Single Daily Regimen Research Articles

Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation

Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 μMol*minute per day in a first cohort (n = 12) and 5000 μMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 ± 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 ± 1239 in the AUC 4000 cohort and 4884 ± 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 μMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 μMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants.

Optimal Frequency of Lithium Administration in the Treatment of Bipolar Disorder

Bipolar disorder is a recurrent chronic illness distinguished by periods of mania and depression. Lithium has been used for about 60 years as a 'mood stabilizer' for bipolar disorder with proven efficacy in preventing relapse of both mania and depression. Despite its long history and ongoing use in current management of bipolar disorder, the optimal dosing of lithium is still the subject of ongoing debate. This article aims to evaluate different dosing schedules, in the light of the unique pharmacokinetic and pharmacodynamic properties of lithium, as well as its adverse-effect and toxicity profiles. This is all the more important given the narrow therapeutic index of lithium. Current recommendations mostly advocate that lithium be administered in multiple daily doses. However, single daily or alternate daily schedules may be viable options for administration. Multiple daily schedules are thought to be advantageous in maintaining more constant plasma lithium concentrations than single daily regimens, which are associated with significant fluctuations throughout the day. When comparing these two schedules with respect to plasma lithium concentrations, adverse-effect profiles and recurrence of symptoms, there are no significant differences between the two regimens. In fact, a single daily regimen may have added advantages in reducing the risk of long-term renal damage and increasing compliance. The evidence for alternate daily dosing is somewhat varied with regard to symptom recurrence; however, this schedule has been shown to be associated with decreased adverse effects, and further research into this issue is therefore warranted. Presently, therefore, clinicians should consider single daily administration of lithium to potentially minimize adverse effects and enhance compliance.

Immediate‐release oral proton pump inhibitors: Panacea or a flash in the pan?

Use of proton pump inhibitors (PPI) after endoscopic hemostatic treatment of bleeding peptic ulcers is a standard therapy for preventing early re-bleeding.1 However, controversy continues regarding the optimal dose and route of administration of PPI.2 While both i.v. and oral PPI are effective in preventing early re-bleeding, meta-analysis of randomized trials found that i.v. infusion of high-dose PPI is superior to low-dose (i.e. oral or repeated i.v. injections) PPI in terms of the need for surgery.1 Oral PPI have two major limitations: a slow onset of action and failure to maintain a stably high intragastric pH. One attempt to overcome the limitations of conventional oral PPI is the development of immediate-release (IR) formulations. In this issue, Banerjee et al.3 shows that healthy volunteers who received buffered IR esomeprazole 40 mg p.o. had superior intragastric pH profile compared to those who received i.v. pantoprazole 40 mg every 12 h for 24 h. After the first dose of buffered IR esomeprazole, the intragastric pH was rapidly raised to 6 in a median time of 2 min whereas it took 80 min for i.v. pantoprazole to achieve this level of intragastric pH. Furthermore, the mean percentage time to an intragastric pH of more than 6.0 was 91% in the buffered IR esomeprazole group compared to 20% in the i.v. pantoprazole group in a 24-h period. While many readers would agree that the intragastric pH profile achieved by buffered IR esomeprazole was close to perfection, was the result too good to be true? The rapid rise in intragastric pH with buffered IR esomeprazole was not unexpected because the bicarbonate content of the formulation would neutralize gastric acid. Similar findings were also reported in an earlier study with buffered IR omeprazole.4 In the previous study, however, IR omeprazole rarely raised the intragastric pH above 6 (reported median 24-h intragastric pH was 3.7 only).4 By contrast, the reported median 24-h intragastric pH was 6.18 with IR esomeprazole in the current study.3 In fact, the pH profile achieved by IR esomeprazole was comparable to that with continuous infusion of high-dose PPI.5 What factors could possibly account for such impressive results with just two p.o. doses of IR esomeprazole in 24 h? One could argue that esomeprazole is superior to omeprazole because the former has a better pharmacodynamic profile. The modest advantage of esomeprazole over omeprazole, however, is unlikely to explain the striking difference between the current and earlier studies.3,4 When interpreting the effects of PPI on intragastric pH, one needs to be aware of factors that may influence the outcome. Helicobacter pylori infection is well known to enhance the acid-suppressing effect of PPI.6 Investigators often recognize the importance of excluding H. pylori infection in pH studies. However, a negative rapid urease test does not exclude hypochlorhydria in patients with past H. pylori infection. In Asian countries where the prevalence of H. pylori infection is high, a considerable proportion of the population with hypochlorhydria associated with past H. pylori infection is not unexpected. It would be useful to know the proportion of subjects with hypochlorhydria or histological evidence of gastric atrophy when interpreting pH studies. Another factor is gastric parietal cell mass. PPI are thought to be more effective in Asians because of the smaller parietal cell mass. Small parietal cell mass may partly explain the observation that PPI reduce mortality associated with peptic ulcer bleeding in Asian studies but not in Western studies.1 Presumably, the study by Banerjee et al.3 was conducted in Indian subjects whereas the IR omeprazole study was done on white subjects.4 The efficacy of PPI is also influenced by genetic polymorphism of certain human drug-metabolizing cytochrome P450 (CYP) enzymes. In particular, polymorphism of CYP2C19 has been reported to affect the efficacy of some PPI,7 and substantial racial difference exists in terms of the relative proportions of extensive and poor metabolizers.8 Unlike other PPI such as omeprazole, the CYP2C19 genetic polymorphism is thought to have little influence on the disposition of esomeprazole.9 Surprisingly, a recent study found that the intragastric pH and plasma level of esomeprazole was affected by the CYP2C19 genotype status, and that a multiple dosing regimen of oral esomeprazole improved acid control compared to a single daily regimen.10 In summary, there is little doubt that buffered IR PPI have certain advantages. Whether they are an alternative to i.v. infusion of high-dose PPI in patients with bleeding peptic ulcers can only be addressed by large-scale, head-to-head trials using predefined clinical outcomes. Until further data are available, i.v. infusion of high-dose PPI after endoscopic treatment of bleeding peptic ulcers remains the most studied and best proven strategy.

Aminoglycoside antibiotics and post-antibiotic effects

Man has been fighting diseases for centuries. One of the major battles is against microorganisms and diseases they cause. A health education course was organized on prescribing aminoglycoside antibiotics and postantibiotic effect. The aim of the course was to change the prescription habits in our colleagues. The postantibiotic effect of aminoglycoside antibiotics as well as impact of subinhibiting doses on duration of postantibiotic effect requires modification of previous therapeutic protocols. Single daily dose has the same or even greater effect than multiple daily doses. The toxicity of aminoglycosides is not increased and remains the same or smaller in single daily regimens. The single daily dose regimen of aminoglycosides has been used in 63.6% of cases in Clinic for Infectious Diseases of the Clinical Center of Novi Sad, 41.2% in Outpatient Health Care Center of Novi Sad "Liman" and this regimen has not been used in General Practice Department, Children's Health Care Department and Ear, Nose and Throat Clinic at all. The twice daily regimen has been used instead. Doctors are aware of the postantibiotic effect, but vast majority are still bound to their old habits in regard to prescribing antibiotics. Our educational course failed to achieve its goal.

Controlled inpatient study of tienilic acid in treatment of gout and hypertension.

Under inpatient controlled conditions 4 patients with gout and hypertension were treated with varying doses of tienilic acid, a new uricosuric diuretic. Plasma urate levels were reduced by an average of 50% in association with significantly increased urinary urate excretion. A twice-daily regimen was considerably more effective than a single morning dosage in reduction of plasma urate, though both regimens were equally effective in antihypertensive potency. The single daily regimen produced greater diurnal fluctuations in plasma urate and was more frequently associated with the development of acute gout attacks.