin) by 27% each. In contrast, APV exposure and Cmin were decreased by 4 and 2%, respectively. Four subjects (21%) experienced greater than 50% declines in both ATV AUC0-24 h and Cmin after the addition of OMP; this was not observed in any subject following receipt of FPV/r. No alterations in APV or ATV trough concentrations were observed following a single dose of OMP. CONCLUSIONS: The addition of 20 mg OMP administered in the evening has minimal effect on APV pharmacokinetics. In contrast, ATV pharmacokinetics were altered; a number of ATV-treated subjects experienced pronounced declines in exposures upon the addition of 20 mg OMP administered in the evening, whereas others experienced little to no change.     

Coronary artery stenting in the elderly: short-term outcome and long-term angiographic and clinical follow-up

Objectives. This study sought to compare the short- and long-term outcomes of elderly patients undergoing coronary artery stenting with those of younger patients and to determine the long-term clinical outcome and survival of elderly patients post stent implantation.Background. Elderly patients undergoing coronary revascularization are considered a high-risk group. Few data exist that relate the results of stenting in treating coronary artery disease in the elderly population.Methods. All elderly patients ≥75 years of age who underwent coronary artery stenting between March 1993 and July 1997 (n = 137) at our center were compared to the patients <75 who underwent coronary artery stenting during the same time period (n = 2,551). Long-term clinical follow-up and survival were determined for the elderly group.Results. Elderly patients presented with lower ejection fractions (54% vs. 58%, p = 0.0001), more unstable angina (47% vs. 28%, p = 0.0001), and more multivessel disease (78% vs. 62%, p = 0.0001) than younger patients. These older patients had higher rates of procedure related complications including procedural myocardial infarction (MI) (2.9% vs. 1.7%, p = 0.2), emergency CABG (3.7% vs. 1.4%, p = 0.04), and death (2.2% vs. 0.12%, p = 0.0001). Angiographic follow-up, obtained in both groups, demonstrated significantly higher restenosis rates in the elderly versus younger patients (47% vs. 28%, p = 0.0007). Longer term clinical follow-up, which was obtained only in the elderly group, showed that at a mean follow-up period of 12 months post coronary stenting, elderly survival free from death, MI, revascularization and angina was 54% and that their overall survival was 91%. Subanalysis of the elderly patients who died showed much higher incidence of combined unstable angina (80%), prior MI (60%), lower ejection fraction (46%), multivessel disease (100%) and complex lesions (100%) than the overall group.Conclusions. Elderly patients who undergo coronary artery stenting have significantly higher rates of procedural complications and worse six month outcomes than younger patients, especially those who present with combined unstable angina, history of MI, EF < 50%, multivessel disease and complex lesions. Overall survival in the elderly population at 12 months postcoronary artery stenting was 91% and event-free survival was 54%.     

Pharmacokinetics of sequential and simultaneous treatment with the combination chloroquine and sulfadoxine-pyrimethamine in acute uncomplicated Plasmodium falciparum malaria in the Philippines

The efficacy and kinetics of the combination chloroquine plus sulfadoxine-pyrimethamine (CQ + SP), given sequentially and simultaneously, were investigated in 32 patients with acute uncomplicated Plasmodium falciparum malaria in Palawan Island, the Philippines. Group 1 with 11 patients received oral CQ 25 mg/kg bw over 3 days followed by a single dose of SP (three tablets 250 mg S + 25 mg P) on Day 4 (CQ0 + SP4). Group 2 with 21 patients received a loading dose of CQ 10 mg/kg plus a single dose of SP three tablets on Day 0, and doses of CQ on Days 1 and 2 (CQ0 + SP0). Patients were followed-up for 28 days until after the clinical and parasitological remission of the disease. Serum samples for CQ, des-ethylchloroquine (DCQ), S and P levels were assayed by high-pressure liquid chromatography with UV and spectrofluorometric detection (HPLC-SF) to determine effective therapeutic concentrations achieved. Parasite and fever clearance times (PCT and FCT) in Group 1 were 48 and 33.5 h, respectively, and 39 and 24 h in Group 2. The parasite elimination half-life (pt1/2) in the CQ + SP0 group was 2.5 h, significantly shorter than the CQ + SP4 group of 5.7 h (P=0.006). Late-treatment failures (R I) were observed in 2/11 patients in Group 1 and in 2/21 patients in Group 2. Serum CQ and DCQ concentrations were effectively adequate. Group 1 pharmacokinetic parameters showed a median maximum concentration (Cmax), area under the curve (AUC) and elimination half-life (t1/2) of 285 ng/ml, 2299 day ng/ml and 5.7 days for CQ, and 89 ng/ml 1845 day ng/ml and 7.3 days for DCQ, respectively. SP was not assayed in Group 1 because of very limited time points. In Group 2, the median Cmax, AUC and t1/2 for CQ and DCQ were at 283 ng/ml 1980 day ng/ml and 5.9 days for CQ and 220 ng/ml, 2680 day ng/ml and 8.5 days for DCQ, respectively. For S and P, the median Cmax, AUC and t1/2 were at 169 microg/ml, 2758 day ng/ml and 10.9 days for sulfadoxine, and 591 ng/ml, 3029 day ng/ml and 2.9 days for pyrimethamine, respectively. Both regimens were well tolerated with a minimum of side-effects, mainly nausea and vomiting. The combination CQ + SP administered simultaneously on Day 0 is more efficacious than when administered sequentially. In the absence of an alternative treatment for acute uncomplicated malaria, this combination is well tolerated, and has an advantage over CQ or SP monotherapy, especially in countries where one drug is still highly effective.