Pharmacokinetics of the four combination regimens of dihydroartemisinin/mefloquine in acute uncomplicated falciparum malaria

The pharmacokinetics of oral dihydroartemisinin and mefloquine were investigated in 40 patients (aged 16-30 y, weighing 45-60 kg) with acute uncomplicated falciparum malaria following the four combination regimens of dihydroartemisinin/ mefloquine [regimen-I: 300 mg dihydroartemisinin (h-0) plus 750 mg mefloquine (h-0); regimen-II: 300 mg dihydroartemisinin (h-0) plus 750 mg mefloquine (h-24); regimen-III: 300 mg dihydroartemisinin (h-0) plus 750 and 500 mg mefloquine (h-24 and 30); regimen-IV: 300 mg dihydroartemisinin (h-0) plus 750 and 500 mg mefloquine (h-0, 24)]. The four combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, 9 patients (4, 4, and 1 cases in regimens-I, II, and IV) had reappearance of parasitemia during the follow-up period. Significant changes in the pharmacokinetic parameters of both mefloquine and dihydroartemisinin were observed in patients with malaria compared with healthy subjects reported in a paralleled study. For mefloquine, Cmax (mg per dose), AUC0-day1 (mg per dose), and AUC0-day7 (mg per dose) were significantly higher in patients. Furthermore, tmax, was prolonged while V/F contracted and tl/2,z, MRT shortened in patients with malaria. For dihydroartemisinin, Cmax AUC, tmax and Vz/F were changed in the same direction as mefloquine, whereas t1/2z and MRT were prolonged. CL/F was also significantly reduced in patients with malaria. Absorption/disposition kinetics of oral dihydroartemisinin were similar among the various regimens. On the other hand, AUC0-day1 (mg per dose) of mefloquine after regimen-III was significantly higher than the other three regimens. Combination regimens with two divided doses of mefloquine (regimens-III and IV) resulted in a significantly delayed tmax (especially regimens-IV) compared with those with single dose regimens (regimens-I and II).     

A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand.

Recently, a combination of artesunate and mefloquine has proved effective, although is contraindicated in early pregnancy and young children. Azithromycin, a widely used antibiotic and has antimalarial effects, replace mefloquine as a new alternative antimalarial regimen. Two hundred and two uncomplicated falciparum malaria patients were randomly assigned to 1 of 3 regimens. Patients in group I (n = 68) received artesunate 200 mg once daily for 3 days, group II (n = 67) received artesunate 200 mg together with mefloquine 10 mg/kg on the first 2 days and artesunate 200 mg together with mefloquine 5 mg/kg on the third day, and group III (n = 67) received artesunate 200 mg together with azithromycin 50 mg once daily for 3 days. The 28 day cure rates were 44, 98 and 56%, respectively. The median time to recrudescence was significantly longer in group III. In conclusion, a combination of artesunate and azithromycin might be useful in treating children in whom bacterial and malarial infections may be concomitant. However, further work is required in order to enhance its clinical efficacy.     

The phenotypic profile of CD34-positive peripheral blood stem cells in different mobilization regimens

The type of regimen used might result in mobilization of phenotypically and functionally different CD34(+) cells. We compared the phenotype of CD34(+) cells in leukapheresis products of three homogeneous groups: I, healthy individuals treated with granulocyte colony-stimulating factor (G-CSF) alone (n = 13); II, patients mobilized with G-CSF following chemotherapy (n = 16); and III, patients mobilized with G-CSF after high-dose chemotherapeutic pretreatment (n = 24). Multiparameter flow cytometry was performed for CD34(+) subpopulation analysis and focused on adhesion molecules, differentiation markers and megakaryocytic markers relevant for stem cell homing, with special reference to the importance of L-selectin expression. Regimens I and II led to higher numbers of mobilized CD34(+) cells (mean 468 x 10(6) and 491 x 10(6) CD34(+) cells per leukapheresis procedure respectively) than regimen III (mean 41 x 10(6) CD34(+) cells per leukapheresis procedure). Both the expression of L-selectin and CD54 on CD34(+) cells was significantly lower in group III, as was the percentage of megakaryocytic (CD41(+)) progenitors. A higher percentage of primitive (CD38(-) and/or HLA(-)DR(-)) CD34(+) cells was found in group III, correlating with a higher clonogenicity of the CD34(+) cells. However, when comparing the CD34(+)_ subpopulations that were also positive for L-selectin, there was no significant difference between the three regimens. A similar approach for the megakaryocytic CD34+ population resulted in an even worse quality of regimen III: 5.1% of CD34(+) being CD41(+)/L-selectin(+) compared with 9.2% and 8.9% in regimens I and II respectively. We concluded that the phenotypes of the CD34(+) cells in the G-CSF (group I) and G-CSF-chemotherapy (group II) regimens are similar, whereas the phenotype of the CD34(+) cells mobilized in the high-dose regimen (group III) displayed features that might negatively influence homing of the cells. Future studies will be directed towards regimens that will lead to the mobilization of a higher amount of CD34(+) cells with a phenotypically favourable phenotype.     

Clinical efficacy of high dose monotherapy of oral dihydroartemisinin in uncomplicated falciparum malaria in viet nam

The clinical efficacy of the monotherapy involving the administration of a high dose of dihydroartemisinin (DHA 900 mg) for 5 days was compared with that of the combination regimen (DHA 600 mg + mefloquine [MQ] 750 mg) in an open randomized study in 90 patients with uncomplicated falciparum malaria in the southern part of Viet Nam. Patients were randomly treated with the DHA-5 day monotherapy regimen (300, 300, 100, 100, and 100 mg given at 0, 24, 48, 72, and 96 h) or the DHA-MQ combination regimen (300 mg DHA at 0 h, then 300 mg DHA plus 750 mg MQ at 24 h). The end points for comparison were the parasite and fever clearance times (PCT and FCT) and recrudescence rates (by day 28 for DHA-5 days and day 42 for DHA-MQ). Eighty-nine patients completed the trial per protocol, including 45 cases receiving DHA-5 day and 44 receiving DHA-MQ. There was no difference in clinical manifestations, parasitemia density or other laboratory tests between the two patient groups. The PCTs were 35.3 +/- 17.4 h (mean +/- SD; range, 12-96) and 37.8 +/- 19.2 h (range, 12-96), respectively for the DHA-5 day and DHA-MQ regimens (P > 0.05). Twelve patients receiving the DHA-5 day regimen relapsed with falciparum malaria by day 28 (26.7%) and 5 patients receiving the DHA-MQ regimen relapsed by day 42 (11.4%) (P=0.07). Survival analysis showed that the DHA-5 day regimen had a radical cure rate significantly lower than that of the DHA-MQ regimen (P=0.003). The high dose of DHA in the monotherapy regimen did not increase the efficacy of the treatment of patients with uncomplicated Plasmodium falciparum malaria. The DHA combination regimens are suggested to be the better regimens for DHA.     

In vitro blood schizonticidal activity of sera containing mefloquine‐quinine against Plasmodium falciparum

Serum samples collected at intervals from healthy volunteers, after the administration of 3 drug regimens (quinine (QN) 600 mg, mefloquine (MQ) 750 mg, and MQ 750 mg plus QN 600 mg) were investigated for their blood schizonticidal activities against K₁ strain Plasmodium falciparum in vitro . Superiority of activity was shown in the sera collected after the combination regimen. In the diluted sera of the QN regimen, a complete inhibitory effect was observed for only 24 hours, whereas the effect was sustained for 72 hours in the sera collected after MQ in either regimen (MQ alone or MQ/QN). The pattern of minimum inhibitory concentrations (MICs) of QNEq of the sera from QN alone was constant throughout a 24‐hour period, with significantly higher concentrations than that from the combination regimen (118–150 vs 21.25–73.5 μg/l). In sera collected after the combination regimen, however, the MIC gradually decreased from 0.5 until 2.5 and 4 h, and thereafter gradually returned to the same levels again during a period of 6–24 hours. The MICs of MQEq when given as MQ alone or in combination appeared constant, with a significantly higher value in the former regimen (24.4–26.8 vs 17–19.2 μg/l).     

Immunosuppressive therapy for acquired severe aplastic anemia (SAA): a prospective comparison of four different regimens

OBJECTIVE: This study was designed to investigate four different immunosuppressive therapy (IST) regimens as treatment of acquired severe aplastic anemia (SAA). PATIENTS AND METHODS: 142 consecutive SAA patients were randomized to receive one of the following IST regimens: equine anti-human thymocyte immunoglobulin (E-ATG) alone (IST regimen I); E-ATG and cyclosporine A (CSA) (IST regimen II); E-ATG, CSA plus recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) and rhu erythropoietin (rhuEPO) (IST regimen III); or rabbit ATG (ATG-F), CSA, rhuGM-CSF, and rhuEPO (IST regimen IV). No repeated courses of E-ATG or ATG-F were given for nonresponders. All patients also received stanozolol or testosteron propionate. RESULTS: The overall response rate to IST regimen I was 58%. The response to IST regimen II (79%) was significantly higher (p = 0.04), more rapid and complete than after IST regimen I. The response rate to IST regimen IV (53%) was significantly lower than that of IST regimen III (73%, p = 0.039). The additional use of growth factors did not reduce early deaths and did not accelerate hematopoietic recovery after IST. Of the 142 patients enrolled in this trial, 92 (65%) are alive at a median follow-up time of 102 months (range, 54-166 months). The 5-year actuarial survival for IST regimens I, II, III, and IV was 58%, 81%, 80%, and 66%, respectively. CONCLUSION: The combination of E-ATG and CSA remains the best combination for the treatment of SAA patients, producing a survival advantage at 5 years. The addition of growth factors did not improve these results. Rabbit ATG-F appeared less effective than E-ATG.     

Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients

BACKGROUND: The efficacy and safety of 750-mg, 5-day levofloxacin was recently shown to be comparable to 500-mg, 10-day levofloxacin in a randomized, double-blind, multicentre clinical trial for mild-to-severe community-acquired pneumonia (CAP). This subgroup analysis attempted to compare the safety and efficacy of a short-course levofloxacin regimen with traditional levofloxacin dosing for PSI Class III/IV patients. METHODS: This retrospective, subgroup analysis focused on Pneumonia Severity Index Class III and IV patients enrolled in the study. Measurements included clinical and microbiological success rates, adverse events, and symptom resolution by day 3 of therapy. RESULTS: Of the 528 patients in the ITT population, 219 (41.5%) were categorized as PSI Class III/IV and included in this analysis. Among the clinically evaluable patients, 90.8% (69/76) of patients treated with the 750-mg regimen achieved clinical success, compared with 85.5% (71/83) treated with 500-mg levofloxacin (95% CI,-15.9 to 5.4). Eradication rates in the microbiologically evaluable population were comparable for the 750- and 500-mg regimens (88.9% vs 87.5%, respectively; 95% CI,-18.3 to 15.6). Both regimens were well tolerated and had comparable safety profiles. A greater proportion of patients in the 750-mg treatment group experienced resolution of fever (48.4% vs 34.0%; P=.046) and purulent sputum (48.4% vs 27.5%; P=.007) by day 3 of therapy. CONCLUSIONS: The 750-mg, 5-day levofloxacin course achieved comparable clinical and microbiologic efficacy to the 500-mg, 10-day regimen. By day 3 of therapy, a greater proportion of patients in the 750-mg group had objective and subjective resolution of fever. Further research is needed to determine the economic significance of short-course levofloxacin therapy.     

Efficacy and safety of individualized growth hormone treatment in adult Japanese patients with growth hormone deficiency

OBJECTIVE: The aim of the study was to evaluate the efficacy and safety of growth hormone (GH) treatment in Japanese adult patients with GH-deficiency. In the extension of the efficacy study, the effect of individualized-dosing (ID), based on insulin-like growth factor-I (IGF-I) levels, and fixed-dose (FD) GH regimens on body composition, were compared in Japanese GH-deficient adults. DESIGN: Randomized, double-blind (DB), placebo-controlled, 24-week treatment period followed by 48-week, open-label study in 43 endocrinology clinics in Japan. Patients received DB treatment with GH (0.012 mg/kg/day; n=57) or placebo (n=60) followed by open-label GH in an ID (n=75) or FD (0.012 mg/kg/day; n=38) regimen. SUBJECTS: Adult Japanese GH-deficient patients (peak GH<3 ng/mL). MEASUREMENTS: Trunk and total body fat (BF), lean body mass (LBM), and adverse events were determined. RESULTS: Percentage trunk fat was reduced significantly more in GH- than in placebo-treated patients at 24 weeks (-16.2 vs. 1.7%, p<0.0001). Open-label treatment with an ID or FD GH regimen provided similar reductions in percentage trunk fat (-8.12 vs. -9.35%), and total BF (-0.92 vs. -0.70 kg) and a comparable increase in LBM (1.032 vs. 0.97 kg). Mean+/-SD GH doses (mg/kg/day) at 48 weeks were significantly lower with the ID GH regimen (ID, 0.0082+/-0.0050; FD, 0.0095+/-0.0033; p<0.05). The safety profile was comparable between ID and FD groups. CONCLUSIONS: Treatment with GH was associated with a significant reduction in trunk fat and improvement in serum lipid profile in Japanese adult GH-deficient patients. The improvement in body composition and tolerability were comparable between ID and FD GH regimens despite a significantly lower daily GH dose with the ID regimen.     

Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study

OBJECTIVE: An effective and well tolerated intravenous (IV) bisphosphonate could provide a new treatment method for patients with osteoporosis. The Dosing IntraVenous Administration (DIVA) study was designed to identify the optimal ibandronate IV injection schedule for the treatment of postmenopausal osteoporosis by comparing the efficacy and tolerability of 2- and 3-monthly injections with the previously evaluated daily oral ibandronate regimen. We report the effects on lumbar spine and proximal femur bone mineral density (BMD) and bone resorption markers over 2 years. METHODS: This randomized, double-blind, double-dummy, noninferiority study recruited 1395 women (aged 55-80 yrs; > or = 5 yrs since menopause) with osteoporosis [mean lumbar spine (L2-L4) BMD T-score < -2.5 and > or = -5.0]. Patients received IV ibandronate (2 mg every 2 mo or 3 mg every 3 mo) plus daily oral placebo, or 2.5 mg daily oral ibandronate plus 2- or 3-monthly IV placebo. Supplemental vitamin D (400 IU) and calcium (500 mg) were provided throughout the 2-year study. RESULTS: At 2 years, the 2- and 3-monthly IV regimens achieved statistically noninferior and also superior increases in lumbar spine BMD compared with the daily regimen (6.4% and 6.3% vs 4.8%, respectively; p < 0.001). Greater increases were also obtained with IV ibandronate versus daily in proximal femur BMD. Serum concentrations of the biochemical marker of bone resorption C-telopeptide of the alpha-chain of type I collagen were reduced to a similar extent in all treatment arms (53.4%-59.9%). The tolerability profile of the IV regimens was similar to that observed with daily oral therapy. CONCLUSION: Ibandronate IV injections are an effective and well tolerated treatment for postmenopausal osteoporosis and provide a useful alternative to oral dosing.     

A randomized trial of corticosteroids for the prevention of restenosis in 102 patients undergoing repeat coronary angioplasty

To examine the effect of corticosteroid therapy on the development of restenosis following successful percutaneous transluminal coronary angioplasty (PTCA), we randomized 102 patients with restenosis following prior PTCA to receive high-dose steroids (n = 52) or no steroids (n = 50). The steroid regimen consisted of 125 mg methylprednisolone I.M. the night before and morning of the PTCA, and prednisone 60 mg p.o. Q.D. for 1 week. post-PTCA. Angiographic follow-up at 6 months was available in 27 steroid-treated patients (52%) and 27 controls (54%). The per lesion incidence of restenosis was similar in the two groups (36% vs. 40%, respectively, P = NS). Clinical follow-up was available in the remaining patients at a mean interval of 1.2 years. The clinical correlates of restenosis (incidence and severity of angina, positive treadmill exercise test, nonfatal infarction or death) were similar in the steroid treated and control groups (24% vs. 39%, respectively, P = .56). At late follow-up, 30 steroid-treated patients (58%) and 26 control patients (52%) had no clinical or angiographic evidence of restenosis (P = NS). In conclusion, a short course of high-dose corticosteroid therapy does not significantly reduce the frequency of restenosis following PTCA.     

Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone

The response to ACTH stimulation, insulin-hypoglycemia and metyrapone in patients with suspected HPA axis dysfunction due to corticosteroid therapy (Group I, n = 10), or pituitary surgery (Group II, n = 7) and in a control population (Group III, n = 8) was studied. Group I patients had been maintained on a stable low dose of prednisone 5.0-7.5 mg/day for 1 month-16 yr (mean = 31 mos) prior to testing. Basal 08:00 h cortisol levels in this group were not different from control values. However, the mean responses to all three testing procedures were suppressed (Group I vs III, ACTH p less than 0.001, insulin p less than 0.01, metyrapone p less than 0.05). Group II patients had undergone surgery 1-26 months (mean = 10 mo) prior to testing and had been maintained subsequently on a stable dose of prednisone 5.0-7.5 mg/day. In this group basal mean 08:00 h cortisol and the cortisol response to ACTH and insulin-hypoglycemia were not significantly different from control values while the response to metyrapone was suppressed (Group II vs III p less than 0.02). Basal serum DHEA-S levels were suppressed in both Groups I and II when compared to Group III (p less than 0.001). Discordant responses to the three testing procedures were noted in 6 patients with suspected HPA dysfunction with abnormal test results in 1/6 using cortrosyn, 3/6 using insulin-hypoglycemia and 4/6 using metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endoscopic injection therapy vs. multipolar electrocoagulation vs. laser vs. injection + octreotide vs. injection + omeprazole in the treatment of bleeding peptic ulcers. A prospective randomized study

BACKGROUND/AIMS: A prospective randomized study was performed to assess the effectiveness and safety of 5 different methods of hemostasis in selected patients with high-risk bleeding peptic ulcers. METHODOLOGY: Two hundred and eight patients (n = 208; mean age: 61.6 yrs) with endoscopic stigmata of active hemorrhage, non-bleeding vessel or adherent fresh clot were randomized during emergency endoscopy to receive one of the following modalities of endoscopic therapy (with or without pharmacological therapy): I) injection of absolute alcohol (n = 44); II) multipolar electrocoagulation (BICAP; n = 42); III) Nd-YAG laser (n = 40); IV) injection of absolute ethanol + octreotide (n = 42); V) injection of absolute ethanol + omeprazole (n = 40). RESULTS: The 5 treatment groups were clinically and endoscopically comparable. The initial hemostatic success was > 90% in every group. No significant differences between groups were found in any of the following parameters assessed during hospitalization: incidence of rebleeding (I = 14.8% vs. II = 19.0% vs. III = 16.6% vs. IV = 18.1% vs. V = 20.0%; P > 0.05 mean = 17.7%); incidence of definitive hemostasis (I = 89.3% vs. II = 85.7% vs. III = 86.6% vs. IV = 84.0% vs. V = 86.6%; P > 0.05; mean = 86.5%); incidence of emergency surgery (I = 8.5% vs. II = 11.9% vs. III = 10.0% vs. IV = 6.8% vs. V = 11.1%; P > 0.05; mean = 9.6%); mortality rate (I = 4.2% vs. II = 4.7% vs. III = 3.3% vs. IV = 13.6% vs. V = 4.4%; P > 0.05; mean = 6.2%). Mean age of deceased patients was significantly higher than living patients (71.2 +/- 13.4 vs. 60.9 +/- 14.4; P < 0.05). Approximately 2/3 of the fatal cases were strongly weakened by coexistent medical diseases. The duration of hospital stay was similar for all groups. The BICAP group required less units of blood transfusion (1.9 +/- 1.8 vs. I = 3.0 +/- 2.6; III = 3.5 +/- 3.6; IV = 2.8 +/- 2.3; V = 3.1 +/- 2.5; P < 0.05), perhaps due to the higher mean value of hemoglobin of these patients at hospital admission, compared to all other groups. No significant complications were reported. CONCLUSIONS: This study provides good evidence that injection of absolute ethanol, multipolar electrocoagulation (BICAP) and Nd-YAG laser are equally safe and effective in the endoscopic therapy of acute bleeding peptic ulcers. In contrast, no additional hemostatic benefits arose from the association of pharmacological agents (octreotide or omeprazole) to sclerosis injection.     

A combination of dexamethasone,cyclophosphamide, etoposide,and cisplatin is less toxic and more effective than high-dose cyclophosphamide for peripheral stem cell mobilization in multiple myeloma

BACKGROUND AND OBJECTIVES: The purpose of this study was to compare the efficacy and toxicity of two regimens for peripheral blood stem cell (PBSC) mobilization in multiple myeloma (MM) patients. DESIGN AND METHODS: From 1995 to 2001, 116 patients were enrolled in two high-dose programs including autologous transplantation, adopting two mobilizing regimens: 61 patients were mobilized with high-dose cyclophosphamide (HD-Cy) at 4 g/m2 (group I), and 55 patients with DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) (group II), both followed by granulocyte colony-stimulating factor (G-CSF 5 mg/Kg/day) started 48 hours after chemotherapy. RESULTS: The median number of CD34+ cells harvested was similar in the two groups (5.9 vs 5.82x106 cells/kg). The target of at least 4x106 cells/kg was reached in a higher percentage of patients in the DCEP group (75 vs 59%) (p=0.05). The proportion of poor mobilizers (<2x106 CD34+ cells/kg) was 21% with HD-Cy and 13% with DCEP (P=NS). In group I, 10 patients (16%) required packed red cell transfusions, 5 patients (8%) platelet support, and the majority of patients (87%) had a neutrophil count below 500/mL, whereas none did so in group II (p=0.0009, p=0.01, p=0.0009, respectively). Neutropenia-related fever occurred in 18% of patients in group I versus 0% in group II (p=0.0005). WHO grade >II extra-hematologic toxicities (microhematuria, cystitis, infections) were seen in 8 patients (13%) of group I vs 0 in group II (p=0.007). INTERPRETATION AND CONCLUSIONS: DCEP is a better tolerated and more effective regimen than HD-Cy for peripheral stem cell mobilization in MM patients assigned to high-dose therapy programs.     

High-dose busulfan, melphalan and thiotepa as consolidation for non-inflammatory high-risk breast cancer

The purpose of this study was to evaluate the toxicity and efficacy of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) in patients with high-risk non-inflammatory breast cancer defined as stage II disease > or =10 lymph nodes (n = 52) or stage III (n = 69), and prognostic factors for treatment outcome. One hundred and twenty-one patients (median age, 46 years) were treated with high-dose Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) (HDC) followed by autologous stem cell infusion (ASCI). One hundred patients were initially treated with surgery followed by standard adjuvant chemotherapy prior to HDC/ASCI. Twenty-one patients with stage III disease had inoperable tumors at diagnosis and were treated with neoadjuvant chemotherapy and surgery before HDC/ASCI. Transplant-related mortality was 6%. The probabilities of event-free survival (EFS) at 3 and 5 years (median follow-up of 36 months) from transplant were, for all patients: 0.62-0.60; stage II: 0.71-0.67: stage III: 0.55-0.55 (for stage III adjuvant and neoadjuvant groups: 0.60-0.60 and 0.42-0.42, respectively). Multivariate analysis did not identify variables associated with poor outcome. The efficacy of Bu/Mel/TT is similar to other HDC regimens reported for patients with high-risk non-inflammatory breast cancer. Bu/Mel/TT has high activity in stage II disease and a moderate benefit in stage III operable tumors.     

Prognostic implication of creatine kinase release after elective percutaneous coronary intervention in the pre-IIb/IIIa antagonist era

Background

The significance of mild elevations in cardiac enzymes after an elective percutaneous coronary intervention (PCI) still remains controversial. We evaluated the significance of creatine phosphokinase level (CPK) elevations in a large cohort of patients who had undergone an elective PCI before the IIb/IIIa receptor antagonist era.

Methods

All patients enrolled in the Emory databank from 1981 to 1996 who had an elective PCI were evaluated. We identified 15,637 patients who met our inclusion and exclusion criteria. Patients were divided into 4 groups on the basis of the magnitude of the CPK elevation noted in the post-PCI period: group I (CPK <250 mg/dL, n = 14,512); group II (CPK 250-500 mg/dL, n = 715); group III (CPK 500-750 mg/dL, n = 164); and group IV (CPK >750 mg/dL, n = 246).

Results

CPK elevations were associated with a significant increase in the periprocedure angiographic complications. Angiographic complication rates were 14.6%, 30.5%, 40.2%, and 43.5% in groups I, II, III, and IV, respectively (P < .001). Long-term survival also correlated inversely with the magnitude of CPK elevations. The 10-year survival rates were 73%, 71%, 69%, and 55% in groups I, II, III, and IV, respectively (P < .0001). After multivariate analysis to correct for clinical factors, a CPK elevation of at least 3-times normal (group IV) was found to be an independent predictor of diminished 30-day and long-term survival (hazard ratio 1.84, 95% CI 1.41-2.41, P < .0001). Elevations in CPK <3-times normal (groups II and III) were not independently predictive of poor long-term survival.

Conclusion

A CPK level >3-times normal after an elective PCI is a strong independent predictor of poor long-term prognosis.     

Intensive conditioning regimen of etoposide (VP-16), cyclophosphamide and carmustine (VCB) followed by autologous hematopoietic stem cell transplantation for relapsed and refractory Hodgkin's lymphoma

Several high-dose therapy regimens are used for autologous hematopoietic stem cell transplantation (auto-HSCT) for relapsed and refractory Hodgkin's lymphoma (HL) with variable disease response. An intensified regimen of etoposide (VP-16) 2,400 mg/m(2), cyclophosphamide 7,200 mg/m(2) and carmustine (BCNU) 600 mg/m(2) (VCB) pre-auto-HSCT was developed to overcome disease recurrence. A total of 43 relapsed and refractory HL patients underwent auto-HSCT between January 1992 and December 2004. At day 100 there were 37 (86%) complete responses. A total of 40 patients survived beyond day 100, 14 of whom subsequently relapsed/progressed. At a median follow-up of 4.9 years (range 1.5-11.4 years), 26 patients (60%) are alive and disease free. Five-year actuarial event-free survival (EFS) was 53% (95% CI 35-70%) and median EFS was 5.9 years. Median progression-free and overall survivals have not been reached. EFS was reduced with an increasing number of prognostic factors (Karnofsky performance status, KPS <90, chemotherapy-resistant disease and >or=3 chemotherapy regimens prior to transplant or=2; P=0.049). Grade III-IV regimen-related toxicity was 9% (n=4). The 1-year cumulative incidence of interstitial pneumonitis (IP) was 36%, however only two patients died of IP complications. Disease progression was the most common cause of death (n=10, 23%). Intensive VCB is an effective and well-tolerated preparative regimen for relapsed and refractory HL auto-HSCT.     

Pharmacokinetics of mefloquine with dihydroartemisinin as 2-day regimens in patients with uncomplicated falciparum malaria

The objective of this study was to investigate the pharmacokinetics of mefloquine (MQ) when given as 750 mg at two different times in combination regimens with dihydroartemisinin (DHA) in patients with acute uncomplicated falciparum malaria. A total of 12 Vietnamese patients (6 in each group) were randomized to receive two MQ-DHA regimens as follows: regimen-A: an initial oral dose of 300 mg DHA, followed by 750 mg MQ and 300 DHA 6 and 24 hours later; regimen-B: an initial dose of 300 mg DHA, followed by 300 mg DHA and 750 mg MQ at 24 hours. Both combination regimens were well tolerated. All patients responded well to treatment with no recrudescence during a 42 day follow-up period. The pharmacokinetics of MQ following both regimens were similar but pooled data from both groups suggest that the kinetics of MQ was different from that observed in Vietnamese healthy subjects reported in a previous study. The median (95% CI) time period for maintenance of whole blood MQ concentrations above 500 ng/ml was 16 (0-24) days. It was concluded that since no pharmacokinetic drug interaction was observed, MQ dose given 24 hours after an initial dose of DHA is a preferable combination treatment regimen with regard to patient compliance.     

Long-term clinical outcomes of platelet glycoprotein IIb/IIIa inhibitor combined with low molecular weight heparin in patients with acute coronary syndrome.

BACKGROUND: Platelet activation and aggregation with resultant arterial thrombus formation play a pivotal role in the pathophysiology of acute coronary syndrome (ACS). In the present study the efficacy of tirofiban, a specific inhibitor of the platelet glycoprotein IIb/IIIa receptor, combined with heparin or low-molecular-weight heparin (dalteparin), was evaluated for the management of ACS. METHODS AND RESULTS: One hundred and sixty patients (60.9+/-11.1 years, 104 male) with unstable angina or non-ST elevation myocardial infarction and who had ST-T changes and elevated troponin were randomly assigned to 4 groups: group I (n=40: heparin alone), group II (n=40: dalteparin alone), group III (n=40: tirofiban + heparin) and group IV (n=40: tirofiban + dalteparin). The occurrence of major adverse cardiac events (MACE) was compared prospectively during a 6-month clinical follow-up. Percutaneous coronary intervention or coronary artery bypass graft was performed in 32 cases in group I, 29 in group II, 28 in group III and 31 in group IV (p=0.72). Minor bleeding complication developed in 2 patients (5.0%) in group I, 2 (5.0%) in group II, 4 (10.0%) in group III and 3 (7.5%) in group IV (p=0.78). During the follow-up MACE occurred in 10 patients (31.3%) in group I, 9 (31.0%) in group II, 4 (14.3%) in group III and 4 (12.9%) in group IV (p=0.02: Group I and II vs Group III and IV). CONCLUSIONS: Tirofiban combined with dalteparin was associated with relatively more bleeding complications in the short term, but was effective in reducing the incidence of MACE during long-term clinical follow-up in patients with ACS.     

Examining the limits of the buprenorphine interdosing interval: daily, every-third-day and every-fifth-day dosing regimens

Aims . Opioid-dependent outpatients may be more likely to present for pharmacological treatment if less than daily dosing can be arranged. These studies compared opioid withdrawal symptoms during 24-, 72-, and 120-hour buprenorphine dosing regimens and evaluated participants' preferences for these different dosing regimens. Participants . Thirty-three opioid-dependent participants received daily sublingual maintenance doses of 4 mg/70 kg ( n = 14) or 8 mg/70 kg ( n = 19) of liquid buprenorphine. Methods . In Study I participants received, in a random order, three dosing regimens for five repetitions of each: daily maintenance doses every 24 hours (4 or 8 mg/70 kg), triple the daily maintenance dose every 72 hours (12 or 24 mg/70 kg) and quintuple the daily maintenance dose every 120 hours (20 or 40 mg/70 kg). Doses were administered under double-blind procedures, and placebos were administered on the interposed days during the latter two regimens. Subjective and observer ratings of opioid withdrawal symptoms were assessed daily prior to receipt of each dose. In Study II, a new group of participants received each of the three dosing regimens under open-dosing procedures and then chose between the different dosing regimens. Findings . Opioid withdrawal symptoms increased significantly during the every-fifth-day dosing regimen in both the blind- and open-dosing studies. In the choice phase of Study II, only one participant (7%) chose quintuple-every-fifth-day dosing over all other dosing options. Conclusions . These results suggest that the maximum duration of action of buprenorphine is less than 5 days when five times the daily maintenance dose is provided.