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Biomedical subjects

H Okamoto

Publications and source records attributed to H Okamoto.

At least 307 records · Page 17Linked to original sources
PubMed1998

Persistent and secondary adenovirus-mediated hepatic gene expression using adenovirus vector containing CTLA4IgG.

Adenovirus vectors can transfer recombinant genes efficiently into a wide variety of cells in vivo, but have serious limitations: gene expression is transient and secondary gene transfer is inefficient or impossible because of cellular and humoral immune responses against adenovirus-transduced cells. To solve these limitations, we have constructed an adenovirus vector, Adex1CACTLA4IgG, that expresses CTLA4IgG molecules. After in vivo administration of Adex1CACTLA4IgG (9.0 x 10(9) PFU), the peak level of serum CTLA4IgG was 29.8 mg/ml on day 4. The serum CTLA4IgG concentration gradually fell but was still 5.7 mg/ml on day 90. However, the serum concentration of CTLA4IgG was elevated after a second administration of Adex1CACTLA4IgG. The production of antibody against adenovirus was completely prevented after treatment with Adex1CACTLA4IgG. In addition, coadministration of Adex1CALacZ with Adex1CACTLA4IgG induced persistent hepatic expression of beta-Gal molecules, while administration of Adex1CALacZ alone induced transient expression of beta-Gal molecules. More importantly, on day 160 a secondary challenge with Adex1CALacZ was possible in mice treated with Adex1CALacZ plus Adex1CACTLA4IgG. Thus, we have demonstrated that (1) gene expression of a recombinant adenovirus, Adex1CACTLA4IgG, is persistent in liver and secondary administration of this adenovirus is possible, (2) coadministration of Adex1CACTLA4IgG virus with another adenovirus, AdexCALacZ, prolongs AdexCALacZ-mediated gene expression, and (3) Adex1CACTLA4IgG is useful for secondary challenge with Adex1CALacZ.

Abatacept↗
PubMed1998

Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients.

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P </= 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P </= 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P </= 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P </= 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM.

ADP-ribosyl Cyclase↗
PubMed1998

A phase I clinical and pharmacologic study of a carboplatin and irinotecan regimen combined with recombinant human granulocyte-colony stimulating factor in the treatment of patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: This Phase I study was designed to determine the toxicity and efficacy of a carboplatin and irinotecan (CPT-11) regimen with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support for patients with advanced nonsmall cell lung carcinoma. METHODS: Treatment consisted of carboplatin administered intravenously (i.v.) on Day 1 plus CPT-11 i.v. on Days 1, 8, and 15. The carboplatin dose was calculated using Calvert's formula, where the target area under the plasma concentration versus the time curve (AUC) was 5 or 6 mg x min/mL. rhG-CSF (2 microg/kg) was administered daily, except on Days 1, 8, and 15, until the leukocyte count exceeded 20,000/mm3 (10,000/mm3 after Day 16). Cycles were repeated every 4 weeks. Groups entered the trial at escalating CPT-11 and carboplatin dose levels of 60 mg/m2 and 5 mg x min/mL, 70/5 and 60/6. RESULTS: Twenty-one patients were enrolled in this study, of whom 20 were assessable for toxicity and therapeutic efficacy. Two of 6 patients experienced Grade 4 diarrhea at the 70/5 dose level, suggesting that this was the maximum tolerated dose (MTD). However, the 60/6 dose level was included because toxicities were very mild at the 60/5 dose level. At the 60/6 dose level, 1 of 6 patients experienced severe, life-threatening toxicity. Therefore, subsequent dose escalation was stopped and the study terminated. There were 7 responses (35%) among the 20 patients. At the 60/6 dose level (n=5), the observed carboplatin AUC after aiming for a target AUC of 6 was 5.9+/-0.9 mg x min/mL, as expected, although the AUCs of both CPT-11 and its active metabolite, SN-38, were lower than expected. CONCLUSIONS: The recommended doses for Phase II studies are 60 mg/m2 of CPT-11 and a target AUC of 5 mg x min/mL for carboplatin, plus rhG-CSF. The combination of AUC-based carboplatin and CPT-11 with rhG-CSF support appears to be an active regimen in the treatment of patients with NSCLC.

Adult↗
PubMed1998

A proteasome inhibitor lessens the increased aortic endothelin-1 content in deoxycorticosterone acetate-salt hypertensive rats.

Deoxycorticosterone acetate (DOCA)-salt-treated rats developed marked hypertension after 4 weeks with an increase in aortic endothelin-1. Treatment of DOCA-salt hypertensive rats with a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, significantly reduced the elevation in systolic blood pressure and the effect was accompanied by a decrease in aortic endothelin- content. Thus, a proteasome-dependent proteolytic pathway appears to play an important role in the enhanced production of endothelin-1 in blood vessels and the consequent increase in blood pressure in this model of hypertension.

Animals↗
PubMed1998

Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits.

Cholesteryl ester transfer protein (CETP) is the enzyme that facilitates the transfer of cholesteryl ester from high density lipoprotein (HDL) to apolipoprotein B (apoB)-containing lipoproteins. However, the exact role of CETP in the development of atherosclerosis has not been determined. In the present study, we examined the effect of the suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides (ODNs) against CETP targeted to the liver on the development of atherosclerosis in rabbits fed a cholesterol diet. The ODNs against rabbit CETP were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method to regulate liver gene expression. Twenty-two male Japanese White rabbits were used in the experiment. Eighteen animals were fed a standard rabbit chow supplemented with 0.3% cholesterol throughout the experiment for 16 weeks. At 8 weeks, they were divided into three groups (six animals in each group), among which the plasma total and HDL cholesterol concentrations did not significantly change. The control group received nothing, the sense group were injected with the sense ODNs complex, and the antisense group were injected with the antisense ODNs complex, respectively, for subsequent 8 weeks. ASOR. poly(L-lysine) ODNs complex were injected via the ear veins twice a week. Four animals were fed a standard rabbit diet for 16 weeks. The total cholesterol concentrations and the CETP mass in the animals injected with antisense ODNs were all significantly decreased in 12 and 16 weeks compared with those injected with sense ODNs and the control animals. The HDL cholesterol concentrations measured by the precipitation assay did not significantly change among the groups fed a cholesterol diet, and triglyceride concentrations did not significantly change in the four groups. However, at the end of the study, when the HDL cholesterol concentrations were measured after the isolation by ultracentrifugation and a column chromotography, they were significantly higher in the animals injected with antisense ODNs than in the animals injected with sense ODNs and in the control animals. A reduction of CETP mRNA and an increase of LDL receptor mRNA in the liver were observed in the animals injected with antisense ODNs compared with those injected with sense ODNs and the control animals. Aortic cholesterol contents and the aortic percentage lesion to total surface area were significantly lower in the animals injected with antisense ODNs than in the animals injected with sense ODNs and in the control animals. These findings showed for the first time that suppression of increased plasma CETP by the injection with antisense ODNs against CETP coupled to ASOR carrier molecules targeted to the liver could thus inhibit the atherosclerosis possibly by decreasing the plasma LDL + very low density lipoprotein (VLDL) cholesterol in cholesterol-fed rabbits.

Animals↗
PubMed1998

Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic beta cells develop insulin-dependent diabetes without insulitis.

We generated transgenic mice carrying the mouse type 2 nitric-oxide synthase (NOS2) cDNA under the control of the insulin promoter. Western and immunohistochemical analyses revealed that NOS2 was expressed abundantly in transgenic islets but not in control islets. When islets were isolated and cultured, high levels of nitrite were released from the transgenic islets. In transgenic mice, the beta cell mass was markedly reduced without the infiltration of macrophages or lymphocytes, and extensive DNA strand breaks were detected in the islets by in situ nick translation. All the transgenic mice developed hypoinsulinemic diabetes by 4 weeks of age, and treatment with an inhibitor of NOS2, aminoguanidine (200 mg/kg body weight every 12 h), prevented or delayed the development of diabetes. The present study shows that the production of nitric oxide by beta cell NOS2 plays an essential role in the beta cell degeneration.

Animals↗
PubMed1998

Cyclic ADP-ribose and inositol 1,4,5-trisphosphate as alternate second messengers for intracellular Ca2+ mobilization in normal and diabetic beta-cells.

Intracellular Ca2+ mobilization occurs in a variety of cellular processes and is mediated by two major systems, the inositol 1,4, 5-trisphosphate (IP3) and cyclic ADP-ribose (cADPR) systems. cADPR has been proposed to be a second messenger for insulin secretion induced by glucose in pancreatic beta-cells (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373). Here we show that the cADPR signal system for insulin secretion is replaced by the IP3 system in diabetic beta-cells such as ob/ob mouse islets and RINm5F cells. We measured the cADPR content in these beta-cells by radioimmunoassay and found that the increase of the cADPR content by glucose did not occur in ob/ob mouse islets and RINm5F cells, whereas the increased cADPR level by glucose was observed in normal rat and mouse islets. Microsomes of these diabetic beta-cells released Ca2+ in response to IP3 but not to cADPR. In the diabetic beta-cells, CD38 (ADP-ribosyl cyclase/cADPR hydrolase) and type 2 ryanodine receptor mRNAs were scarcely detected and, in contrast, an increased expression of IP3 receptor mRNAs was observed. The diabetic beta-cells secreted insulin rather by carbamylcholine than by glucose.

ADP-ribosyl Cyclase↗
PubMed1998

Endothelium is required for 12-hydroperoxyeicosatetraenoic acid-induced vasoconstriction.

The pharmacological effects of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) were examined using isolated canine basilar artery segments and isometric tension recording. 12-HPETE produced transient contraction of the artery segment while arachidonic acid or 12-hydroxyeicosatetraenoic acid (12-HETE) had a much lower potency. 12-HPETE-induced contraction which showed a requirement of a functional endothelium and a rapid insensitivity to re-administered 12-HPETE, was completely inhibited by the potassium channel blocker, glibenclamide. Other hydroperoxides did cross-desensitize the 12-HPETE-induced contraction, however, arachidonic acid or 12-HETE did not affect markedly. Here, we present that 12-HPETE is involved in the regulation of vascular tension via its effects on the endothelium.

Animals↗
PubMed1998

Clinical and molecular virological differences between fulminant hepatic failures following acute and chronic infection with hepatitis B virus.

Clinical and molecular biological characteristics were compared between patients who presented with fulminant hepatic failure following acute infection with hepatitis B virus (HBV) and those who developed hepatic failure during they carried HBV. The 11 patients with acute HBV infection had higher levels of alanine aminotransferase (mean +/- SD: 4943 +/- 2867 vs 1157 +/- 678 IU/L, P < 0.01), more often with a single peak (91% vs. 0%, P < 0.001), and lower total bilirubin level (15.3 +/- 4.4 vs 28.1 +/- 14.3 mg/1000 ml, P < 0.01) than the 13 patients with chronic HBV infection. Hepatitis B surface antigen was detected less often (55% vs. 100%, P < 0.05) and viral DNA polymerase less frequently (0% vs. 46%, P < 0.05) in the patients with acute than chronic HBV infection. Hepatitis B e antigen was detected in one (9%) patient with acute infection, less frequently than in six (46%) patients with chronic infection (P < 0.05). Mutations in the precore region was detected in HBV DNA clones from ten (91%) patients with acute infection and only in those from eight (62%) patients with chronic infection. All HBV DNA clones from the five (38%) patients with chronic infection that did not have precore mutations, however, possessed mutations in the core promoter. These results indicate that HBV mutants incapable of translating hepatitis B e antigen would play a major role in fulminant hepatic failure occurring after acute HBV infection. In contrast, HBV variants with core promoter mutations for reducing the transcription of hepatitis B e antigen would play an additional role in fulminant hepatic failure developing during chronic infection.

Acute Disease↗
PubMed1998

Infection with an unenveloped DNA virus (TTV) associated with posttransfusion non-A to G hepatitis in hepatitis patients and healthy blood donors in Thailand.

An unenveloped single-stranded DNA virus (TTV) has been reported in association with posttransfusion and acute and chronic hepatitis of unknown etiology. DNA of TTV was tested for by polymerase chain reaction with heminested primers in 127 patients with chronic liver disease and 105 healthy blood donors in Thailand. TTV DNA was detected in 23 (59%) of the 39 patients without hepatitis B surface antigen or RNA of hepatitis C virus, at a frequency significantly higher than the detection in 21 (36%) of the 59 patients with HBsAg (P < 0.05) or in 38 (36%) of the 105 blood donors (P< 0.05). Among patients with chronic liver disease, TTV DNA occurred in those with liver cirrhosis and hepatocellular carcinoma more frequently than in those with chronic hepatitis (35 of 65 or 54% vs. 20 of 62 or 32%, P< 0.05). There were no differences in age, sex, or markers of infection with hepatitis B, C and GBV-C/HGV viruses, indicating a mode of transmission of TTV different from those of the other hepatitis viruses. Phylogenetic analysis indicated three different genotypes of TTV with six distinct subtypes in Thailand. Based on these results, TTV would have a role in the development of chronic liver disease of unknown etiology in Thailand.

Base Sequence↗
PubMed1998

Clinical management of nonpalpable or small breast masses by fine-needle aspiration biopsy (FNAB) under ultrasound guidance.

BACKGROUND AND OBJECTIVES: Open breast biopsy of palpable breast masses is widely accepted. Now, the use of high-resolution, real-time ultrasound (US) makes it easy to detect nonpalpable or small breast nodules, as well as palpable breast masses. METHODS: We performed fine-needle aspiration biopsy (FNAB) under US guidance to manage the nonpalpable or small breast masses detected by US examination and to distinguish between benign and malignant tumors. To investigate the usefulness and sensitivity of FNAB under US guidance, we reviewed a total of 137 FNAB records for cases diagnosed between January 1993 and December 1994. RESULTS: Fifty-five cases were classified as benign, 70 as atypical/indeterminate, 1 as suspicious/probably malignant, 6 as malignant, and 5 as unsatisfactory. Of these, five cases were confirmed as malignant, but one case showed no malignancy at surgery. Four cases were nonpalpable breast cancer, two were in stage 0, and two were in stage I. One case in the suspicious/probably malignant group on the initial FNAB was shown to be malignant by re-aspiration on follow-up study. The sensitivity of FNAB under US guidance was 83.3% (5/6) and the specificity was 99.2% (125/126). The diagnostic accuracy was 83.3% (5/6) and the negative predictive value was 99.2% (125/126). CONCLUSIONS: FNAB under US guidance is useful for the management of nonpalpable or small breast masses; it is sensitive for distinguishing between benign and malignant tumors and may reduce unnecessary surgical procedures and replace conventional manual aspiration biopsy.

Adult↗
PubMed1998

Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis.

OBJECTIVE: To examine the importance of interleukin-12 (IL-12) as a factor in the interferon-gamma (IFNgamma)-dominant T cell cytokine response in the synovial tissue of patients with rheumatoid arthritis (RA). METHODS: The expression of IL-12 in synovial tissue samples from patients with chronic RA (> or = 2 years) was compared with that in samples from osteoarthritis (OA) patients by detection of IL-12 p40 messenger RNA (mRNA) using reverse transcriptase-polymerase chain reaction, measurement of IL-12 p70 protein in culture supernatants of tissue cells by immunoassay, and immunostaining of tissue sections with anti-IL-12 p70. The production of IFNgamma by RA synovial tissue cells cultured with or without IL-12 was determined. In addition, T cells were obtained 14 days after culturing RA synovial tissue cells with IL-2 alone or with IL-2 plus IL-12, neutralizing anti-IL-12, or IL-4, and cytokine patterns (i.e., IFNgamma and IL-4 levels) were determined by stimulating cells for 24 hours with anti-CD3 plus phorbol myristate acetate. RESULTS: Synovial tissues from RA patients more strongly expressed IL-12 p40 mRNA than did OA tissues. Dissociated tissue cells from 21 of 37 RA patients spontaneously released detectable amounts of IL-12 p70 (> or = 12.5 pg/ml) in culture, whereas production of IL-12 by OA tissues was limited. By immunohistochemical analysis, IL-12-producing cells were localized mainly in the sublining layer of RA synovium, and mostly expressed the CD68 antigen. Levels of IFNgamma production by RA synovial tissue cells were potently and selectively enhanced by IL-12. The ability of IL-2-expanding synovial T cells to produce IFNgamma was augmented by costimulation with IL-12 and diminished by anti-IL-12, while it was not affected by IL-4. CONCLUSION: These data suggest that IL-12, produced mainly by macrophage-lineage cells, may be involved in IFNgamma-dominant cytokine production by infiltrating T cells in joints with chronic RA.

Arthritis, Rheumatoid↗
PubMed1998

Human lens epithelial cell line.

Although primary cultures of human lens epithelial (HLE) cells provide important information concerning the role of epithelium in normal lens and cataract formation, the lack of a cell line precludes a broad range of studies on the metabolism and molecular biology of these cells. We have, therefore developed an HLE cell line. Primary cultures of HLE cells were transfected with plasmid vector DNA containing a large T antigen of SV40. The immortalized cells were characterized with regard to morphology, growth rate, karyotype, and expression of crystallins, aldose reductase and other enzymes. A single clone of the immortalized cells, SRA 01/04, formed a monolayer and grew constantly over 130 passages. Isozyme phenotype showed that SRA 01/04 was of human origin, and the chromosome counts were in the hypotetraploid range. Western blot analysis showed that the cells expressed a very low level of crystallins (alphaA and betaB2) and aldose reductase. Messenger RNA (mRNA) for both alpha and beta crystallins was detected by reverse transcription polymerase chain reaction (RT-PCR) in both early and late passages. Sequence analysis of the PCR products, corresponding to alphaA and betaB2 crystallins in the cell line and in primary cultures of HLE, revealed a 100% match with published human alphaA and betaB2 sequences. These characteristics were unchanged in the cell line in early and late passages. This is the first report of the presence of alphaA and transcripts of mRNA for both alphaA and betaB2 in an established human cell line. This new HLE cell line makes it possible to undertake many future studies on the role of epithelium in lens and cataract formation.

Aldehyde Reductase↗
PubMed1998

Combined surgery for mitral regurgitation associated with extensive annular calcification and left main coronary artery disease.

Although extensive calcification of the mitral annulus is encountered infrequently, it presents a formidable problem in mitral valve surgery. We describe a case of severely calcified mitral annulus associated with grade IV mitral regurgitation in addition to left main coronary artery disease. The patient was a 66-year-old woman who successfully underwent thorough excision of the calcified bar, annular reconstruction with a autologous pericardial strip, mitral valve replacement with a mechanical prosthesis, and double coronary artery bypass grafting using arterial grafts.

Aged↗
PubMed1998

[Coronary artery bypass grafting in cases with poor left ventricular function].

From January 1987 through June 1992, 18 patients with poor left ventricular function (left ventricular ejection fraction [LVEF] less than 0.3) underwent elective isolated primary coronary artery bypass surgery. The mean age was 56.4 years (range, 46 to 72 years), and 15 were males and 3 were females. Mean pre-operative LVEF measured by ventriculography was 0.26 +/- 0.03 (range, 0.19 to 0.30). Sixteen patients (88.9%) had a prior myocardial infarction and 9 (50%) had a history of congestive heart failure. Complete revascularization was the goal for all patients, and the mean number of bypass grafts was 3.0 +/- 0.8 per patient. The left anterior descending coronary artery (LAD) was revascularized in all patients. There were no operative deaths. Post-operative LVEF improved significantly from 0.26 +/- 0.03 to 0.42 +/- 0.11 (p = 0.0002), and the regional left ventricular wall motion improved in the diaphragmatic and posterobasal regions (p < 0.01). The patency of the grafts was 93.9% in all, and 100% for LAD. The mean follow-up period was 77 months, and the overall actuarial survival rate was 88.9% at 10 years. During follow-up periods, two patients died of congestive heart failure (CHF), and two required three rehospitalizations because of CHF. The overall cardiac event free rate was 75.8% at 10 years. In patients with poor left ventricular function, surgical revascularization can be performed safely, but congestive heart failure sometimes occurs during follow-up periods and may be the cause of death. Therefore alternate forms of therapy such as cardiac transplantation and/or TMLR should be considered in selected patients.

Aged↗
PubMed1998

A missense mutation in the CD38 gene, a novel factor for insulin secretion: association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro.

Cyclic adenosine 5'diphosphate-ribose (cADPR) is thought to have a second messenger role in insulin secretion through mobilisation of Ca2+. As human lymphocyte antigen CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activity, it may be important in glucose-induced insulin secretion in islets. Thirty one randomly selected Japanese patients with Type II diabetes mellitus who had first-degree and/or second-degree relative(s) with Type II diabetes mellitus were screened for mutations of this gene using single-stranded conformation polymorphism. Two variant patterns in exon 3 and exon 4 of the CD38 gene were identified. The variant in exon 3 resulted in an amino acid substitution from Arg140 (CGG) to Trp (TGG). The Arg140Trp mutation was observed in 4 of 31 patients, and allele frequencies were significantly different in patients and the control subjects (p = 0.004). One patient with this mutation has two missense mutations on beta cell/liver glucose transporter (GLUT2) gene; her mother, who has impaired glucose tolerance, also has this mutation on the CD38 gene and one missense mutation on the GLUT2 gene. Enzyme activity studies using COS-7 cells expressing the Arg140Trp mutation showed a reduction in ADP-ribosyl cyclase and cADPR hydrolase activity of around 50%. The Arg140Trp mutation on CD38 thus appears to contribute to the development of Type II diabetes mellitus via the impairment of glucose-induced insulin secretion in the presence of other genetic defects.

ADP-ribosyl Cyclase↗
PubMed1998

Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae.

PURPOSE: Carboplatin doses can be individualized using the formula of Calvert et al. (Calvert formula) dose (mg) = area under the plasma concentration versus time curve (AUC) x [glomerular filtration rate (GFR) + 25]. Creatinine clearance (Ccr), either measured by the 24-h method or calculated by the formula of Cockcroft and Gault [Cockcroft-Gault (CG) formula], is often substituted for the GFR. The CG formula is based on patient weight, age and sex, and the serum creatinine (Cr) concentration. Another method for predicting carboplatin clearance (CL) using patient characteristics has also been proposed by Chatelut et al. (Chatelut formula). This study was undertaken to evaluate the performance of the three formulae in predicting standard- and low-dose carboplatin pharmacokinetics. METHODS: A total of 52 patients with advanced lung cancer were enrolled in this pharmacokinetic study; 37 received standard-dose carboplatin and 25 received low-dose carboplatin. The Cr concentration was measured using an enzymatic assay. The three formulae were used to predict carboplatin CL. The median absolute percent error (MAPE) for each formula was evaluated by comparing the calculated and observed CL. For comparison of AUCs, free platinum plasma concentrations were measured at intervals up to 24 h after carboplatin administration. AUCs were determined and compared with predicted values. RESULTS: In the standard-dose carboplatin group, the MAPEs for the prediction of carboplatin CL from the 24-h Calvert, CG-Calvert and Chatelut formulae were 13%, 12% and 23%, respectively. In the low-dose carboplatin group, the corresponding MAPEs were 27%, 18% and 44%, respectively. Observed standard-dose carboplatin AUCs after aiming for target AUCs of 5 and 6 mg x min/ml using the Calvert formula based upon the 24-h Ccr were 5.3+/-0.8 and 5.9+/-0.8, respectively, indicating a small and acceptable bias compared with that predicted from the dosing formula. CONCLUSIONS: The pharmacokinetics of standard-dose carboplatin were accurately predicted by the Calvert formula based upon either 24-h or CG-calculated Ccr, but not by the Chatelut formula. Either CG-calculated or 24-h Ccr can be substituted for the GFR in the Calvert formula for the determination of individual doses. The poor predictability of the Chatelut formula found in this study might be the result of a differences in either the Cr assay or the patient population. Therefore, formulae which attempt to estimate GFR are not necessarily valid if either the Cr assay or the patient population is changed.

Age Factors↗