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Biomedical subjects

Shinya Ito

Publications and source records attributed to Shinya Ito.

At least 37 records · Page 2Linked to original sources
PubMed2004

When breastfeeding mothers need CNS-acting drugs.

BACKGROUND: Breastfeeding is the ideal method of infant nutrition. However, if mothers need medications such as the central nervous system (CNS) acting drugs, infant safety concerns arise. Summarized information on infant exposure levels to drugs in milk and associated side effect profiles will help clinicians to rationalize and justify important drug therapy for a breastfeeding patient. METHODS: Electronic searches of MEDLINE and PsycINFO from 1966-2003, and of EMBASE from 1980-2003, were conducted for studies on breastfeeding or breast milk and medications in the following categories: antidepressants, antipsychotics, antiepileptics (or anticonvulsants) and anxiolytics. The infant exposure level (%) was defined as follows: [Drug concentration in milk (mg/mL)] x [Daily milk intake (mL/kg/d)] x 100 / Maternal dose (mg/kg/d). RESULTS: A total of 129 papers were eligible for analyses. Our findings indicate that the majority of the CNS-acting drugs, if taken by nursing women, result in average exposure levels to their breast-fed infants of less than 10% of the therapeutic doses per kg body weight. Exceptions are lithium, ethosuximide, phenobarbital, primidone, lamotrigine and topiramate. Adverse effect profiles do not always correlate with a higher exposure level. Overall, most reported adverse effect profiles appear benign. Where adverse effects were reported, they were often confounded by intrauterine exposure. CONCLUSIONS: CNS-acting drugs taken by the mother do not appear to pose any major risks of immediate adverse effects to the breastfeeding infant, although with most of the newer drugs further research is needed to be conclusive.

Anticonvulsants↗
PubMed2004

Nanoflow gradient generator for capillary high-performance liquid chromatography-nanoelectrospray mass spectrometry.

A novel nanoflow gradient generator using a 10-port switching valve with two injection loops installed, which is referred to here as the "Asymptotic-Trace-10-Port-Valve" (AT10PV) nanoGR generator, has been applied to capillary high-performance liquid chromatography (HPLC)-microelectrospray (microESI) or nanoelectrospray (nanoESI) time-of-flight mass spectrometry (TOF MS). In this study, performance of this capillary HPLC-micro/nanoESI-MS system was tested at a flow rate of 200 nl/min by using three typical peptides (angiotensins I, II, and III: 50 fmol each). The result demonstrated that this system provides reasonably good repeatability of peak retention times (R. S.D. of less than 0.5%). Sequential runs of a series of sample injections were performed in the same manner as conventional analysis at microflow rates.

Chromatography, High Pressure Liquid↗
PubMed2004

Nanoflow gradient generator for capillary high-performance liquid chromatography.

A novel method of generating a nanoflow gradient elution for a capillary high-performance liquid chromatography (HPLC) system has been developed. An important feature of this system is that any gradient (GR) profile generated by a conventional microflow GR pump can be asymptotically traced and converted as a corresponding nanoflow GR profile simply by using a 10-port switching valve with two injection loops installed. Consequently, it has been called an "asymptotic trace 10-port valve" (AT10PV) nanoflow GR generator. Performance of the AT10PV nanoflow GR generator was tested in the range of flow rates from 50 to 500 nL/min. The test demonstrated that the AT10PV nanoflow GR generator can asymptotically trace the original gradient profile with good reproducibility. A capillary HPLC system using the AT10PV nanoflow GR generator provides reasonably good repeatability of peak retention times on the chromatogram of the tryptic digest of a BSA sample, RSD of less than 0.3% at a flow rate of 200 nL/min. It also enables sequential running of a series of sample injections in the same manner as conventional analysis at microflow rates.

Acetone↗
PubMed2004

Structural assignment of isomeric 2-aminopyridine-derivatized oligosaccharides using MSn spectral matching.

Two isomeric pairs of 2-aminopyridine (PA)-derivatized fucosylated and non-fucosylated oligosaccharides (complex-type N-glycans of IgG) were analyzed using liquid chromatography/ion trap mass spectrometry (LC/ITMS) with a sonic spray ionization source and by varying the collision-induced dissociation voltage. Reproducibility of MS(n) (n = 2) spectra obtained by LC/ITMS was tested considering both fragment ions (m/z) and intensities. A comparison of their MS(n) spectra and evaluation of similarities (or matching), based on correlation coefficients between MS(n) spectra, was investigated as a possibility for structural assignment of the isomers. It is shown that such MS(n) spectral matching is useful and applicable to the structural assignment of relatively large fucosylated and sialylated PA-oligosaccharides released from IgG based on Bn- and Yn-type fragmentations of the corresponding [M+H+Na](2+) ions.

Aminopyridines↗
PubMed2004

Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: pharmacokinetic modeling for estimation of intracellular levels.

Ifosfamide (IF) improves survival in children with solid tumors but causes a high rate of nephrotoxicity. We hypothesized that this is caused by an oxidative metabolite of IF, chloroacetaldehyde, which is produced locally by the cells of the renal tubule (RT). For this hypothesis to be viable, one must document that chloroacetaldehyde concentrations in the RT cell are consistent with levels shown to cause nephrotoxicity in experimental systems. Using pharmacokinetic modeling of experimental data, we show that the median level of chloroacetaldehyde in RT cells is 80 micromol/L, ranging from 35 to 320 micromol/L. These concentrations are consistent with levels shown experimentally to cause functional and structural RT damage and lends validity to the hypothesis that local renal production of chloroacetaldehyde causes nephrotoxicity.

Acetaldehyde↗
PubMed2004

Renal ontogeny of ifosfamide nephrotoxicity.

Ifosfamide-induced nephrotoxicity adversely affects the health and well-being of children with cancer. We have recently shown age-dependent nephrotoxicity induced by ifosfamide, with younger children (<3 years) substantially more vulnerable. The mechanisms leading to this age-related ifosfamide-induced renal damage have not been identified. Underlying this work is the hypothesis that renal ontogeny is involved in the expression and activity of the cytochrome P450 (CYP) enzymes responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. We evaluated renal CYP3A and 2B22 activity in pigs between the ages of 1 day and adulthood, as well as the metabolism of ifosfamide by renal microsomes to 2- and 3-dechloroethylifosfamide (2-DCEIF and 3-DCEIF, respectively). Kidney CYP3A messenger RNA expression peaked 15 to 60 days (0.7-76 +/- 0.19 CYP3A/actin ratio; P < 0.001). Subsequently, this level decreased to adult values (0.54 - 0.03 CYP3A/actin ratio; P = 0.04). Similarly, we detected an increase in the ifosfamide-metabolism rate between young (18 +/- 2 pmol/mg protein/min) and adult (12.2 +/- 0.17 pmol/mg protein/min) animals (P = 0.002). Ours is the first documentation of ontogeny of renal CYP3A and of renal ifosfamide metabolism. These data suggest that age-dependent ifosfamide nephrotoxicity is, at least in part, due to ontogeny in the production chloroacetaldehyde.

Acetaldehyde↗
PubMed2004

Frequency of infant adverse events that are associated with citalopram use during breast-feeding.

OBJECTIVE: The purpose of this study was to determine the frequency of infantile adverse events from exposure through breast-feeding to maternal citalopram therapy. STUDY DESIGN: This was a prospective, observational cohort study. Women who were breast-feeding were placed in three groups on the basis of citalopram use: group 1 consisted of 31 women who were depressed and were undergoing citalopram therapy, group 2 consisted of 12 women who were depressed but were not undergoing citalopram therapy, and group 3 consisted of 31 healthy women who were matched to group 1 by maternal age and parity. Data collection included infant feeding method, medication use, and adverse events. RESULTS: There was no statistically significant difference in the rate of adverse events in the three groups (3/31 events, 0/12 events, and 1/31 events in groups 1, 2, and 3, respectively). The average dose of citalopram that was used in group 1 was 25.3+/-11.4 mg per day (range, 10-60 mg/d). CONCLUSION: To our knowledge, this is the first prospective, controlled study to examine the safety of citalopram during breast-feeding, which should be continued during maternal citalopram therapy.

Adult↗
PubMed2004

Pediatric resident education and needs assessment in clinical pharmacology.

OBJECTIVE: To identify perceived and unperceived educational needs of residents to organize a seminar series in clinical pharmacology. METHOD: All pediatric residents (48) and all attending general pediatric staff (20) were sent structured questionnaires with potential seminar topics. Data from previous pharmacy chart audits and complaints lodged with patient care representatives were analyzed as the environmental scans. RESULTS: There was a 75% response rate from both residents and staff. The responses were very similar and the only significant difference was the response to a seminar on correcting electrolyte imbalances which the residents favoured (p = 0.005). The environmental scans identified pain management as one of the main areas needing improvement. CONCLUSION: Perceived learning needs of residents are similar but not identical to those identified by the faculty. Environmental scanning can be used to identify unperceived learning needs.

Chi-Square Distribution↗
PubMed2004

[Mediastinal seminoma difficult to differentiate from thymoma through preoperative biopsy; report of a case].

A case of a 36-year-old male patient with mediastinal seminoma is presented. He consulted a physician with a complaint of back pain and an abnormal shadow was detected on chest X-ray. Chest computed tomography (CT) scan revealed a pulmonary nodule and an anteriormediastinal mass. Preoperative percutaneous needle biopsy suggested that the tumor was similar to thymoma. Complete surgical excision of the mediastinal mass was performed. Immunohistochemical studies showed positive staining of the tumor cells with placental alkaline phosphatase. The final diagnosis was seminoma. Additional postoperative chemotherapy (cisplatin + etoposide) was done. He is alive and well 34 months after the operation.

Adult↗
PubMed2003

Cyclosporine excretion into breast milk.

Although many female patients of childbearing age who are receiving cyclosporine have successful pregnancies, these women may be advised not to breast-feed. During recent years, cases of uneventful pregnancies and subsequent successful breast-feeding have been reported in the literature. The infant's blood cyclosporine concentration was usually very low. Based on these findings and the lack of detectable adverse effects, some investigators have suggested that women on cyclosporine may breast-feed, challenging the conventional view that cyclosporine is contraindicated during breast-feeding. Here, we report our experience with cyclosporine use during breast-feeding in five mother-infant pairs. We show a wide range of infant exposures to the drug in milk, noting that one of the infants had therapeutic blood concentrations of cyclosporine despite relatively low concentrations of the drug in milk.

Cyclosporine↗
PubMed2003

Xenobiotic transporter expression and function in the human mammary gland.

Xenobiotic transport in the mammary gland has tremendous clinical, toxicological and nutritional implications. Mechanisms such as passive diffusion, carrier-mediated transport, and transcytosis mediate xenobiotic transfer into milk. In vivo animal and human studies suggest the functional expression of both xenobiotic and nutrient transporters in the lactating mammary gland and the potential involvement of such systems in the significant accumulation of certain compounds in milk. In vitro cell culture systems provide further evidence for carrier-mediated transport across the lactating mammary epithelium. Additionally, molecular characterization studies indicate the expression of various members of the organic cation transporter, organic anion transporter, organic anion polypeptide transporter, oligopeptide transporter, nucleoside and nucleobase transporter, multidrug resistant transporter, and multidrug resistant-like protein transporter families at the lactating mammary epithelium. The in vivo relevance of the expression of such xenobiotic and nutrient transporters and their involvement in drug disposition at the mammary gland requires investigation.

Carrier Proteins↗
PubMed2003

Drug excretion into breast milk--overview.

Breastfeeding is the optimal form of infant feeding for the first months of an infant's life, and the majority of healthy women initiate breastfeeding after the birth of their infant. However, women on medication may default to formula feeding or not taking their drug therapy for fear of exposing their infant to the medication through the breast milk. Although the majority of medications are considered to be compatible with breastfeeding, cases of significant infant toxicity exist, suggesting a case by case risk assessment to be made before the mother initiates breastfeeding or drug therapy. Unfortunately, current clinical risk assessment is often compromised by the paucity of data, as studies in breastfeeding women and their infants are ethically difficult to conduct. Circumventing the ethical constraints, approaches have been proposed to estimate drug excretion into milk from physicochemical characteristics of the drug, which diffuses through the mammary gland epithelia. However, as our understanding on drug transfer mechanisms increases, it has become abundantly clear that carrier-mediated processes are involved with excretion of a number of drugs into milk. This article provides an overview of the benefits of breastfeeding, the effect of medication use during breastfeeding on maternal decisions and infant health, and factors determining infant exposure to medication through the breast milk.

Breast Feeding↗
PubMed2003

Monitoring lithium in breast milk: an individualized approach for breast-feeding mothers.

Lithium is a drug of choice for the management of bipolar disorder, a disease frequently affecting women in their childbearing years. Unfortunately, this drug has typically been contraindicated in nursing women. Data in humans are limited with respect to the use of this drug in lactating women, and early reports suggest high excretion into milk. The purpose of this report was to verify the excretion of lithium into human milk and to assess infant safety after breast-feeding. The authors found wide interpatient variability in lithium dose offered to the infant through breast milk (from 0% to 30% of maternal weight-adjusted dose), indicating that therapeutic drug monitoring of lithium in milk and/or in infant's blood, coupled with close monitoring of adverse effects, is a rational approach. Since therapeutic drug monitoring of lithium is routine, physicians caring for these women and infants should be encouraged to individualize their recommendations.

Bipolar Disorder↗
PubMed2003

Verapamil metabolites: potential P-glycoprotein-mediated multidrug resistance reversal agents.

Multidrug resistance in cancer chemotherapy frequently correlates with overexpression of the P-glycoprotein drug transporter. Attempts to reverse P-glycoprotein-mediated multidrug resistance with racemic verapamil or its less toxic (R)-enantiomer have been complicated by cardiotoxicity. The objective of this study was to investigate the effects of the major verapamil metabolite, norverapamil, as well as the PR-22 and D-620 metabolites, on P-glycoprotein-mediated drug transport. We measured the basolateral-to-apical fluxes of the P-glycoprotein substrates digoxin and vinblastine in the presence and absence of verapamil, (R)-norverapamil, (S)-norverapamil, racemic norverapamil, PR-22, or D-620 across confluent monolayers of Madin-Darby canine kidney (MDCK) cells that express P-glycoprotein on their apical membranes. Verapamil and norverapamil nonstereospecifically inhibited the renal tubular secretion of digoxin and vinblastine similarly in a dose-dependent manner. However, there was no decrease in the cellular accumulation of digoxin and vinblastine, suggesting that neither verapamil nor norverapamil prevent the substrates from entering the MDCK cells. Furthermore, the norverapamil metabolite P-22 also inhibited the secretion of these P-glycoprotein substrates. Our results suggest that the verapamil metabolites norverapamil and PR-22, which are less cardiotoxic than the parent compound, have comparable inhibitory abilities to verapamil (norverapamil greater than PR-22) and may be useful in reversing resistance to P-glycoprotein substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Prediction of milk/plasma concentration ratio of drugs.

OBJECTIVE: The milk to plasma (m/p) concentration ratio of drugs is used to estimate the amount of drug offered to the suckling infant. Published literature was reviewed to identify drugs for which sufficient data exist for calculation of m/p ratio and to examine whether the existing empiric data agree with the published method of Atkinson for mathematical prediction of m/p ratios based on physiochemical characteristics. METHODS: Using a comprehensive reference text, we identified studies reporting sufficient data to calculate m/p ratio based on the AUC for milk and plasma. Subsequently, we calculated the m/p ratio with Atkinson's formula based on pKa, lipophilicity, and protein binding. We then correlated the empiric versus predicted (calculated) m/p ratios. RESULTS: Of 192 drugs of which at least some data on milk accumulation have been published, there were sufficient data to quantify m/p ratios for only 69 medications (78 studies). There was no significant correlation between the empiric m/p ratios and the predicted values using the Atkinson's model. CONCLUSIONS: Reliable data on m/p concentration ratios exist for few medications. Presently, there is no appropriate model to predict milk concentrations of drugs in humans.

Area Under Curve↗