Real-time analgesic efficacy and factors determining drug requirements of combined spinal-epidural analgesia for labor: a prospective cohort study.

PURPOSE: Combined spinal-epidural analgesia (CSEA) is effective but not sufficient for labor pain. This study was conducted to assess the real-time analgesic efficacy, side effects of anesthetic drug dosage, and maternal satisfaction in labor to provide reference for the optimization of labor analgesia. METHODS: This was a prospective, cohort, single-center study that included 3020 women who received CSEA for labor analgesia. The visual analogue scale (VAS) for labor pain, real-time anesthetic drug dosage, side effects, adverse labor outcomes, factors influencing average drug dosage, and maternal satisfaction with CSEA were assessed. RESULTS: Overall, the VAS labor pain score was lowest at the first hour after the anesthesia was given. After 4 h for primiparas and 3 h for multiparas, the VAS score was greater than 3 but the anesthetic drug dosage did not reach the maximum allowed dosage at the same time. The average anesthetic drug dosage was positively correlated with fever, urinary retention, uterine atony, prolonged active phase, prolonged second stage, assisted vaginal delivery, and postpartum hemorrhage. The average anesthetic drug dosage was the highest in women ≤ 20 years old, those with a body mass index (BMI) ≥ 24.9 kg/m2, and those with a primary or secondary education level. CONCLUSION: Appropriate age guidance and emphasis on education of labor analgesia, weight management during pregnancy, and real-time anesthetic dosage adjustment during labor based on VAS pain score may have positive effects on the satisfaction of labor analgesia. CLINICAL TRIAL NUMBER AND REGISTRY: Clinicaltrials.gov (ChiCTR2100051809).

Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug-resistant focal seizures.

OBJECTIVE: Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug-related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug-resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate. METHODS: A three-stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration. RESULTS: The expert panel agreed that tailored titration and close follow-up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period. SIGNIFICANCE: Cenobamate is an effective ASM with a dose-dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co-medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co-medication in cenobamate-treated patients with DRE and a high drug load. PLAIN LANGUAGE SUMMARY: Patients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug-resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate.

Rheumatoid arthritis - medication dosage in chronic kidney disease.

Renal failure in the course of rheumatoid arthritis (RA) is a consequence of many factors, including drug-induced nephrotoxicity, comorbidities and chronic inflammation. Contemporary treatment strategies have reduced the incidence of renal failure in the population of RA patients. However, it remains a problem for approximately 25% of patients. Therefore, special attention should be paid to the potential need for dosage modifications of administered medications. Many drugs used in the therapy of rheumatic diseases have not been thoroughly studied for their safety in patients with reduced glomerular filtration, resulting in limited data in this area. The establishment of precise, transparent, and consistent dosage recommendations for antirheumatic drugs in chronic kidney disease would significantly facilitate the care of patients with RA. The following review provides a general summary of the available knowledge regarding the dosage of rheumatic medications in renal insufficiency and aims to highlight the need for further research in this area.

Drug dose adjustment in patients with renal impairment attending a specialized referral hospital, Northwest Ethiopia.

Background: Numerous drugs and their metabolites are removed from the body through the kidney. Improper use of drugs in renal impaired patients may therefore, be harmful and have deleterious effects. Thus, this study was aimed at investigating drug dose adjustment in renal impaired patients attending a specialized hospital. Methods: A prospective cross-sectional study was performed at the medical ward in University of Gondar comprehensive specialized hospital from March to May 2018. During the study period, a total of 2100 patients were admitted to the general medical wards. We located and assessed 210 patient files, of which 189 patient files had complete notes. Based on our inclusion criteria, 105 patients had Crcl of ≥ 59 ml per min per 1.73 m2. Therefore, 84 patients fulfilled our inclusion criteria and were included in the final analysis. The collected data were entered into Epi Info version 7 and exported to the statistical package for the social sciences (SPSS) version 20 for statistical analysis. A chi-square test was applied to test the relationship between renal status and dosage adjustment. P-value ≤ 0.05 was considered as statistical significance. Since the number of co-morbidities and number of drugs prescribed was non-normally distributed using the Shapiro-Wilk test (P < 0.001), the spearman correlation test was used (r = 0.228, p = 0.037). Results: The mean age of study participants was 57 years with 57.1% male and 42.9% female. The highest number of renal impaired patients was in stage three 56(66.7%). The mean creatinine clearance (Crcl) was 41.8 ml/min (IQR 24.8-60.9), and the mean serum creatinine (Scr) value of 2.63 mg/dl (IQR 1.3-3.1). More than two third (76.2%) of the study participants had comorbidities. Eighty-four patients with 257 prescription entries were included in the study. Of which 75 prescription entries need a drug dose adjustment. The overall rate of inappropriate dose adjustment was 42.6% (32/75). Inappropriate dose adjustment was more common with vancomycin (14.3%) and ciprofloxacin (6%). Inappropriate drug dose adjustments were associated with patients having intermediate renal insufficiency (P < 0.002) and co-morbid conditions (P < 0.02). Conclusion: The present study demonstrated that inappropriate dose adjustment was common at University of Gondar comprehensive specialized hospital that needs great attention. Vancomycin and ciprofloxacin were the most frequently identified drugs that were inappropriately adjusted. Intermediate renal insufficiency and co-morbidities were statically significant with inappropriate dose adjustment.

Maintenance of recovered dilated cardiomyopathy patients with half-dose neurohumoral blockades (MED-CHARM): A protocol for an open-label, pilot, randomized trial.

Dilated cardiomyopathy (DCM) has brought great damage to the patients' health and social economy. The number of patients with recovered dilated cardiomyopathy (recDCM) has increased over the years as treatment progresses. However, there is a lack of relevant evidence to support the clinical management of patients with recDCM, thereby, the recommendations in guidelines remains sparse. Accordingly, the exploration of recDCM is important to improve patient prognosis and reduce societal burden. This is an open-label, randomized controlled, prospective study that will compare the safety and efficacy of original dose and halved dose of neurohumoral blockades for patients with recDCM. Methods: An open-label, randomized controlled, prospective study will be conducted among eligible patients with recDCM. During the pilot study phase, we will recruit 50 patients. The primary endpoint is hospitalization for heart failure or heart failure relapse within 12 months. Secondary endpoint is major adverse cardiovascular events, including cardiovascular mortality, myocardial infarction, stroke, sustained atrial tachycardia, or ventricular tachycardia. The results will be analyzed using intention-to-treatment analysis. Discussion: The study will provide important evidence of whether it is safe and effective to halve the dosage of neurohumoral blockades in recDCM patients. Trial registration number: ChiCTR2100054051 (www.chictr.org.cn).

Pesticide dose based on canopy characteristics in apple trees: Reducing environmental risk by reducing the amount of pesticide while maintaining pest and disease control efficacy.

Although many different designed air-assisted sprayers can be used for pesticide application in apple orchards, the lack of adequate adjustments according to specific crop characteristics leads to application inefficiencies and failures. To evaluate the spray coverage and biological efficacy of different application techniques combined with an alternative dosage adjustment based on tree row volume (TRV), field tests with five different techniques were carried out at three crop stages on a commercial apple orchard. The results showed that conventional mist-blower with a high application volume (800 L ha-1) exhibited an excessive coverage with a high risk of contamination at the early crop stage (BBCH19), whereas other treatments using different application techniques, with a reduced volume rate and pesticide dose of 75%, were equivalent with good uniformity, revealing the great importance of suitable adjustment for the sprayers. For the middle and late stages (BBCH64 and 75), the orchard sprayer equipped with vertical booms provided the maximum coverage, and the pneumatic sprayer achieved significantly higher impacts density, which revealed their advantages and high efficiency for dense apple trees. The newly developed multi-fan sprayer and pneumatic sprayer achieved consistent coverage during the entire crop stage, independent of the changes in canopy structure (TRV). This indicates that a suitable setting and adjustment of the sprayer can contribute to a consistent spray quality. In general, benefiting from these new spraying technologies, an average reduction of 60.7% in pesticide dose and volume rate were achieved within the entire season, maintaining the same threshold of pest and disease control as that of the higher reference dose normally applied. These results demonstrate the importance of an alternative dose adjustment method to meet the requirements of the Farm to Fork strategy.

Nemonoxacin dosage adjustment in patients with severe renal impairment based on population pharmacokinetic and pharmacodynamic analysis.

AIMS: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic (PPK)/pharmacodynamic analysis. METHODS: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of a 0.5-g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 72 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment and the cumulative fraction of response against Streptococcus pneumoniae and Staphylococcus aureus was calculated by Monte Carlo simulation. RESULTS: The data best fitted a 2-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L) and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4 ± 6.5% in severe renal impairment patients and 66.1 ± 16.8% in healthy controls. PPK/pharmacodynamic modelling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g every 48 hours (q48h) was the optimal dosing regimen in severe renal impairment patients, evidenced by higher probability of target attainment (92.7%) and cumulative fraction of response (>99%) at nemonoxacin minimum inhibitory concentration ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if minimum inhibitory concentration = 1 mg/L. CONCLUSION: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.

INTRODUCTION: Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD. PRESENTATION OF CASE: A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life. CONCLUSION: We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.

Quality assessment and cost saving of renal dosing recommendation by clinical pharmacists at medical wards in Thailand.

Background Renal dosage adjustment for patients with reduced kidney function is a common function of clinical pharmacy service. Assessment of pharmacist's intervention in the aspect of quality and economic impact should be conducted to evaluate the benefit of this service. Objective This study aimed to assess the quality and cost saving of clinical pharmacists' recommendation on renal dosage adjustment among patients with reduced kidney function. Setting Eight medical wards of the Siriraj Hospital, a tertiary-care hospital in Bangkok, Thailand. Method A retrospective study was conducted using medical records and clinical pharmacist's intervention database. All patients admitted to the study wards whose estimated creatinine clearance were less than 60 mL/min or presented with acute kidney injury on admission during October 2016-December 2017 were included. The targeted medications were antimicrobial agents. Main outcome measure Percentage of the concordance between pharmacists' recommendation compared to standard dosing references and related cost saving. Results Among 158 patients, pharmacists provided 190 recommendations, including 151 (79.1%) dose reduction, 17 (8.9%) dose increase and 22 (11.5%) recommendations to provide supplemental dose after dialysis. These recommendations were 90.5% consistent with standard references. Physician accepted and complied with 89.5% of pharmacists' recommendations. Average direct cost saving was €5,114.11 while cost avoidance was €863.47. Conclusion Trained clinical pharmacists were able to provide high-quality recommendation on dosage adjustment in these patients in accordance to standard dosing guidelines. In addition, dosage adjustment also led to a significant direct cost saving and cost avoidance from prevention of adverse drug reactions.

Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam.

An extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (PK) modeling and Monte Carlo simulations using clinical PK data supported modified ceftazidime-avibactam dosage adjustments for patients with moderate or severe renal impairment (comprising a 50% increase in total daily dose compared with the original dosage adjustments) to reduce the risk of subtherapeutic drug exposures in the event of rapidly improving renal function. The modified dosage adjustments were included in the ceftazidime-avibactam labeling information at the time of initial approval and were subsequently evaluated in the final phase 3 trial (in patients with HAP, including VAP), providing supportive data for the approved U.S. and European ceftazidime-avibactam dosage regimens across renal function categories. This review describes the analyses supporting the ceftazidime-avibactam dosage adjustments for renal impairment and discusses the wider implications and benefits of using modeling and simulation to support dosage regimen optimization based on emerging clinical evidence.

Adjustments of medication dosages in patients with renal impairment in Botswana; findings and implications to improve patient care.

Background and aims: Medication dosage adjustments for renally impaired patients have not been studied in Botswana. This study was conducted to determine prescribing practices among patients with renal impairment in medical wards to improve future patient care.Methods: We conducted a retrospective study involving medical charts of patients admitted at a tertiary level hospital in Gaborone Botswana. Study participants included all patients admitted between August and October 2016 who were hospitalized for ≥24 h. 'Drug prescribing in renal failure: dosing guidelines for adults and children'. was used to determine the extent of dosage adjustments. A logistic regression model was used to assess which patient factors were associated with inappropriate dosage adjustment.Results: Twenty-nine percent (233/804) of patients had renal impairment. Of these, 184 patients with renal impairment were included in the final analysis. There were 1143 prescription entries, of which 20.5% (n = 234) required dosage adjustment for renal function but only 45.7% (n = 107) were adjusted correctly. Of note, 112 patients were prescribed at least one drug that required dosage adjustment and only 30.4% (n = 34) patients had all of their medications appropriately adjusted. Patient factors associated with inappropriate dosage adjustment included a higher number of medicines being prescribed. Mortality among patients with renal impairment was independently associated with higher scores of the Charlson comorbidity index and hospital stay duration of 1-7 days.Conclusion: The renal function status of patients was not sufficiently taken into account when prescribing medicines especially in patients with severely impaired kidney function in Botswana. Continuous medical education needs to be encouraged to address this, which is being implemented. We will be following this up in future studies.

[Prevention of iatrogenic risk and screening of chronic kidney disease]. / Maladie rénale chronique : prévention des risques de iatrogénies médicamenteuses et dépistage de la maladie.

Ten percent of the world's population is affected by chronic kidney disease that can lead to kidney failure. In France, nearly three million people are concerned, half of whom are undiagnosed, 85,000 people are on dialysis or waiting for a kidney transplant. Each year, 11,000 new diagnoses of severe renal failure are made, one third of which had not been treated before. Kidney failure is constantly increasing due to the aging of the population and the resurgence of chronic diseases, including obesity and cardiovascular diseases such as high blood pressure and diabetes, two conditions that impair renal function. The pharmacist, a local actor, is well placed to help patients adhere to their treatment and manage it to the best of their quality of life. It is up to the pharmacist to check the dosages according to the degree of renal involvement, ideally noted on the prescription or, failing that, by asking the patient the results of his recent biological examinations. The consultation of the pharmaceutical file and, ultimately, the shared medical file, will make it possible, in a concerted management of the patient's care pathway, to also detect possible drug interactions. By dispensing the prescribed drugs, the pharmacist can also warn against those known to be known for their nephrotoxicity, especially nonsteroidal anti-inflammatory drugs. In the case of over-the-counter products, the pharmacist may discourage a person at risk from taking certain drugs containing nonsteroidal anti-inflammatory drugs, including aspirin and ibuprofen. Because of their potential renal toxicity, the pharmacist is competent to alert, especially on certain food supplements, herbal products, and is legitimate to participate in screening campaigns.

Use of renal risk drugs in a nation-wide Polish older adult population: an analysis of PolSenior database.

BACKGROUND: Numerous medications should be avoided, or require dose adjustment in subjects with impaired kidney function. We aimed to assess the prevalence of potentially inappropriate use of renal risk drugs in a nation-wide, community-dwelling Polish older adult population. METHODS: We analysed regular intake of 38 medications that should be avoided, requiring dose modification, increase the risk of pre-renal kidney injury, or may cause potassium retention in subjects with moderately to severely impaired renal function in the PolSenior data base (N = 4514, mean age 76 ± 11 yrs). Kidney function was assessed with short Modification of Diet in Renal Disease formula estimated glomerular filtration rate (sMDRD) and Cockcroft-Gault creatinine clearance (CC). RESULTS: There were 855 (19%) individuals with sMDRD < 60 ml/min/1.73m2, and 1734 (38%) with CC <  60 ml/min. Among drugs that should be avoided, spironolactone (20.4% of patients as classified by sMDRD and 17.5% by CC), non-steroidal anti-inflammatory drugs (13.4 and 11.3%), hydrochlorothiazide (11.1 and 11.0%), and metformin (6.9 and 8.2%) were most frequently used. The most frequently used drugs requiring dose modification were piracetam (13.9% by sMDRD, and 11.9% by CC), digoxin (8.3 and 8.8%), and gliclazide (6.8 and 5.9%). Classification of a drug use as 'appropriate' or 'inappropriate' was discordant depending on the method of kidney function assessment (sMDRD or CC) in up to 30%. Subgroups with sMDRD < 60 ml/min/1.73m2 and with CC <  60 ml/min were taking ≥2 drugs increasing the risk of pre-renal kidney injury more frequently than individuals with better kidney function (46.6 vs. 23.1 and 33.0% vs. 24.4%, respectively). There were 24.7% of individuals with sMDRD < 60 ml/min/1.73m2 and 18.0% with CC <  60 ml/min taking 2 or more drugs increasing serum potassium level. The proportion of subjects with hyperkalaemia increased with the number of such drugs. CONCLUSIONS: Use of drugs that should be avoided or require dose adjustment due to renal impairment, and potentially inappropriate drug combinations is a common problem in older adults in Poland. Assessment of kidney function with sMDRD may result in overlooking of requirements for dose adjustment formulated based on creatinine clearance. TRIAL REGISTRATION: Not applicable.

Dosage adjustments in pivotal clinical trials with oral targeted therapies in solid tumors conducted in Europe.

PURPOSE: The aim of this study was to evaluate in what measure is dosage adjustment particularly prevalent in pivotal clinical trials of oral targeted therapy drugs approved by the European Medicine Agency as of July 31, 2018, for the treatment of solid tumors. METHODS: We performed a search on the official EMA site on human medicines, using as Keyword Search the ATC Code L01X (other antineoplastic agents); from the list of drugs results, we subsequently excluded antineoplastic drugs for hematological diseases, as well as refused and withdrawn drugs. For all analyzed drugs, we recorded full dosages, dose adjustments with relative reduction percentage, reason for the adjustments, number of patients included in the trial, percentage of patients who reduced their dosage or temporarily discontinued therapy, cause of dose reduction, and presence or absence of reference to a clinical outcome in patients who reduced their dose or discontinued therapy. RESULTS: We considered 74 pivotal trials on 29 target therapies, of which 56 (76%) provide information on dosage reduction, 41 (55%) on therapy suspension, and 29 (39%) on the dose taken by the sample. Trials that provide information on dosage adjustment include reduction and suspension data widely used to manage side effects; they concern, respectively, 32 and 44% of the samples considered. No trial results take account of the possible role of adjustment in clinical outcomes. CONCLUSION: It would be advisable for pivotal clinical trials to give more relevance to dose management, which is a widely used tool for the management of adverse events in clinical practice. To date, such information is lacking.

Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 Polymorphisms Using HRMA in Psychiatry Patients with Schizophrenia and Bipolar Disease for Personalized Medicine.

BACKGROUND: The interindividual genetic variations in drug metabolizing enzymes effects the impact and toxicity in plenty of drugs. OBJECTIVE: CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene polymorphisms were characterized using high resolution melting analysis (HRMA) in follow-up patients in psychiatry clinic as a preliminary preparation for personalized medicine. METHOD: Genotyping of CYP1A2*1F, CYP2C9 *2, *3, CYP2C19 *2, *3 and *17 and CYP2D6 *3, *4 was conducted in 101 patients using HRMA. Genotype and allele frequencies of the CYP variants were found to be in equilibrium with the Hardy-Weinberg equation. RESULTS: The frequency of the CYP1A2*1F allele in schizophrenia and bipolar disease was 0.694 and 0.255, respectively. The CYP2C9 allele frequencies were 0.087 (CYP2C9*2), and 0.549 (CYP2C9*3) for bipolar; 0.278 (CYP2C9*2) and 0.648 (CYP2C9*3) in schizophrenias. The CYP2C19*2 and *17 allele frequencies was 0.111 and 0.185 in schizophrenia and variant *2 was 0.117 and variant *17 was 0.255 in bipolar group. The frequency of the CYP2D6*3 allele was 0.027 in schizophrenias. The frequencies for the CYP2D6*4 variant were 0.092 and 0.096 in schizophrenia and bipolar groups, respectively. CONCLUSION: The knowledge in pharmacogenomic and also the developments in molecular genetics are growing rapidly. In future, this can be expected to provide new methodologies in the prediction of the activity in drug metabolizing enzymes. The HRMA is a rapid and useful technique to identify the genotypes for drug dosage adjustment before therapy in psychiatry patients.

Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan.

BACKGROUND: Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. PATIENTS AND METHODS: The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. RESULTS: Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. CONCLUSION: Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully.

Empirically Reduced Dosages of Tinzaparin in Patients with Moderate-to-Severe Renal Insufficiency Lead to Inadequate Anti-Xa Levels.

BACKGROUND: Due to the higher molecular weight of tinzaparin, the low molecular weight heparin (LMWH) is less dependent on renal excretion than other LMWH preparations. However, several international guidelines recommend the same preemptive dosage reduction for all therapeutic dose LMWHs prescribed in renal insufficient patients, to ensure that there is no accumulation of anticoagulant activity and increased risk of bleeding. This study is aimed at assessing whether a preemptive dosage reduction of tinzaparin in all renal insufficient patients (comprising 25% reduction in patients with Modification of Diet in Renal Disease - estimated glomerular filtration rate (MDRD-eGFR) 30-60 mL/min/1.73 m2 and 50% reduction in patients with MDRD-eGFR <30 mL/min/1.73 m2) leads to adequate anti-Xa levels. METHODS: We selected the anti-Xa levels of in-hospital patients (≥18 years) with moderate-to-severe renal insufficiency (MDRD-eGFR <60 mL/min/1.73 m2), on therapeutic dosages of tinzaparin. Anti-Xa levels were measured using a chromogenic assay. RESULTS: Preemptive dosage reduction resulted in a median anti-Xa activity of 0.50 IU/mL (interquartile range [IQR] 0.38-0.60). In 92.3% of patients the anti-Xa level was below the target anti-Xa level of >0.85 IU/mL for therapeutic indications. Unadjusted dosages led to a median anti-Xa activity of 0.74 IU/mL (IQR 0.56-0.92). The preemptive dosage reduction was significantly associated with anti-Xa activity below therapeutic range (p = 0.007). No difference in anti-Xa activity was observed between patients with moderate (0.71 IU/mL, IQR 0.61-0.95) versus severe (0.65 IU/mL, IQR 0.41-1.06) renal insufficiency in whom an unadjusted dose had been administered (p = 0.77). None of the anti-Xa levels were above the upper margin of the presumed therapeutic range of 2.0 IU/mL. CONCLUSION: In renal insufficient patients, the preemptive dosage reduction of tinzaparin leads to inadequate anti-Xa levels.

[Dosing adjustment and renal function: Which equation(s)?]. / Adaptation posologique des médicaments et fonction rénale : quel(s) estimateur(s) faut-il choisir ?

While the CKD-EPI (for Chronic Kidney Disease Epidemiology) equation is now implemented worldwide, utilization of the Cockcroft formula is still advocated by some physicians for drug dosage adjustment. Justifications for this recommendation are that the Cockcroft formula was preferentially used to determine dose adjustments according to renal function during the development of many drugs, better predicts drugs-related adverse events and decreases the risk of drug overexposure in the elderly. In this opinion paper, we discuss the weaknesses of the rationale supporting the Cockcroft formula and endorse the French HAS (Haute Autorité de santé) recommendation regarding the preferential use of the CKD-EPI equation. When glomerular filtration rate (GFR) is estimated in order to adjust drug dosage, the CKD-EPI value should be re-expressed for the individual body surface area (BSA). Given the difficulty to accurately estimate GFR in the elderly and in individuals with extra-normal BSA, we recommend to prescribe in priority monitorable drugs in those populations or to determine their "true" GFR using a direct measurement method.

Drug Toxicity in Kidney Disease: A Standardized Patient Case for Clerkship Students.

INTRODUCTION: A disconnect appears to exist for medical students between learning drug facts in a basic science context and applying those facts in a clinical context when they begin working with authentic patients. In patients with kidney dysfunction, dosages of medications that are renally eliminated often need to be adjusted, due to potentially toxic accumulation in the body. To gain insight into the thought processes and gaps underlying student thinking, we developed this standardized patient (SP) case featuring a patient with drug-related renal dysfunction. METHODS: This activity was conducted in a simulation center, in a setting reminiscent of an emergency department. It took place over 2 days, with all 23 third-year medical students at our regional campus. After reporting to the simulation center at their assigned time, students completed four different medication scenarios. This specific case involved two parts. The first part, an SP-student encounter, was allotted 15 minutes, followed by 1 minute to walk to a computer station. For the second part, writing a SOAP (subjective, objective, assessment, and plan) note, 15 minutes were allotted. This was followed by 3 minutes for the SP to provide student feedback and 1 minute to rotate to the next station. In total, 35 minutes were allotted for each student to complete the case. RESULTS: All third-year medical students at our regional campus completed this activity at the midpoint of their academic year. Students were well prepared to gather necessary background information from the standardized patient. However, few made the connection between the patient's symptoms and the way in which her medications were contributing. Nor did they recommend an appropriate course of action for medications that required adjustment. DISCUSSION: From this activity, we gained insight into the student thought process with regard to medication management and have been able to develop new ways of revisiting basic science concepts in clinically relevant contexts to help bridge the gap between the basic and clinical components of pharmacology education.

Onco-nephrology: an appraisal of the cancer and chronic kidney disease links.

A bidirectional relationship has been observed for kidney disease and cancer. On the one hand, cancer is an important complication noted in kidney disease as well as a major cause of morbidity and mortality in this group. On the other hand, improved cancer treatment has prolonged survival, but also increased the development of acute and chronic kidney disease. The combination of cancer and kidney disease makes it challenging for clinicians to provide comprehensive and safe therapies for this group of patients. As such, clinicians caring for this group must develop expertise and become competent in the practice of a newly evolving subspecialty of nephrology known as 'onco-nephrology'. This brief narrative review will focus on the cancer risk in patients with underlying kidney disease, the therapies such as erythropoiesis-stimulating agents on cancer progression and other outcomes, and the appropriate dosing of anti-cancer agents in patients with underlying kidney disease.