Hiroki Satoh

Medications associated with falls in older people: systematic review of publications from a recent 5-year period

PurposeFalls are an important public health problem in older people. Medication use is considered a risk factor for falls. This study systematically reviewed recent studies to determine the medications that might be associated with the risk of falling in older people.MethodsWe conducted a systematic review of prospective and retrospective studies identified through the MEDLINE and CINAHL databases that quantitatively assessed the contribution of medications to falls risk in participants ≥60xa0years old published in English between May 2008 and April 2013.ResultsThe search identified 1,895 articles; 36 articles met the inclusion criteria. Of the 19 studies that investigated the effect of polypharmacy on the risk of falling, six studies reported that the risk of falling increased with polypharmacy. Data on the use of antihypertensive medications including calcium channel blockers, beta-blockers, and angiotensin system blocking medications were collected in 14 studies, with mixed results. Twenty-nine studies reported an association between the risk of falls and psychotropic medications including sedatives and hypnotics, antidepressants, and benzodiazepines.ConclusionsThe use of sedatives and hypnotics and antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors appears to be related with an increased risk of falls. It is not clear if the use of antihypertensive medications is associated with the risk of falls in older people.

Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies.

AIMnThe use of nonsteroidal anti-inflammatory drugs (NSAIDs) in full-term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies.nnnMETHODSnHuman fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration-response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats.nnnRESULTSnThe risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine.nnnCONCLUSIONSnThis study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs.

Increased anticoagulant activity of warfarin used in combination with doxifluridine

PurposeThe purpose of this article is to report the first case of markedly increased anticoagulant activity of warfarin when used in combination with doxifluridine, given as a replacement for capecitabine.MethodsInternational normalized ratio (INR) of a 73-year-old female patient receiving warfarin was increased after starting chemotherapy using oral fluoropyrimidines (capecitabine or doxifluridine). Since the concomitant use of warfarin and the oral fluoropyrimidines was unavoidable in this case, the warfarin dosage was adjusted to keep INR within goal range (1.7–2.7). To evaluate the effects of the oral fluoropyrimidines on the anticoagulant activity of warfarin, the INR/Dose (warfarin dose in mg/day) was used.ResultsTo keep INR within goal range, the maintenance dosage of warfarin was reduced during the treatment with doxifluridine as well as capecitabine. It was finally reduced from 5xa0mg daily in the absence of oral fluoropyrimidines to 1.5xa0mg daily during the concomitant use of doxifluridine (600xa0mg daily). In contrast, the higher INR/Dose (1.03–1.66) was continued during the concomitant use of warfarin and doxifluridine compared with the INR/Dose before the start of chemotherapy (about 0.5). These results clearly indicate that the anticoagulant activity of warfarin was markedly increased by the concomitant use of doxifluridine as well as capecitabine.ConclusionsIt is important that physicians closely monitor anticoagulant activity in patients concomitantly receiving doxifluridine and warfarin, and appropriately adjust the dose of warfarin.

Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.

Questionnaire Survey for Pharmacists to Identify Factors Associated with Confusion Errors Involving Similar-appearing Press-through Package (Blister Pack)

u3000Similar-appearing press-through package (PTP) sheets (also known as blister packs) that contain different medicines may result in incorrect medication due to confusion errors. To evaluate the significance of this problem and to identify the factors that may lead to such errors, we conducted a questionnaire survey for pharmacists. Three hundred and eighty-two pairs of PTP sheets with similar appearance were included in the questionnaire. Factors related to color (sheet color at the front of the sheet 90.9%, color of tablet/capsule 57.1%, print color at the front of the sheet 45.9%) were most frequently selected as influencing the perceived similarity of the reported pairs, followed by tablet/capsule shape (46.2%), sheet size (32.4%), and mark and character positioning on sheets (6.8%). In the pairs of similar PTP sheets, pairs manufactured by the same pharmaceutical company accounted for 15%. The frequency of confusion errors or near-errors due to similar appearance of PTP sheets was highest at the time of collecting PTP sheets from the medicine shelf and returning the sheets to the medicine shelf, followed by the time of inspection of prepared medicines and medication instructions. The questionnaire results also indicate that patients themselves can confuse similar PTP sheets and take the wrong medicine. Further quantitative studies are needed to clarify the key factors that cause confusion errors due to similar appearance and to identify potential remedial measures.

Quantitative prediction of fetal plasma concentration of fluvoxamine during dosage-tapering to the mother

INTRODUCTIONnAlthough selective serotonin reuptake inhibitors have been used during pregnancy for the treatment of depression and anxiety disorders, the fetal plasma concentration profiles of them remained unclear. Therefore, the aim of this study was to develop a pharmacokinetic model to estimate fetal plasma concentration profiles of fluvoxamine, and to clarify the differences with those of paroxetine.nnnMETHODSnPerfusion studies using human placentae obtained from full-term pregnant women were conducted to estimate transplacental pharmacokinetic parameters for fluvoxamine. The characteristics of placental permeability were compared with those of paroxetine in our previous report. Using a developed model and these parameters, fetal plasma concentration profiles of fluvoxamine administered to mothers were simulated.nnnRESULTSnThe results of perfusion studies and transplacental transfer kinetic parameters indicated that fluvoxamine is less efficiently distributed to placental tissue than paroxetine. The model predicted a maternal-fetal plasma concentration ratio of 0.376 after repeated maternal administration of fluvoxamine, similar to the ratio for paroxetine. However, if the mother ceased taking drug, the model predicted a half-life of fluvoxamine in fetal plasma of 35xa0h, which is longer than that of paroxetine (10xa0h). We used the model to evaluate a proposed taper regimen for full-term pregnant women taking fluvoxamine that would minimize the risk of neonatal withdrawal syndrome.nnnDISCUSSIONnThe obtained parameters and developed model enabled us to predict the fetal plasma concentration profiles of fluvoxamine. The risk of neonatal withdrawal syndrome due to abrupt discontinuation may be less with fluvoxamine than with paroxetine.

Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data

AIMnWe encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of ketoprofen.nnnMETHODSnHuman placenta perfusion studies were conducted to estimate transplacental pharmacokinetic (PK) parameters. Using a developed model and these parameters, human fetal plasma concentration profiles of ketoprofen administered to mothers were simulated. Using pregnant rats, DA constriction and fetal plasma drug concentration after ketoprofen administration were measured, fitted to an Emax model, and extrapolated to humans.nnnRESULTSnTransplacental transfer value at the steady state of ketoprofen was 4.82%, which was approximately half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma concentration of ketoprofen after administration to rat dams were observed at different times: 4xa0h and 1xa0h, respectively. The model accurately described the delay in DA constriction with respect to the fetal ketoprofen concentration profile. The model with effect compartment and the obtained parameters predicted that use of multiple ketoprofen patches could potentially cause severe DA constriction in the human fetus, and that fetal toxicity might persist after ketoprofen discontinuation by the mother, as observed in our case.nnnCONCLUSIONnThe present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.