[Show abstract][Hide abstract] ABSTRACT: Continuous hemodiafiltration (CHDF) is used as renal replacement therapy for critically ill patients with renal failure, and to treat hypercytokinemia. Since CHDF also clears therapeutic agents, drug pharmacokinetics (PK) should be dependent upon CHDF conditions. Although the antibiotic biapenem (BIPM) is used in patients undergoing CHDF, the optimal therapeutic regimen in such patients has not been fully clarified. In this study, we investigated the PK of BIPM in patients with various levels of renal function undergoing CHDF with polysulfone (PS) membrane, and used PK models to identify the optimal administration regimen.
BIPM (300 mg) was administered by infusion in patients undergoing CHDF (n = 7). Blood and filtrate-dialysate were collected for compartment and non-compartment analysis.
The sieving coefficient of PS membrane was 1.00 ± 0.06 (mean ± S.D., n = 7), and CHDF clearance of BIPM was found to be the sum of the dialysate flow rate (Q D ) and filtrate flow rate (Q F ). Non-CHDF clearance showed inter-individual variability (4.82 ± 2.48 L/h), depending on residual renal function and non-renal clearance. Based on the average PK parameters obtained with a compartmental model, maximal kill end point (over 40 % T > MIC 4 μg/mL ) was achieved with regimens of 300 mg every 6 h, 300 mg every 8 h, and 600 mg every 12 h. Monte Carlo simulation indicated that 300 mg infusion for 1 h every 6 h was optimal, and the probability of target attainment at MIC 2 μg/mL was 90.2 %.
Our results establish the optimal regimen of BIPM in patients with various levels of renal function undergoing CHDF with a PS membrane.
[Show abstract][Hide abstract] ABSTRACT: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs). The increasing interest in newborn screening procedures for LSDs underlines the need for alternative cellular and gene therapy approaches to be developed during the perinatal period, supporting the treatment of MPS patients before the onset of clinical signs and symptoms. The rationale for considering these early therapies results from the clinical experience in the treatment of MPSs and other genetic disorders. The normal or gene-corrected hematopoiesis transplanted in patients can produce the missing protein at levels sufficient to improve and/or halt the disease-related abnormalities. However, these current therapies are only partially successful, probably due to the limited efficacy of the protein provided through the hematopoiesis. An alternative explanation is that the time at which the cellular or gene therapy procedures are performed could be too late to prevent pre-existing or progressive organ damage. Considering these aspects, in the last several years, novel cellular and gene therapy approaches have been tested in different animal models at birth, a highly early stage, showing that precocious treatment is critical to prevent long-term pathological consequences. This review provides insights into the state-of-art accomplishments made with neonatal cellular and gene-based therapies and the major barriers that need to be overcome before they can be implemented in the medical community.
No preview · Article · Nov 2015 · Journal of Inherited Metabolic Disease
[Show abstract][Hide abstract] ABSTRACT: Introduction: Following a Phase III, randomized, double-blind, placebo (PBO)-controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older.Areas covered: Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48
No preview · Article · Oct 2015 · Expert Opinion on Orphan Drugs
[Show abstract][Hide abstract] ABSTRACT: Patients with severe tracheal obstruction in Morquio A syndrome are at risk of dying of sleep apnea and related complications. Tracheal obstruction also leads to life-threatening complications during anesthesia as a result of the difficulty in managing the upper airway due to factors inherent to the Morquio A syndrome, compounded by the difficulty in intubating the trachea. A detailed description of the obstructive pathology of the trachea is not available in the literature probably due to lack of a homogenous group of Morquio A patients to study at any one particular center. We present a series of cases with significant tracheal obstruction who were unrecognized due to the difficulty in interpreting tracheal narrowing airway symptoms. Our goal is to provide the guidelines in the management of these patients that allow earlier recognition and intervention of tracheal obstruction.
Full-text · Article · Oct 2015 · Molecular Genetics and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Morquio A syndrome features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio A has been described. We conducted HSCT for 4 cases with Morquio A (age at HSCT: 4-15years, mean 10.5years) and followed them at least 10years (range 11-28years; mean 19years). Current age ranged between 25 and 36years of age (mean 29.5years). All cases had a successful full engraftment of allogeneic bone marrow transplantation without serious GVHD. Transplanted bone marrow derived from HLA-identical siblings (three cases) or HLA-identical unrelated donor. The levels of the enzyme activity in the recipient's lymphocytes reached the levels of donors' enzyme activities within two years after HSCT. For the successive over 10years post-BMT, GALNS activity in lymphocytes was maintained at the same level as the donors. Except one case who had osteotomy in both legs one year later post BMT, other three cases had no orthopedic surgical intervention. All cases remained ambulatory, and three of them could walk over 400m. Activity of daily living (ADL) in patients with HSCT was better than untreated patients. The patient who underwent HSCT at four years of age showed the best ADL score. In conclusion, the long-term study of HSCT has demonstrated therapeutic effect in amelioration of progression of the disease in respiratory function, ADL, and biochemical findings, suggesting that HSCT is a therapeutic option for patients with Morquio A.
Full-text · Article · Oct 2015 · Molecular Genetics and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated wi
Full-text · Article · Apr 2015 · Drug Design, Development and Therapy
[Show abstract][Hide abstract] ABSTRACT: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by the deficiency of lysosomal enzymes. The enzymes are required to break down glycosaminoglycans (GAGs) that help build bone, cartilage, tendons, corneas, skin and connective tissue. In patients with MPS, a missing enzyme leads to the accumulation of GAGs in the cells, blood, connective tissues, and multiple organs. The consequence is permanent, with progressive cellular damage affecting patients' appearance, physical abilities, organ and system function, and skeletal and mental development. The measurement of each specific GAG in a variety of specimens is required to establish the correlation between GAGs and physiological status of patients and/or prognosis and pathogenesis of the disease and to separate the patients with MPS from the healthy controls. We have developed a highly accurate, sensitive, and cost-effective liquid chromatography tandem mass spectrometry (LC-MS/MS) method for measurements of disaccharides derived from four specific GAGs [chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)]. Disaccharides were produced by specific enzyme digestion of each GAG, and subsequently, quantified by negative ion mode of multiple reaction monitoring. Subclasses of GAGs with the same molecular weights can be separated by liquid chromatography. We have also developed another GAG assay by high-throughput mass spectrometry (HT-MS/MS). The HT-MS/MS consists of an integrated solid phase extraction robot that binds and de-salts samples from assay plates and directly injects them into a MS/MS detector, reducing sample processing time to within ten seconds. HT-MS/MS consequently yields much faster throughput than conventional LC-MS/MS-based methods; however, the HT-MS/MS system does not use a chromatographic step, and therefore, cannot separate GAGs that have the same molecular weights. Both techniques can be applied to the analysis of dried blood spots, blood, and urine specimens. In this review, we describe the assay methods for GAGs and the application to newborn screening and diagnosis of MPS.
[Show abstract][Hide abstract] ABSTRACT: A retrospective analysis suggested that blood tacrolimus concentrations were consistent among patients with a body mass index (BMI) < 18.5 (lean), normal (≥18.5 and <25) and ≥ 25 (overweight or obese). The average maintenance dose of tacrolimus in patients with BMI ≥ 25 were significantly lower compared with that in patients with a BMI of less than 25. Lean and obese Zucker rats fed a normal diet were given tacrolimus intravenously or orally. The blood concentrations of tacrolimus in obese rats were significantly higher than those in lean rats after administration via both routes. The moment analysis has suggested that CLtot and Vdss of tacrolimus were not significantly different between lean and obese rats. The bioavailability was higher in obese rats, compared with that in lean rats. The protein expression of Cyp3a2 in the liver was significantly decreased in obese rats, compared with lean rats, while P-gp in the small intestine was also significantly decreased in obese rats. These results suggested that the steady-state trough concentration of tacrolimus in obese patients were well maintained by relatively low dose compared with that in normal and lean patients, presumably due to increased bioavailability.
No preview · Article · Mar 2014 · Drug Metabolism and Pharmacokinetics
[Show abstract][Hide abstract] ABSTRACT: This study was designed to clarify the influence of long-term enteral nutrition (EN) on the pharmacokinetics of digoxin. Rats were fed EN diets (semi-digested, digested, and elemental) for 4 weeks, then digoxin (0.05 mg/kg) was administered orally. The AUC(0-∞) and k(a) of digoxin were significantly reduced in the semi-digested diet group versus the control, while the AUC(0-∞) was significantly increased in the digested and elemental diet groups. The mRNA level of Slco1a4 was significantly reduced at the upper small intestine in all EN groups. Further, the expression levels of P-glycoprotein (P-gp) protein and Abcb1a mRNA were increased at the same site in all EN groups, and the increases were significant in the elemental diet group. Cyp3a2 protein and mRNA expressions were significantly reduced in the liver in the digested and elemental diet groups. Abcb1a mRNA was also significantly reduced in the kidney in these groups. These results indicate that the absorption kinetics at the small intestine is influenced by semi-digested diet, and the elimination kinetics in the liver and kidney are influenced by digested and elemental diet. Semi-digested diet also altered digoxin pharmacokinetics in humans. Thus, the effect of long-term EN on digoxin pharmacokinetics depended on the dietary components.
No preview · Article · Jul 2012 · Drug Metabolism and Pharmacokinetics
[Show abstract][Hide abstract] ABSTRACT: Treatment of cancers in the abdominal cavity, such as peritoneal dissemination, is difficult, but in principle intraperitoneal administration of anticancer drugs is expected to be preferable to systemic administration. Taxane anticancer drugs are used to treat gastric cancer patients with peritoneal dissemination. They are administered as micellar preparations, Taxol and Taxotere, which consist of paclitaxel in Cremophor EL (crEL) and docetaxel in Polysorbate-80 (PS-80), respectively. In this paper we review the disposition kinetics of taxane anticancer drugs after intraperitoneal administration in peritoneal dissemination patients and animal models and also discuss the effect of the surfactant vehicle on the behavior of taxanes.
Full-text · Article · May 2012 · Gastroenterology Research and Practice
[Show abstract][Hide abstract] ABSTRACT: C-C motif chemokine receptor (CCR)2 and its ligand, monocyte chemoattractant protein (MCP)-1, are pivotal for adipose tissue macrophage (ATM) recruitment and the development of insulin resistance. However, other chemokine systems also may play a role in these processes. In this study, we investigated the role of CCR5 in obesity-induced adipose tissue inflammation and insulin resistance. We analyzed expression levels of CCR5 and its ligands in white adipose tissue (WAT) of genetically (ob/ob) and high-fat (HF) diet-induced obese (DIO) mice. Furthermore, we examined the metabolic phenotype of Ccr5(-/-) mice. CCR5 and its ligands were markedly upregulated in WAT of DIO and ob/ob mice. Fluorescence-activated cell sorter analysis also revealed that DIO mice had a robust increase in CCR5(+) cells within ATMs compared with chow-fed mice. Furthermore, Ccr5(-/-) mice were protected from insulin resistance, glucose intolerance, and hepatic steatosis induced by HF feeding. The effects of loss of CCR5 were related to both reduction of total ATM content and an M2-dominant shift in ATM polarization. It is noteworthy that transplantation of Ccr5(-/-) bone marrow was sufficient to protect against impaired glucose tolerance. CCR5 plays a critical role in ATM recruitment and polarization and subsequent development of insulin resistance.