Standard Dose In Patients Research Articles

Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction

We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer. We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m(2) day 1, 8 and oral capecitabine 650 mg/m(2) b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ≤15 μmol/L] and 3 cohorts with increasing TB (16-39, 40-80, >80 μmol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography-tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis. Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10(-3)) and capecitabine (p = 10(-5)), and low intracellular gemcitabine triphosphate concentrations (p = 10(-3)). Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine's activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.

OP0148 Reduced dose and frequency of anti-TNF therapy in rhemuatic diseases

BackgroundThe anti-TNFα drugs Adalimumab (ADA) and Etanercept (ETA) are given in standard doses and intervals. Many patients on these drugs achieve long-term remission or low disease activity yet continue on...

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.Design Double blind randomised trial.Setting Thirteen hospitals in...

Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study

Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

Clopidogrel up-titration versus standard dose in patients with high residual platelet reactivity after percutaneous coronary intervention: A single-center pilot randomised study

Clopidogrel up-titration versus standard dose in patients with high residual platelet reactivity after percutaneous coronary intervention: A single-center pilot randomised study

Double-Dose Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Patients With Chronic Liver Disease

determine the effect of double-dose gadoxetic-acid (Gd-EOB-DTPA) on lesion-liver contrast ratio in arterial- and hepatocyte-phase images and arterial-phase image quality in patients with chronic liver disease. the ethics committee at our institute approved this study. This study included 28 patients (13 with Child-Pugh class A and 15 with class B) with 54 hepatocellular carcinomas. All patients received the standard Gd-EOB-DTPA dose (0.025 mmol/kg bodyweight) and double dose (0.050 mmol/kg bodyweight). The lesion-liver contrast ratio was evaluated in arterial- and hepatocyte-phase images. The artifacts in arterial-phase images were evaluated with a 4-point scale. Wilcoxon signed-rank test were used for comparisons. the hepatocyte-phase lesion-liver contrast ratio after the double dose was significantly higher than that after the standard dose in patients with Child-Pugh class B disease(standard dose vs. double dose; 0.20 ± 0.16 vs. 0.25 ± 0.17; P < 0.0001); however, the ratio after both the standard and double doses was equivalent in patients with Child-Pugh class A disease (0.35 ± 0.18 vs. 0.35 ± 0.14; P = 0.3038). The double dose significantly increased the arterial-phase lesion-liver contrast ratio (0.34 ± 0.19 vs. 0.58 ± 0.33; P < 0.0001). The artifacts in the arterial-phase images were more prominent after the standard dose (2.7 vs. 2.4 for reader 1, 2.8 vs. 2.4 for reader 2; P = 0.0195 and 0.0010). administration of double dose of Gd-EOB-DTPA provided better arterial enhancement of hepatocellular carcinomas in patients with chronic liver disease, and also improved the lesion-liver contrast in hepatocyte-phase images in patients with Child-Pugh class B disease.

Intracoronary Compared to Intravenous Abciximab and High-Dose Bolus Compared to Standard Dose in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Transradial Primary Percutaneous Coronary Intervention: a Two-by-Two Factorial Placebo-Controlled Randomized Study

Platelet aggregation inhibition (PAI) of > or =95% has been associated with improved outcomes after percutaneous coronary intervention (PCI) and glycoprotein IIb/IIIa inhibitor treatment. A greater thrombotic burden in acute ST-segment elevation myocardial infarction (STEMI) might require higher doses and/or intracoronary delivery of glycoprotein IIb/IIIa inhibitors to achieve optimal PAI. Using a 2 x 2 factorial placebo-controlled design, 105 patients with STEMI who had been referred for primary PCI within 6 hours of symptom onset were randomized to intracoronary (IC) or intravenous (IV) delivery of an abciximab bolus at a standard dose (0.25 mg/kg) or high dose (> or =0.30 mg/kg) of abciximab. The primary end point was PAI measured at 10 minutes after the bolus of abciximab. Secondary end points included the acute and 6-month outcomes using angiographic parameters, cardiac biomarkers, cardiovascular magnetic resonance imaging, and clinical end points. At 10 minutes after the bolus, the proportion of patients with > or =95% PAI was not different between the IC and IV groups (53% vs 54%, p = 1.00) nor between the high-dose and standard-dose bolus groups (56% vs 51%, p = 0.70). Acutely, the angiographic myocardial blush grades, peak release of cardiac biomarkers, necrosis size, myocardial perfusion, and no reflow as assessed by magnetic resonance imaging, and clinical end points were similar between the groups and did not suggest a benefit for IC compared to IV or high-dose versus standard-dose bolus of abciximab. No increase occurred in bleeding complications with the high-dose bolus or IC delivery. The clinical, angiographic and cardiac magnetic resonance imaging outcomes at 6 and 12 months were similar between the 4 groups. In conclusion, in patients with STEMI presenting with symptom onset <6 hours and undergoing transradial primary PCI, PAI remained suboptimal, despite a higher dose bolus of abciximab. A higher dose bolus or IC delivery of abciximab bolus was not associated with improved acute or late results compared to the standard IV dosing and administration.

Dismal response to high-dose methylprednisolone after failure to respond to standard dose in patients with acute GVHD

Corticosteroids such as methylprednisolone (MP) remain the primary therapy for acute GVHD (aGVHD). Patients who are refractory to standard treatment (MP 2 mg/kg/day) may be treated with high-dose MP. This study evaluated the response to high-dose MP in children with aGVHD refractory to standard dose MP. Children who underwent hematopoietic SCT (HSCT) at our hospital between 1 June 2002 and 31 July 2006 and were treated with high-dose MP upon developing steroid-refractory aGVHD were included. Response to aGVHD therapy, adverse effects attributed to MP and overall outcomes were documented. Ten children received high-dose MP (≥ 20mg/kg/day) on 3-5 consecutive days followed by a tapering dose for steroid-refractory aGVHD, at a median of 12 days after starting standard treatment. Nine patients had ≥ grade III aGVHD. Only one patient with grade III aGVHD had a complete response. Two patients had a partial response but flared when MP was tapered. Complications included hypertension (100%), hyperglycemia requiring insulin therapy (33%) and four documented severe infections. Five children (50%) died (median follow-up: 5.9 years). Salvage therapy other than high-dose MP should be considered in children who fail to respond to MP 2 mg/kg/day.

P58 Chemotherapy treatment for prostate cancer in the elderly: a comparison between docetaxel reduced dose in patients over 70 years old versus docetaxel standard dose in patients under 70

P58 Chemotherapy treatment for prostate cancer in the elderly: a comparison between docetaxel reduced dose in patients over 70 years old versus docetaxel standard dose in patients under 70

The Use of the Pre-Test Clinical Score (4T's) Alone Does Not Detect All Diagnoses of Heparin-Induced Thrombocytopenia in the Critically Ill.

Background: Heparin induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction to heparin. The 4T scoring system is a well validated system for assessing the pre-test probability of HIT and has a high negative predictive value for excluding HIT in most clinical situations, however, only a minority of patients have been evaluated in the ICU setting. The critically ill pose different challenges when compared with other medical and surgical patients. They have increased rates of thrombotic and haemorrhagic complications. Thrombocytopenia is reported in approximately 30–50%. We examined our ICU experience to evaluate the pairing of the 4T scoring system and EIA-GTI PF4 ELISA assay to evaluate their diagnostic accuracy in confirming a diagnosis of HIT in the acute setting. The gold standard measure is the serotonin release assay (SRA), but this is not routinely available in the UK.Methods: This single centre, retrospective, observational study involved reviewing the records of 75 consecutive patients investigated for HIT on our ICU from February 2006 to April 2008. We follow the British Society of Haematology guidelines for the management of HIT. Initial testing is with the EIA-GTI PF4 assay (positive if >0.4 OD) coupled with a heparin induced platelet activation assay (HIPA).Results: During the 26 months studied, 3.5% of ICU admissions were screened for HIT. A diagnosis of HIT, defined in this study as an intermediate or high 4T pre-test probability score and an ELISA result >0.7 OD was present in 0.46%. 45% of patients were medical, 40% had cardiothoracic surgery, the remaining 15% were general surgical patients. 66% had three or more organ failure, 70% received haemofiltration. Severe sepsis and haemofiltration were alternative causes of thrombocytopenia in 97% of patients. The 4T's were used to risk stratify patients, 68% of patients had a low score, 29% were at intermediate risk and 3% had a high probability of HIT. 76% of patients with a low pre test probability had a negative ELISA and none developed a thrombosis. 4 (8%) patients with a low pre-test probability had a positive ELISA with an optical density >0.7 OD. 4 patients had a low pre-test probability but a positive ELISA, none of whom developed a thrombus. 2 patients had a positive ELISA and a positive HIPA, both had an intermediate pre-test probability. 1 patient had a negative ELISA (<0.4 OD) in the context of a high pre-test probability, he became thrombocytopenic on repeated heparin exposure. There was no correlation between a high pre-test probability and the magnitude of the ELISA result. 10 patients were treated with lepirudin, 2 developed haemorrhage requiring interruption of anticoagulation and transfusion.Discussion: The incidence of HIT recorded over the 26 month study period at GSTT is similar to the incidence of 0.3 -0.5% reported by Selleng. No diagnoses of HIT were missed after increasing our ELISA threshold from 0.4 - 0.7 OD. Neither the 4T pre-test probability nor the EIA GTI PF4 ELISA alone are sufficient to exclude a diagnosis of HIT. The 4T scoring system although well validated system may not work as well in the critically ill. The high prevalence of thrombocytopenia and alternative causes of thrombocytopenia mean the presence of thrombosis and the timing of the thrombocytopenia post heparin exposure are the major discerning features. Lo has previously reported the potential to over diagnose HIT by 100% when using the EIAGTI ELISA (Lo GK. Am J Hematol. 2007; 82: 1037–43). The positive ELISA results in those patients with a low pre-test probability may be false positives secondary to cross-reacting autoantibodies. The high prevalence of acute renal failure highlights the importance of making an accurate diagnosis of HIT. Use of lepirudin in renal failure is associated with an increased risk of haemorrhage. We use 10% of the standard dose in patients with renal failure, haemorrhage occurred despite intensive monitoring in 20% of the patients. Our study is limited by its retrospective design and the lack of SRA testing. We recommend that both tests are performed in patients at risk of HIT. Increasing the positive ELISA threshold to 0.7 OD improves the specificity of the ELISA for detecting clinically significant heparin/PF4 antibodies in critically ill patients.

Pharmacogenetic-Guided Dosing of Warfarin: Results of the Couma-Gen Study

More than 2 million patients in the United States take warfarin as anticoagulant therapy. The dose of warfarin may vary depending on patient genotypes, which has resulted in changes in the prescribing guidelines for this agent. The effect of pharmacogenetic (PG)-guided dosing, however, has not been established in controlled studies. The Couma-Gen study was a prospective, randomized, double-blind trial of a PG-guided algorithm for warfarin dosing compared with standard dosing in patients starting oral anticoagulation therapy [Anderson JL, Horne BD, Stevens SM et al. Circulation 2007].

Low Dose Rituximab in Adult Patients with Idiopathic Thrombocytopenic Purpura.

Rituximab 375 mg/sqm weekly for 4 weeks has significant activity in patients with idiopathic thrombocytopenic purpura (ITP). In this setting, different biological and clinical evidence suggests the possible use of lower doses of Rituximab. Twenty-eight adult patients, median age 43 years (range 16–71 years), with previously treated, active and symptomatic ITP were treated prospectively with Rituximab at the fixed dose of 100 mg iv weekly for 4 weeks. Exclusion criteria were positive HIV, HBsAg and pregnancy test, any B-cell lymphoprolipherative disease or other malignancies. Response assessment was evaluated considering the rate of overall and complete responses (OR = platelet count ≥ 50 x 109/L; CR= platelet count ≥ 100 x 109/L and discontinuation of steroid therapy, if present), the time to response (TTR; time necessary to reach a platelet count ≥ 50 x 109/L), the time to complete response (TCR; time necessary to reach a platelet count ≥ 100 x 109/L) and the duration of response. B-cell count and pharmacokinetics (PK) were monitored and related with clinical outcome. Stepwise logistic regression was used to assess whether response was associated with age, gender, diagnosis-Rituximab interval and basal CD20+ve lymphocytes. Results were considered statistical significant when P ≤ 0.05. All patients completed the therapeutic program receiving the four infusions of Rituximab as scheduled, none experiencing short term toxicity. All patients achieved B-cell depletion. OR and CR were achieved in 21/28 (75%) and 12/28 (43%) patients, respectively. CR rate was associated with younger age (OR=0.92 CI95%[0.85;0.99]). The median TTR and TCR were 31 and 44 days, significantly longer then those observed with standard dose in patients with similar characteristics (Haematologica 2003; 88:538). After a median follow-up of 11 months (range 3–18), 7/21 (33%) patients relapsed, and 3 needed further treatments. PK data showed a concentration time-course profile of Rituximab that was super-imposable, once corrected for the difference in the dose, to that observed previously in patients treated with standard dose, diseases with a median value of 4.1 micrograms/milliliter (range 0–11.9), 12 weeks after the start of treatment. In patients with ITP, low dose Rituximab led to short and mid-term response rates similar to standard dose but with slower timing of response.

High-dose omeprazole is more beneficial than standard-dose in patients with high-risk peptic ulcer bleeding,

High-dose omeprazole is more beneficial than standard-dose in patients with high-risk peptic ulcer bleeding,

Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose

Because HIV and hepatitis B virus share many common risk factors, it is important to try to vaccinate HIV patients against hepatitis B. There are numerous reports describing a variety of dose schedules, limited success and markers associated with impaired response to HBV vaccine in these individuals. All studies have been small in size making it difficult to draw conclusions within and between studies. The purpose of this study was to evaluate a double dose of hepatitis B vaccine under more definitive guidelines: double blinded, randomized, controlled, with numbers for statistical validity. Two hundred and ten HIV infected subjects received a standard dose (20 μg) or a double dose (40 μg) of recombinant hepatitis B vaccine IM 0, 1 and 6 months. Ninety-four receiving standard dose and 98 receiving double dose completed the study. The seroconversion rate (anti-HBs ≥ 10 mIU/mL) was 47 and 34% for double dose and standard dose, respectively ( p = 0.07). A statistically significant higher seroconversion rate was associated with double dose comparing with standard dose for patients with CD4 cell counts ≥350 cells/mm 3 (64.3% × 39.3%; p = 0.008) but made no difference to seroconversion in those with CD4 <350 (23.8% × 26.3%; p = 0.80). Double dose also improved seroconversion comparing with standard dose for patients with HIV viral load <10,000 copies/mL (58.3% × 37.3%; p = 0.01) but made no difference to seroconversion in those with HIV viral load ≥10,000 copies/mL (16% × 17%; p = 0.7). Based on the results of this study, the best current strategy for hepatitis B vaccination in HIV patients would be to use a double dose as a primary series when the viral load is likely to be low and CD4 ≥ 350, when there is likely to be an adequate immune response.

Tolerability and effects of high doses acipimox as additional lipid-lowering therapy in familial hypercholesterolemia

Background: Acipimox, a derivative of nicotinic acid, lowers serum lipid levels by reducing the production of very-low-density and low-density lipoproteins (LDL).Methods: We studied the additional lipid-lowering effect of high doses of acipimox in 12 patients with severe familial hypercholesterolemia (FH) who were on treatment with an HMG CoA reductase inhibitor, in some cases in combination with a resin.Results: There was a significant reduction in total serum cholesterol (−9%), LDL-cholesterol (−9%) and serum triglycerides (−21%) when the standard doses of acipimox (750 mg/day) was added to treatment with simvastatin (and a resin). However, higher doses had no further hypolipidemic effect. In concordance with the reduction of serum cholesterol and LDL-cholesterol there was a significant decrease in apolipoprotein (apo)-B (−11%). There was no change in HDL-cholesterol, apo-A1 and lipoprotein(a). Acipimox in high doses up to 2250 mg/d was well tolerated except for initial gastric complaints and of flushing; because of these side effects one patient dropped out of the study.Conclusions: Acipimox in high doses, which were well tolerated, has no additional lowering effect on LDL-levels compared to the standard dose in patients with severe FH who are already treated with simvastatin.

Utility of In Vitro Heparin and Protamine Titration for Dosing During Cardiopulmonary Bypass Surgery

Methods used to maintain a hemostatic balance during cardiopulmonary bypass surgery include the optimization of heparin and protamine dosing. Higher heparin doses have been associated with increased bleeding, while other studies have attributed reduced blood loss and transfusion requirements to lower protamine doses. We have evaluated the use of an in vitro heparin and protamine titration system and compared it to standard dosing in patients undergoing surgery requiring cardiopulmonary bypass. Based upon the principle of the Hemochron® RxDx® system, Heparin Response Tests (HRT) and Protamine Response Tests (PRT) were performed for 40 patients undergoing cardiac surgery at three hospital centers. The Activated Clotting Time (ACT) was used to monitor adequate heparin dosing prior to placing the patient on bypass, and to monitor heparin reversal after protamine dosing. The efficacy of heparin reversal was determined using the Protamine Dose Assay (PDA-O) test. All centers used standard hospital pharmaceutical preparations of heparin and protamine. Heparin and protamine RxDx dosing was compared to standard hospital practice for each site. Based on the HRT, the average heparin dose was not different from empirical dosing; however, individual differences were as high as 11,000 units. Only a single patient required a second heparin bolus prior to initiation of bypass. On average, the protamine dose predicted by the PRT was only 67% of the empirical protamine dose. The PDA-O test identified the need for additional protamine in 13% of patients. Patients administered additional protamine at the request of the surgical team, despite the presence of a normal PDA-O test, had no further decrease in ACT. In summary, the in vitro HRT and PRT system did not alter the initial heparin dose yet significantly decreased the protamine doses administered. Based on prior clinical outcome studies, this reduction is expected to have a beneficial effect on postoperative bleeding and transfusion requirements.