Divided Dose Regimen Research Articles

Dexamethasone-based Prophylactic Therapy for Prevention of Post-Embolization Syndrome: A Systematic Review and Meta-Analysis Assessing its Efficacy and Influence of Dosage and Timing in Patients Undergoing Arterial Embolization.

Post-embolization syndrome (PES), characterized by pain, fever, nausea, and vomiting, is a common but non-serious adverse event following arterial embolization, negatively impacting patient satisfaction with the procedure. This study aimed to evaluate the efficacy of dexamethasone-based prophylactic therapy in preventing PES, as well as to assess the effects of its dosage and timing of administration. A systematic search was conducted across three databases, two trial registries, and citation searches to identify relevant studies. Data related to postoperative pain, fever, nausea, and vomiting were extracted and meta-analyzed using a random-effects model and the Mantel-Haenszel method. Meta-regression was performed to examine the role of dexamethasone dose and timing of administration as mediators. Dexamethasone-based prophylactic therapy significantly reduced the risk of postoperative pain (RR=0.58, 95% CI: 0.48-0.69; P<0.00001), fever (RR=0.36, 95% CI: 0.22-0.61; P<0.00001), nausea (RR=0.52, 95% CI: 0.41-0.67; P<0.00001), and vomiting (RR=0.54, 95% CI: 0.36-0.82; P=0.004) compared to placebo or no treatment. A higher dose of dexamethasone was associated with a significantly lower incidence of postoperative pain (P=0.038). Regarding timing, postoperative and continuous (extending throughout the perioperative period) administration, was more effective than preoperative administration (P=0.024; P=0.007). A dosage of 6-12 mg was particularly effective in reducing the risk for all four symptoms. Dexamethasone effectively prevents PES in patients undergoing arterial embolization. An optimal protocol may involve a divided dose regimen within the range of 6-12 mg, extending throughout the recovery period for maximum benefit.

Optimal treatment strategy for older patients with esophageal squamous cell carcinoma: A multicenter retrospective study.

The appropriate treatment strategy for esophageal squamous cell carcinoma (ESCC) in older patients remains unclear. The efficacy of preoperative chemotherapy using a divided-dose regimen of biweekly docetaxel, cisplatin and 5-fluorouracil (DCF) neoadjuvant chemotherapy (NAC) was compared with upfront surgery (US) in patients aged ≥70 years with ESCC. The present study retrospectively analyzed the multicenter data of patients who received esophagectomy for ESCC between January 2015 and December 2021. The present study investigated patient prognosis using inverse probability weighting analysis and psoas muscle index (PMI) as a background factor for older patients with ESCC potentially deriving greater benefit from this NAC regimen. Among 86 eligible patients, 47 received NAC (NAC group) and 39 underwent US (US group). No significant differences were observed between the groups in 3-year overall survival [OS; hazard ratio (HR), 0.576; P=0.325) and 3-year recurrence-free survival (HR, 0.483; P=0.141). Among the patients with low PMI, 3-year OS was significantly prolonged in the NAC group vs. the US group (HR, 0.342; 95% CI, 0.144-0.812; P=0.015). In the older patients with ESCC, a divided-dose regimen of DCF did not improve prognosis. When the PMI is low, a biweekly DCF regimen may contribute to extending OS. Future prospective large studies are needed.

Effect of oral pregabalin on post operative analgesia in patients undergoing lumbar spine fusion surgeries under general anesthesia

Pregabalin has been used successfully as a component of multimodal analgesia regimen in a variety of surgical procedures. However, side effects such as dizziness and somnolence have been reported especially with doses ≥300mg. We hypothesized that using a lower cumulative dose of oral pregabalin in a divided dosing regimen would lower the incidence of side effects while providing adequate postoperative analgesia in patients undergoing lumbar spine fusion surgery. Seventy adult patients of either sex of ASA 1-3, undergoing lumbar spine fusion surgery under general anesthesia were randomly divided into two equal groups. Group B received oral pregabalin 150mg one hour before induction and 75mg 2 hours after surgery. Group A received oral placebo at the corresponding time points. Pain was assessed using Visual Analogue Score (VAS) at extubation, 2, 4, 6, 12, 18 and 24 hours after surgery. In the first 24 hours after surgery, the mean VAS scores were significantly lower in Group B (P0.001) at all time points while tramadol consumption for rescue analgesia (P0.001) and postoperative nausea (P0.013) and vomiting (P0.011) were significantly higher in Group A. Preoperative anxiety and sedation scores and postoperative incidence of dizziness and somnolence were comparable between the two groups. Low dose oral pregabalin preoperatively and postoperatively using a divided dose regimen can be safely used to provide adequate postoperative analgesia with low incidence of side effects after lumbar spine fusion surgeries.

Compare the Effectiveness of Carbimazole Single Dose and Divided Dose Regimens for Euthyroid Induction in Hyperthyroid Patients

Objective: The purpose of the current study was to examine the effectiveness of carbimazole administered as a single dose with a divided dose regimen for inducing euthyroidism in hyperthyroid patients. Study Design: Prospective/Randomized study Place and Duration: This Prospective/Randomized study was conducted at Khyber Teaching Hospital Peshawar in the duration from June, 2022 to November, 2022. Methods: There were 92 patients of hyperthyroidism were presented in this study. Age, sex, BMI, and residency details for each enrolled case were recorded after receiving informed written consent. Patients were divided into two groups equally. Carbimazole (OD-CMZ) was administered as a single dosage to 46 patients in group I, and as two separate doses to 46 patients in group II (DD-CMZ). For six months, the effectiveness of the treatment was monitored on a regular basis (every four weeks). SPSS 22.0 was used to analyze all data. Results: There were 54 (58.7%) females and 38 (41.3%) males in this study. In group I mean age was 35.13±6.60 years and in group II mean age was 40.10±8.86 years. Mean duration of disease was 3.6±10.57 months in group I and in group II mean duration was 4.3 ±8.35 months. There was no discernible difference between the two groups in terms of baseline TSH and T4 concentrations or their cumulative rates of reduction (p-value, 0.014). Frequency of euthyroidism in group I after final follow up was 46 (100%) and in group II found in 45 (97.8%) cases but difference is insignificance. Conclusion: In this study, we came to the conclusion that a single dosage regimen is a more effective way to treat hyperthyroidism since there is no discernible difference in efficacy and a greater risk of developing hypothyroidism with a split dose strategy. Keywords: Hyperthyroidism, Drug therapy, Single dose, Carbimazole, Multidose

Weekly split-dose regimen for oral methotrexate reduced polyglutamation in red blood cells in patients with rheumatoid arthritis compared with single-dose regimen: Results from a multicentered randomized control trial.

We compared the incidence of adverse events between single and divided-dose regimens of methotrexate (MTX) by using a multicenter randomized controlled trial. Eighty-nine patients with insufficient control on MTX 8mg/wk were randomly assigned into single-dose (39 patients) or triple dose (39 patients) groups. The MTX dose for all patients was gradually increased to 16mg/wk. The primary endpoint was the occurrence of liver dysfunction during the observation period (20weeks). There were no differences in baseline data and MTX dose at Week 20 between groups. There was no significant difference in the incidence of liver dysfunction between groups (single dose, 3 [7.7%] patients vs. triple dose, 5 [13.2%] patients; P=.455). The incidence of adverse event increased in triple dose (single dose, 12 [30.8%] patients vs. triple dose, 20 [51.3%]), but the difference was not significant (P=.066). There was no significant difference in disease activity between groups, although MTX-triglutamate (PG3), MTX-PG4, and MTX-PG5 were significantly higher in the single dose group. Weekly split dosing reduced the polyglutamation of MTX. There was no significant difference in efficacy and safety between the 2 groups.

A Comparative Study of High-Dose Colistin Administration for the Management of Multidrug-Resistant Gram-Negative Infections in the ICU

The aim of this study was to assess the clinical and microbiological efficacy and toxicity of different high-dose regimens of colistin in the ICU patients with colistin-sensitive MDR Gram-negative infections. In this prospective, open label, randomized clinical trial, patients with clinical features of infection and positive culture for MDR colistin-sensitive Gram-negative bacteria were randomly allocated to receive colistin, 3 or 9 million units every 8 and 24 hours, (groups A and B), respectively. For each dose regimen, clinical and microbiological response, the rates of nephrotoxicity, and its risk factors were analyzed. Forty-three patients were enrolled, and 35 completed the study protocol, of whom 30 (88.2%) had ventilator-associated pneumonia (VAP) and 5 (14%) had bacteremia. Although there were no statistically significant differences in the clinical or microbiological response between the study groups, the microbiological response favored the divided dose group numerically ( p = 0.40 ). Clinical response was achieved in 27 of 35 (77.1%) patients ( p = 0.999 ). Twelve (34.28%) patients developed AKI during colistin treatment, 4 and 8 in groups A and B, respectively ( p value =0.193). Significant risk factors for nephrotoxicity related to colistin were age, hyperbilirubinemia, and coadministration of other nephrotoxic agents. In multivariate regression analysis, the only independent risk factor for CMS-associated AKI was hyperbilirubinemia ( p value =0.008). Although the clinical and microbiological responses to colistin administration were not statistically different in two groups, the microbiological response favored the divided dose regimen group numerically. We did not observe any significant safety concerns with high-dose colistin administration in this population.

Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies

BackgroundOcrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20+ B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS). MethodsOPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of ocrelizumab or placebo. ResultsSafety analyses included 1651 patients with RMS from OPERA I and OPERA II (ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs. ConclusionFindings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.

Tranexamic acid is effective in lower doses with infusion in total knee arthroplasty

ObjectiveTo identify the most effective intravenous regimen with reduced doses of tranexamic acid (TXA). MethodsWe retrospectively evaluated the two most frequently used TXA regimens (infusion and divided-dose regimens) in total knee arthroplasty in comparison with patients not treated with TXA, in three groups. Group NO (n = 134; 19 men and 115 women; mean age: 66.48 ± 7.66) (patients who were not treated with TXA); group DIV (n = 158; 14 men and 144 women; mean age: 65.67 ± 7.98) (total dose of 10 mg/kg intravenous TXA divided into two doses: 15 minutes before tourniquet inflation and 15 minutes before tourniquet deflation), an extra 5 mg/kg intravenous TXA dose was administered 2 hours after surgery in the orthopedic ward, if needed; and group INF (n = 193; 33 men and 160 women; mean age: 67.08 ± 7.2) (10 mg/kg TXA perioperative intravenous infusion starting 15 minutes before surgery until closure of the wound, and 5 mg/kg additional intravenous dose was administered 12 hours after surgery). Pre-postoperative hemoglobin (Hb) and hematocrit (Htc) difference, total blood loss (TBL), number of transfused packed red blood cells (pRBC), and length of hospital stays (LOS) were compared between the groups. ResultsTBL was lower in group INF (531.61 ± 316.76 mL) in comparison with group DIV (999.91 ± 352.62 mL). TBL was statistically significantly higher in Group NO (1139.23 ± 43 mL). The mean number of transfused pRBC was significantly higher in the control group (1.22 ± 0.58 units) than the in the other TXA groups. The mean number of transfused pRBC was significantly lower in INF group (0.33 ± 0.56 units) than DIV group (0.75 ± 0.63 units). The number of patients requiring transfusion was significantly lower in INF group (28.5%) than DIV group (65.2%). Group NO had the highest number of patients requiring transfusion (96.3%). Pre-postoperative Hb and Htc difference was significantly lower in INF group (−1.19 ± 0.9 gr/dL and −3.74 ± 2.96%). The mean LOS of the control group, group DIV and group INF were 7.16 ± 2.29, 6.93 ± 2.39 and 5.06 ± 1.24 days, respectively. Group INF had the lowest hospital stay time in comparison with the other groups (p < 0.005). There was no statistically significant difference between the control group and group DIV in the LOS. ConclusionA total dose of 10 mg/kg of TXA perioperative intravenous infusion starting 15 minutes before the surgery until wound closure can significantly decrease TBL. Intraoperative infusion regimen is more effective than the divided-dose regimen. Level of EvidenceLevel III, Therapeutic Study.

A comparison of single-dose and multiple divided daily-dose oral steroids for sudden sensorineural hearing loss

IntroductionGlucocorticoids are considered the first-line therapy for sudden sensorineural hearing loss. But there is currently no consensus on administering them as a single dose versus multiple divided daily doses. ObjectiveWe aim to evaluate the treatment outcome of sudden sensorineural hearing loss between a single-dose and multiple divided daily doses of steroid treatment. MethodsA total of 94 patients who were diagnosed and treated for sudden sensorineural hearing loss and followed up for more than three months were reviewed retrospectively. Patients were divided into single-dose and multiple divided-dose groups, based on their medication regimens. Hearing thresholds were repeatedly measured: on the initial visit and 1 week, 1 month, and 3 months after the initial treatment. Treatment outcomes were analyzed by comparing hearing recovery rates and post-treatment audiometric changes. ResultsThe hearing threshold was significantly reduced at three months post-treatment in both groups. The hearing recovery rate of the single-dose group was significantly higher than that of the multiple divided-dose groups. Audiometric changes showed no statistical difference either in pure tone threshold or speech discrimination. ConclusionWhen oral steroids are indicated for sudden sensorineural hearing loss, both a single dose and multiple divided doses can be effective for treatment and have comparable results. However, the single-dose regimen seems to be more efficacious than the divided-dose regimen.

Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version).

Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version).

Tolerability and Dose Proportional Pharmacokinetics of Pasireotide Administered as a Single Dose or Two Divided Doses in Healthy Male Volunteers: A Single-Center, Open-Label, Ascending-Dose Study

BackgroundPasireotide is a multireceptor-targeted somatostatin analogue with high binding affinity for somatostatin receptor subtypes SST 1, 2, 3, and 5. ObjectiveTo evaluate the safety profile, tolerability, and pharmacokinetic profile of pasireotide in single- and divided-dose regimens in healthy volunteers. MethodsA single-center, open-label, ascending-dose study was performed in healthy volunteers. Pasireotide, 900, 1200, and 1500 μg SC, was administered as either a single dose or as two divided doses given 12 hours apart, with a 7-day washout period between treatments. ResultsSeventeen men (median age, 26 years) were enrolled. Their median weight was 81 kg, and 65% were white. One participant dropped out because of a grade 2 adverse event; most other adverse events were mild and affected the gastrointestinal tract. Blood glucose concentration increased after pasireotide administration, but returned to normal within 10 hours. After single-dose administration, pasireotide plasma concentration peaked rapidly at 15 minutes to 1 hour after dosing, followed by a tri-exponential (α, β, and γ phases) decline over time. Mean t½ values during the α, β, and γ phases were approximately 2 to 3, 12 to 17, and 54 to 97 hours, respectively. In the single-dose cohort, the mean (SD) AUC∞ was 110 (29), 149 (42), and 188 (52) h · ng/mL in the 900-, 1200-, and 1500-μg groups, respectively. Time to reach Cmax was 0.69 (0.41), 0.59 (0.38), and 0.56 (0.18) hours in the 900-, 1200-, and 1500-μg groups, respectively. AUC∞ values were similar in the single-dose and divided-dose cohorts. Mean total body clearance was 8 to 9 L/h across the dosage groups and dosing regimens, indicating a linear pharmacokinetic profile between doses. ConclusionsWhen administered as a single- or divided-dose regimen, pasireotide had a favorable tolerability profile in this selected group of healthy male volunteers. Its pharmacokinetic profile indicated rapid absorption, low clearance, high volume of distribution, and a long terminal half-life.

A pediatric phase I trial and pharmacokinetic study of MLN8237, an oral selective small molecule inhibitor of aurora a kinase: A Children's Oncology Group Phase I Consortium study.

9529 Background: MLN8237, a selective small molecule inhibitor of Aurora A Kinase, has activity in a broad range of in vitro and in vivo preclinical models of pediatric cancer. We performed a phase I trial to determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MLN8237 in children with refractory solid tumors. Methods: MLN8237 was administered orally either once daily (part A1) or divided twice daily (part A2) for 7 days, every 21 days. Using the rolling-six design, four dose levels (45, 60, 80, 100 mg/m2/d) were evaluated on the once daily regimen, and subsequently two dose levels (60 and 80 mg/m2/d) on the twice-daily regimen. Pharmacokinetic studies were performed with the initial dose, with trough drug concentrations also being obtained at steady-state. Results: 37 patients were enrolled, 32 were fully evaluable for toxicity [median (range) age 12.5 yrs (4.8 - 21.6)]: 21 on part A1 and 11 on part A2. In part A1, 1/6 pts developed DLT (grade 3 mucositis) at 45 mg/m2 and 1/6 developed DLT (grade 4 mood alteration) at 80 mg/m2. At 100 mg/m2, 3/4 patients developed DLT (neutropenia –thrombocytopenia), thus exceeding the MTD. In part A2, 2/6 patients developed dose limiting myelosuppression at 80 mg/m2; one of whom also experienced grade 3 mucositis. 1/5 patient experienced DLT (grade 3 alkaline phosphatase) at 60 mg/m2. Of note, 5/11 patients experienced hand-foot-skin syndrome (grade 1 - 3) on the bid schedule versus 1/21 (grade 2) on qd schedule. A high degree of inter- patient variability in systemic exposure was observed. Average trough concentrations exceeded 1 μ M, the efficacious concentration in preclinical studies. The mean (±SD) steady state MLN8237 trough concentrations at the 45, 60, 80 and 100 mg/m2/d dose levels were 5.1 ± 5.7, 4.9 ± 6.3, 3.7 ± 3.8, and 5.5 ± 4.9 μ M, respectively. Conclusions: Although the divided dose regimen appears to be well tolerated in adults, children experienced more myelosuppression and hand-foot-skin syndrome with divided versus once daily dosing. Therefore the recommended pediatric phase 2 dose and schedule of MLN8237 is 80 mg/m2/d administered once daily for 7 days. No significant financial relationships to disclose.

Primary chemotherapy patterns for ovarian cancer treatment in Japan

Evidence-based clinical practices can improve patient outcomes, especially in the area of chemotherapy. In Japan, it is not known how well physicians adhere to evidence-based chemotherapy guidelines. This study aimed to assess physician compliance with national guidelines for ovarian cancer primary chemotherapy in Japan. Using an administrative database, we analyzed 209 cases of surgical laparotomy without neoadjuvant chemotherapy as the primary intervention for adnexal cancer. Cases were identified across seven teaching hospitals between 2003 and 2006. Of the 136 patients receiving inpatient chemotherapy, 101 cases (74%) were treated with platinum-taxane therapy. In five hospitals, platinum-taxane therapy was used in more than 75% of patients, compared to 56% and 32% in the other two hospitals, respectively. The proportion of patients receiving paclitaxel and carboplatin concomitant therapy (TC therapy) was 67%, although significant variation was noted between hospitals (range 32% to 94%, P < 0.001). Of the 91 patients receiving TC therapy, 59 (65%) were given full-dose monthly regimens, while 32 cases (35%) were treated with divided doses weekly. Weekly TC therapy was more frequently provided in hospitals with a low volume of patients receiving TC therapy. Patients under the age of 65 receiving inpatient chemotherapy were more likely to receive full-dose regimens than patients 65 or older (68% vs 43%, P = 0.005). Publication of national treatment guidelines did not appear to substantially impact chemotherapy practice patterns. Adherence to standardized chemotherapy was comparable to rates in European countries, although rates among hospitals differed significantly. Elderly patients were more likely to receive divided-dose regimens.

Insulin Therapy in Divided Doses Coupled With Blood Transfusion Versus Large Bolus Doses in Patients at High Risk for Hyperkalemia During Liver Transplantation

To assess the effectiveness of an insulin regimen in divided doses designed to target risk factors of hyperkalemia in patients undergoing liver transplantation. Retrospective comparison of the divided insulin dose regimen with a conventional large-bolus insulin method during liver transplantation. University-based, academic, tertiary center. Adult patients whose baseline potassium levels were >/=4.0 mmol/L and received insulin therapy during liver transplantation at the authors' medical center between January 2004 and April 2007. Insulin was administered either in divided doses (1-2 units) for each unit of red blood cells transfused or in a large-bolus in patients at high risk for hyperkalemia during liver transplantation. Among 717 patients who underwent liver transplantation, 50 patients received insulin in divided doses, and 101 patients received a large-bolus of insulin. Perioperative characteristics were comparable except for higher insulin doses in the large-bolus group. The divided insulin regimen was associated with significantly lower mean potassium levels within 2 hours before reperfusion of the graft compared with the conventional group (p < 0.005). The mean glucose levels in the divided group were significantly lower in both the pre- and postreperfusion periods than in the conventional group (p < 0.05 to <0.001). The divided insulin dose regimen that specifically targets the risk factors for prereperfusion hyperkalemia is associated with significantly lower prereperfusion potassium and pre- and postreperfusion glucose levels and provides a useful alternative to the conventional large-bolus method in management of intraoperative hyperkalemia during liver transplantation.

Single-dose mitoxantrone in combination with continuous infusion intermediate-dose cytarabine plus etoposide for treatment of refractory or early relapsed acute myeloid leukemia

This prospective phase II clinical trial evaluated the effects of single-dose mitoxantrone (36 mg/m 2 on day 1) in combination with continuous infusion intermediate-dose cytarabine plus etoposide in 25 patients with refractory or early relapsed acute myeloid leukemia (AML). We compared the results of our current study with those of a previous phase II trial, which had the same eligibility criteria and chemotherapy schedule except that a conventional divided dose of mitoxantrone (12 mg/m 2 on days 1–3) was used. The complete remission (CR) rate was significantly lower with the single-dose mitoxantrone regimen than with the divided-dose regimen (24.0% vs. 51.5%; P = 0.034), mainly owing to an increased incidence of hypoplastic deaths. CR duration and overall survival were not significantly different between the two regimens. In conclusion, single-dose mitoxantrone was inferior to conventional divided-dose mitoxantrone for treatment of refractory or early relapsed AML in terms of CR rate.

Divided-Dose Administration of Miglitol just before and 15 Minutes after the Start of a Meal Smoothes Postprandial Plasma Glucose Excursions and Serum Insulin Responses in Healthy Men

We recently demonstrated that administration of miglitol at 15 min after the start of a meal decreased the area under the curve (AUC) of plasma glucose, similar to the observation following its administration just before a meal. This finding prompted us to examine whether a divided-dose regimen of miglitol might attenuate postprandial glucose excursions even more effectively. We, therefore, examined several schedules of miglitol administration in 15 healthy men. Miglitol was administered by four different schedules in each subject (control: no miglitol, intake 1: drug administered just before a meal (50 mg); intake 2: drug administered at 15 min after the start of a meal (50 mg); intake 3: drug administered in two divided doses: just before a meal (25 mg) and at 15 min after the start of a meal (25 mg). The AUC of glucose excursions, defined as increment above the fasting glucose level, (AUC(0-180 min) of glucose excursions) was significantly reduced as compared with that in the control condition after miglitol administration by intake schedule 3, while this parameter showed a tendency towards decrease after the drug administration by intake schedules 1 and 2. The AUC(0-180 min) of the serum insulin level was also significantly decreased for all the intake schedules of miglitol, as compared with that in the control condition. Thus, administration of miglitol in two divided doses appeared to be the most suitable for obtaining effective regulation of postprandial glucose excursions in healthy men. This result may suggest that the divided-dose administration regimen may also be effective in diabetic patients.

Use of pramipexole in REM sleep behavior disorder: Results from a case series

Background and purposeRapid eye movement (REM) sleep behavior disorder (RBD) has a known association with other medical conditions, including narcolepsy and neurodegenerative diseases such as synuclienopathies. RBD is currently treated with clonazepam as a first-line therapy. Recent research suggests that the pathophysiology underlying RBD may involve a dopaminergic deficiency, given its association with Parkinson syndromes and restless legs syndrome (RLS). We report on the efficacy of pramipexole, a dopaminergic D2-3 receptor agonist, in the treatment of RBD. Patients and methodsThe first 10 consecutive patients presenting with a history and polysomnographically confirmed RBD were given pramipexole as either a single dose before bedtime or as a divided dose regimen with the first dose given in the early evening and the second dose at bedtime. Medication was titrated to control RBD symptoms and the clinical response was monitored through interviews with the patient, spouse, and close family members during the course of the study at regularly scheduled follow-up visits. ResultsThe mean length of treatment was 13.1 months, and the average total evening dose of pramipexole at the end of the study was 0.89±0.31mg. A divided dose regimen of pramipexole was used in 56% of patients remaining on pramipexole. We found that 89% of patients experienced either a moderate reduction or complete resolution in the frequency of RBD symptoms throughout the duration of the study. Moreover, 67% reported at least a moderate reduction in the severity of remaining symptoms. ConclusionsPramipexole markedly reduced the frequency and severity of RBD symptoms and appeared to maintain efficacy for up to 25 months as assessed at follow-up visits. Clonazepam may have numerous unwanted side effects in the elderly or narcoleptics with RBD, such as prominent sedation and the potential exacerbation of underlying obstructive breathing in sleep. The potential role of pramipexole in improving RBD and its associated dopamine deficient syndromes warrants further research in the use of dopaminergic agonists as a potential first-line alternative therapy for RBD.

Evaluation of a single dose versus a divided dose regimen of amoxycillin in treatment of Actinobacillus pleuropneumoniae infection in pigs

The theory of a time-dependent effect of amoxycillin was examined in a model of porcine Actinobacillus pleuropneumoniae (Ap)-infection using clinically relevant dosage regimens. Twenty hours after infection of fourteen pigs, when clinical signs of pneumonia were present, one group of pigs received a single dose of amoxycillin (20 mg/kg, i.m.), whereas another group received four doses of 5 mg/kg injected at 8-h intervals. A similar AUC of the plasma amoxycillin concentration versus time curve was obtained in the two groups, whereas the maximum concentration was threefold higher using the single high dose. Plasma amoxycillin was above the MIC for twice as long using the fractionated dosage scheme. The condition of the animals was evaluated by clinical and haematological observations combined with quantification of biochemical infection markers: C-reactive protein, zinc and ascorbic acid. Within 48 h of treatment, the pigs in both treatment groups recovered clinically. No significant differences in the time-course of clinical observations or plasma concentrations of the biomarkers of infection were observed between the two treatments. In conclusion, the efficacy of these two dosage regimens of amoxycillin was not significantly different in treatment of acute Ap-infection in pigs.

Evaluation of a single dose versus a divided dose regimen of danofloxacin in treatment of Actinobacillus pleuropneumoniae infection in pigs

A single versus a divided dose regimen of danofloxacin was evaluated in treatment of porcine Actinobacillus pleuropneumoniae infection using clinical observations combined with biochemical infection markers: C-reactive protein, zinc and ascorbic acid. Twenty hours after experimental infection, the 18 pigs received danofloxacin intravenously as a single dose of 2.5 mg/kg or four doses of 0.6 mg/kg administered at 24 h intervals. These dosage regimens resulted in similar AUCs of the plasma danofloxacin vs time curve. The maximum concentration was 3.5-fold higher using the single dose regimen, while the time with concentrations above the MIC was 2.5-fold longer using the fractionated regimen. Using the single dose regimen, temperature was normalised 32 h post-infection. In contrast, normalisation was delayed until 44 h post-infection using four low doses and a relapse with elevated temperatures at 52 and 68 h was observed. No other significant differences between the treatments were found, neither regarding clinical, haematological nor biochemical observations. The use of the more convenient single dose regimen was appropriate, as it was at least equivalent to the fractionated regimen.

The emergence of rational therapeutics from the traditions of clinical practice

The emergence of rational therapeutics from the traditions of clinical practice