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S Kaul

Publications and source records attributed to S Kaul.

At least 55 records · Page 3Linked to original sources
PubMed2001

Stereoselective metabolism and pharmacokinetics of tegafur.

OBJECTIVES: UFT is composed of racemic tegafur (FT), a prodrug of 5-fluorouracil (5-FU), and uracil in a fixed molar combination (1:4). FT contains a chiral center and has two stereoisomers, R-FT and S-FT. The objectives of this study were to assess the stereoselectivity in the metabolism of FT to 5-FU in vitro and to determine stereoselective differences in the disposition of FT in vivo. METHODOLOGY: R-FT, S-FT, and racemic FT were incubated with pooled human liver microsomes and S-9 fraction for a period of up to 30 min for in vitro studies. For pharmacokinetics, plasma samples were obtained from fasted cancer patients over a period of 24 h after oral administration of 200 mg UFT. Samples from in vitro studies and patient plasma samples were analyzed for FT using a validated achiral and a chiral assay, and for 5-FU using a validated GC/MS assay. RESULTS: R-FT was metabolized at a rate 5.6-times faster than S-FT by human liver microsomes. Similarly, stereoselective metabolism of R-FT was also seen in the S-9 incubations. In cancer patients, the peak plasma concentrations (C(max)) and the time to reach C(max) (T(max)) were similar for the two isomers after the administration of UFT suggesting no apparent differences in their absorption kinetics. However, the area under the curve from zero to infinity [AUC(INF)] and the terminal elimination half-life (T-HALF) values for R-FT were about 4.6- and 4.4-fold lower compared to S-FT, respectively, suggesting the preferential elimination of R-FT. The T-HALF of racemic FT (8.3 h) was comparable to the T-HALF of S-FT (10.3 h) which indicated that the kinetics of the racemate are governed by S-FT. The active cytotoxic moiety, 5-FU, exhibited formation rate limited kinetics from R-FT because the T-HALF of 5-FU (3.4 h) was similar to that of R-FT (2.4 h). CONCLUSIONS: The R-isomer of FT is preferentially metabolized to 5-FU compared to the S-isomer in vitro. The distinct kinetic profiles of the stereoisomers of FT following the administration of UFT is apparently due to the stereoselective disposition of the R-isomer relative to the S-isomer. These data suggest that the R-isomer of FT is worthy of further preclinical and clinical evaluation for safety, efficacy, and pharmacokinetics.

Antimetabolites, Antineoplastic↗
PubMed2001

Evaluation of MUC1 and EGP40 in bone marrow and peripheral blood as a marker for occult breast cancer.

Mucin1 (MUCI) is a class of high molecular weight glycoproteins found in the cell membranes of human epithelial cells. Epithelial glycoprotein 40 (EGP40) is a homophilic cell-cell adhesion molecule and expressed on the surface of most simple epithelial cells and the majority of carcinomas. We analyzed the expression of MUC1 and EGP40 in human bone marrow (BM) and peripheral blood (PB) by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry (ICC). Eight BM and 95 PB samples from healthy donors, 39 BM and 17 PB samples from patients with haematological malignancies and 45 BM samples from patients with breast cancer were analyzed. MUC1 mRNA and EGP40 mRNA and protein were detected in BM samples and PB samples from healthy donors and from patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and chronic myelogenous leukaemia (CML). The positive cells showed erythroblast-like and plasmacell-like morphology by immunocytochemistry. The MUC1 and EGP40 nested PCR were positive in 83.3% (10/12) and in 100% (33/33) respectively of BM from patiens with breast cancer who had no evidence of distant metastases. It is concluded that MUC1 and EGP40 is expressed in haematopoietic tissues and haematological malignancies. Therefore, MUC1 and EGP40 expression as a marker for detection of breast cancer cells and micrometastatic epithelial cells in BM and PB is not specific using RT-PCR technique and immunocytochemistry.

Antigens, Neoplasm↗
PubMed2001

Bladder preservation in adult classic exstrophy: early results of four patients.

OBJECTIVES: To report our experience with the treatment of classic exstrophy of the bladder in a small series of adult patients using ileocystoplasty, bladder neck reconstruction, and abdominal wall closure with flaps. The presentation of exstrophy of the bladder in adulthood is rare. The problems encountered include difficulty in abdominal closure, malignant potential, and upper tract dysfunction. The treatment of choice has been cystectomy with urinary diversion in all reported cases. METHODS: We treated 4 adult male patients with classic exstrophy of the bladder and complete epispadias. They had not received any previous treatment. Multiple random bladder biopsies revealed nonspecific inflammatory changes with focal areas of keratinization. Three patients were treated in two stages. The first stage included ileocystoplasty, bladder neck reconstruction, and abdominal wall closure with the use of flaps. The epispadias was repaired in the second stage. In 1 patient, the reconstruction was completed in a single stage. RESULTS: All patients were continent at the last follow-up visit, with three using self-catheterization and one voiding spontaneously. The renal parameters and ultrasound scans were normal at a follow-up of 2 to 48 months. Cystoscopy performed at 6 months postoperatively revealed normal-looking mucosa in 2 patients and mild inflammation in 1 patient. Three patients were satisfied with the cosmetic results and one complained of the small size of his penis. All patients were evaluated by psychiatrists and revealed anxiety disorders preoperatively. After surgery, all demonstrated improved social interaction. CONCLUSIONS: Vesical preservation with primary reconstruction of bladder exstrophy in adults is safe and feasible in the absence of significant histologic changes in the bladder mucosa. Abdominal closure can be achieved without difficulty with the use of transposition flaps. However, these patients require strict follow-up to detect malignant transformation at an early stage.

Abdominal Muscles↗
PubMed2001

Pretargeting of human mammary carcinoma xenografts with bispecific anti-MUC1/anti-Ga chelate antibodies and immunoscintigraphy with PET.

We recently demonstrated the feasibility of combining enhanced tumor-to-tissue contrast and PET imaging for immunoscintigraphic tumor localization in pancreas and colon carcinoma bearing nude mice. Contrast enhancement was obtained with a multistep targeting technique that consists of the sequential administration of an antitumor/antihapten bispecific antibody (BS-MAb), a blocker to saturate the antihapten binding sites of the BS-MAb that remains in circulation, and a low molecular weight Ga chelate, labeled with the positron emitter 68Ga, which serves as the hapten. To evaluate the efficacy of this pretargeting technique for breast cancer localization, we synthesized a BS-MAb from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12 which reacts with the vast majority of human breast carcinomas, and the F(ab') fragment of an anti-Ga chelate MAb using a bifunctional chemical linker. The BS-MAb was tested for its affinity and its biokinetics in nude mice bearing a human mammary carcinoma. Equilibrium binding of the BS-MAb for mammary carcinoma cells was low (1.2 x 10(7) M(-1)) while the binding capacity of cells was high (8.4 x 10(6) BS-MAbs per cell). Tumor uptake of the 67Ga labeled chelate in pretargeted animals was to 5.8 +/- 0.8% iD/g resulting in a tumor-to-blood ratio of 2.6 at 1h postinjection. This compares with a ratio of 0.65 and 0.85 obtained with 125I-labeled native 12H12 at 24h and 48h postinjection. No difference in the tumor uptake of both the 68Ga and 67Ga labeled chelate was observed. PET imaging of mice, started 1h postinjection of the 68Ga chelate, clearly visualized all tumors.

Animals↗
PubMed2001

Tandem high-dose chemotherapy in high-risk primary breast cancer: a multivariate analysis and a matched-pair comparison with standard-dose chemotherapy.

Stem cell-supported high-dose chemotherapy (HDCT) is currently being evaluated in patients with high-risk primary breast cancer (HRPBC), as defined by extensive axillary lymph node involvement. Conclusive results from randomized studies with sufficient patient numbers and follow-up are pending. We retrospectively analyzed 144 HRPBC patients enrolled in a single-arm trial of tandem HDCT at the University of Heidelberg to evaluate the prognostic value of nodal ratio, HER2/neu status, and cytokeratin-positive bone marrow cells and to compare the outcomes of these patients with those of a conventionally treated control group of 91 patients matched by nodal ratio, tumor size, combined hormone-receptor status, and HER2/neu status. The tandem HDCT regimen consisted of 2 cycles of induction chemotherapy followed by 2 cycles of blood stem cell-supported high-dose ifosfamide, 12 g/m2; carboplatin, 900 mg/M2; and epirubicin, 180 mg/m2. Conventionally treated patients received a regimen containing anthracycline without taxanes (52 patients) or CMF (cyclophosphamide, methotrexate, and 5-flurouracil; 39 patients). With a median follow-up of 3.8 years, disease-free, distant disease-free, and overall survival rates were 62%, 65%, and 84%, respectively. In univariate analysis, besides the hormone receptor status (P = .007), HER2/neu overexpression was the strongest predictor of earlier death (P = .017). In multivariate analysis, a nodal ratio of > or =0.8 was found to be the only independent predictor of relapse (relative risk [RR] = 2.09; 95% confidence interval [CI], 1.21-3.60; P = .008) and only the absence of hormone receptors was associated with earlier death (RR = 3.59; 95% CI, 1.45-8.86; P = .006). Despite a trend toward later distant relapse after HDCT compared with standard-dose chemotherapy with a median follow-up of 3 years (P = .059), thus far, matched-pair analysis has not demonstrated significantly better survival rates after HDCT in all matched patients (P = .786) or in the subgroups of anthracycline-treated patients and patients with and without overexpression of HER2/neu. So far, the follow-up time has been too short to draw definite conclusions; however, patients with a nodal ratio of > or =0.8, receptor-negative tumors, or HER2/neu overexpression are at high risk for relapse and death, irrespective of the kind of adjuvant chemotherapy.

Adolescent↗
PubMed2001

Delivery of drugs with ultrasound.

In this article we discuss the potential role of microbubbles, traditionally used as ultrasound contrast agents, for site-specific drug delivery. To reach this goal, microbubbles capable of carrying a drug payload are being developed. To ensure that these microbubbles reach sufficient local concentration at disease sites, specific targeting for diseased tissues can be accomplished using several strategies. These strategies rely on either the intrinsic properties of microbubble shells or conjugation of monoclonal antibodies or other ligands to these shells that recognize antigens expressed in regions of disease. Site-specific delivery of antiinflammatory, antineoplastic, and thrombolytic drugs with microbubbles can be further enhanced by the ability to locally destroy microbubbles within an acoustic field, thereby releasing drugs and improving drug efficacy without systemic adverse effects. In the case of thrombi, ultrasound-mediated microbubble destruction also may facilitate the process of clot lysis. This review also will consider current limitations and technological advances required for the development of this field.

Contrast Media↗
PubMed2001

Concept, development, administration, and analysis of a certifying examination in echocardiography for physicians.

In 1993, the American Society of Echocardiography appointed a committee to develop an objective examination in echocardiography. In 1995, a pilot of this examination was administered, with operational examinations offered each year from 1996 to 1999. This report describes the development of the examination, including its underlying philosophy, the test itself, and the scoring process, and includes results from the first 4 examinations. To date, 1266 physicians have taken the examination, and roughly 60% of those have passed. The number of echocardiograms performed or interpreted each week had the largest effect on examination scores; the effects of both the amount of training and the practice discipline were small but significant. The evolution of the original committee and new directions for the testing organization are also discussed.

Certification↗
PubMed2001

Mechanism of myocardial dysfunction in the presence of chronic coronary stenosis and normal resting myocardial blood flow: clinical implications.

In chronic coronary artery disease, resting myocardial dysfunction can exist despite normal resting transmural myocardial blood flow (MBF). We hypothesized that this phenomenon occurs because of diminished endocardial MBF reserve. MBF (measured with radiolabeled microspheres) and wall thickening (WT) (measured with echocardiography) were assessed in 7 dogs after the development of severe left ventricular dysfunction caused by placement of ameroid constrictors on the left anterior descending (LAD) and left circumflex arteries and 3 weeks after selective bypass surgery to the LAD. Before surgery, the mean transmural MBF at rest and at peak dobutamine dose in the LAD bed were 1.1 +/- 0.5 and 3.0 +/- 1.5 mL/min per gram, respectively, and were not significantly changed after LAD bypass. The resting endocardial-to-epicardial MBF ratio (EER) was also normal before bypass (1.5 +/- 0.6) and remained unchanged after surgery. The prebypass EER at peak dobutamine dose, however, was markedly diminished in the LAD bed (0.7 +/- 0.3) and improved significantly (1.3 +/- 0.8, P <.01) after surgery. Resting WT in the LAD bed also improved to normal levels (36% +/- 4% versus 13% +/- 6%, P =.0001) and no longer demonstrated a biphasic response to dobutamine. In comparison, the nonbypassed left circumflex bed continued to show reduced resting WT (12% +/- 6%), a biphasic response to dobutamine, and abnormal EER during rest and dobutamine (0.7 +/- 0.3). We conclude that persistent myocardial dysfunction in the presence of normal resting transmural MBF can occur as a result of diminished endocardial MBF reserve, with transmural MBF reserve remaining normal.

Animals↗
PubMed2001

Quantification of myocardial perfusion and determination of coronary stenosis severity during hyperemia using real-time myocardial contrast echocardiography.

Although regional myocardial perfusion can be currently quantified with myocardial contrast echocardiography (MCE) by using intermittent harmonic imaging (IHI), the method is tedious and time-consuming in the clinical setting. We hypothesized that regional myocardial perfusion can be quantified and the severity of coronary stenosis determined during hyperemia with MCE using real-time imaging (RTI) where microbubbles are not destroyed. Six open-chest dogs were studied during maximal hyperemia induced by adenosine in the absence or presence of coronary stenoses varying from mild to severe. Myocardial blood flow (MBF) was measured at each stage by using radiolabeled microspheres. MCE was performed using both IHI and RTI. Data for the latter were acquired in both end-systole and end-diastole. No differences were found between myocardial flow velocity (MFV) derived from IHI and RTI when end-systolic frames were used for the latter. MFV was consistently higher for RTI (P <.01) when end-diastolic frames were used. A linear relation was noted between MFV and radiolabeled microsphere-derived MBF ratios from the stenosed and the normal beds when end-systolic frames were used for RTI (r = 0.78, P <.001), whereas no relation was found when end-diastolic frames were used (r = 0.08, P =.78). The scatter for assessing MBF (A.beta) was minimal for IHI and RTI (9%-10%) with end-systolic frames, whereas that for RTI with end-diastolic frames was large (30%). Furthermore the correlation with radiolabeled microsphere-derived MBF was significantly (P <.01) weaker with RTI when end-diastolic frames were used (r = 0.53) than when end-systolic frames (r = 0.94) or IHI was used (r = 0.99). Data acquisition for IHI was 10 minutes, whereas it was 8 seconds for RTI. Thus, RTI can be used to quantify regional myocardial perfusion and stenosis severity during MCE. Only end-systolic frames, however, provide accurate data. RTI offers a rapid and easy means of assessing regional myocardial perfusion with MCE.

Animals↗
PubMed2001

A novel gene encoding a 54 kDa polypeptide is essential for butane utilization by Pseudomonas sp. IMT37.

Twenty-three propane- and butane-utilizing bacteria were isolated from soil samples collected from oilfields. Three of them have been identified as Rhodococcus sp. IMT35, Pseudomonas sp. IMT37 and Pseudomonas sp. MT40. SDS-PAGE analysis of the membrane of Rhodococcus sp. IMT35 revealed the presence of at least four polypeptides induced by propane. Polyclonal antibody raised against a 58 kDa polypeptide from Rhodococcus sp. IMT35 specifically detected bacteria which were actively utilizing propane or butane. Immunoscreening of a genomic library in lambdagt11 with this antibody resulted in isolation of a clone containing a 4.9 kb EcoRI genomic DNA fragment. This 4.9 kb DNA fragment was found to hybridize specifically with organisms which could grow on propane or butane. This fragment could therefore be used as a probe for detection of such bacteria. A 2.3 kb fragment having an ORF encoding a polypeptide of 54 kDa was identified by screening a genomic library of Pseudomonas sp. IMT37 with this 4.9 kb EcoRI fragment. The sequence of the ORF (designated orf54) was found to be novel. Primer extension and S1 nuclease mapping showed that transcription of the ORF starts at base 283 and it had sequences upstream similar to that of a Pseudomonas promoter (-12, -24 type). Disruption of the ORF by a kanamycin ('kan') cassette prevented the organism from growing on any alkane but did not affect its ability to utilize the respective alkanols and acids, indicating that alcohol dehydrogenase and subsequent steps in the pathway remained unaltered. The mutants had no detectable level of butane monooxygenase activity. Therefore, the product of this gene plays a crucial role in the first step of the pathway and is an essential component of monooxygenase. The findings imply that this bacterium either employs a common genetic and metabolic route or at least shares the product of this gene for utilization of many alkanes.

Bacterial Proteins↗
PubMed2001

Determination of dosing guidelines for stavudine (2',3'-didehydro-3'-deoxythymidine) in children with human immunodeficiency virus infection.

The results of the development of dosing guidelines for stavudine in human immunodeficiency virus (HIV)-infected children are summarized. Included in the integrated analyses were 21 and 33 HIV-infected pediatric and adult patients, respectively, from three phase I-II studies. Data for 21 children and 18 adults who received intravenous doses of 0.125 to 2 and 0.5 to 1 mg/kg of body weight, respectively, were used for the determination of dosing guidelines; exposure data for 16 children and 15 adults who received oral doses of 1 to 2 and 0.5 to 1 mg/kg/day, respectively, were used to validate the dosing recommendations for children. Significant relationships were observed between total body clearance (in milliliters per minute) in children and adults combined and demographic parameters of age, body weight, and body surface area (R(2) = 0.77 to 0.80; P = 0.0001). Models of approximated pediatric dose based on clearance values and direct adult exposure yielded a stavudine dosage of 2 mg/kg/day for children of < or =30 kg of body weight and 1 mg/kg/day (adult dose) for children of >30 kg of body weight.

Administration, Oral↗
PubMed2001

Mechanism of reversible (99m)Tc-sestamibi perfusion defects during pharmacologically induced vasodilatation.

Reversible perfusion defects on (99m)Tc-sestamibi imaging during hyperemia are thought to occur due to myocardial blood flow (MBF) "mismatch" between regions with and without stenosis. We have recently shown that myocardial blood volume (MBV) distal to a stenosis decreases during hyperemia, resulting in a reversible perfusion defect on myocardial contrast echocardiography (MCE). In this study, we hypothesized that a reversible perfusion defect on (99m)Tc-sestamibi imaging during hyperemia results from the same mechanism. We tested our hypothesis under the following conditions: 1) increases in MBF in the absence of changes in MBV by using direct intracoronary infusion of adenosine (group I, n = 10 dogs); 2) decrease in MBV despite an increase in MBF by left main infusion of adenosine proximal to a noncritical coronary stenosis placed on either coronary artery (group II, n = 13 dogs); and 3) reduction in both resting MBF and MBV by placement of a severe stenosis (group III, n = 7 dogs). In group I dogs, no difference in MBV or (99m)Tc-sestamibi uptake was found between the two coronary beds despite an up to fourfold increase in MBF in one bed with adenosine. In group II dogs, MBV distal to the stenosis decreased during hyperemia despite a twofold increase in mean MBF. A good correlation was found between (99m)Tc-sestamibi uptake and MBV ratios from the stenosed versus normal bed (r = 0.91, P < 0.001). In group III dogs, both MBF and MBV were decreased in the stenosed bed at rest with a good correlation noted between (99m)Tc-sestamibi uptake and MBV ratios from the stenosed versus normal bed (r = 0.92, P = 0.004). We conclude that reversible defects on (99m)Tc-sestamibi during vasodilator stress imaging are related to decreases in MBV distal to a stenosis and not to "flow mismatch" between beds. The decrease in MBV results in reduced (99m)Tc-sestamibi uptake during hyperemia.

Adenosine↗
PubMed2001

Intravenous magnesium in experimental stent thrombosis in swine.

We investigated the effects of magnesium on acute platelet-dependent stent thrombosis in an ex vivo porcine arteriovenous shunt model of high-shear blood flow. Control nitinol stents were expanded to 2 mm in diameter in a tubular perfusion chamber interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100 s(-1) for 20 minutes (n=156 perfusion runs in 10 swine). Animals were treated with intravenous heparin or MgSO(4) alone (2 g bolus over 20 minutes, followed by 2 g/h infusion) and combined heparin plus MgSO(4) in random fashion. Effects on thrombus weight (TW), platelet aggregation, bleeding time, activated clotting time, mean arterial blood pressure, and heart rate were quantified. Data points in the magnesium-treated animals were examined within 20 minutes after bolus (Mg-early) and >40 minutes after bolus (Mg-late). Stent TW (20+/-3 mg, pretreatment) was reduced by 42+/-21%, 47+/-19%, 48+/-16%, 67+/-12%, and 86+/-8% in the groups treated with Mg-early alone, Mg-late alone, heparin alone, heparin+Mg-early, and heparin+Mg-late, respectively (all P<0.001 versus pretreatment, P<0.001 for heparin+Mg-early and Mg-late versus heparin or magnesium alone, and P<0.05 for heparin+Mg-late versus heparin+Mg-early, ANOVA). Magnesium had no significant effect on platelet aggregation, activated clotting time, or bleeding time. There were no significant effects on heart rate or mean arterial blood pressure. The serum magnesium level was inversely correlated with TW (r=-0.70, P=0.002). In conclusion, treatment with intravenous MgSO(4) produced a time-dependent inhibition of acute stent thrombosis under high-shear flow conditions without any hemostatic or significant hemodynamic complications. Thus, magnesium may be an effective agent for preventing stent thrombosis.

Animals↗
PubMed2001

Oral bioavailability and disposition of [14C]omapatrilat in healthy subjects.

The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This single-dose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of omapatrilat averaged 31%. Total body clearance of omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady-state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first-pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of omapatrilat. Plasma concentrations of omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.

Absorption↗
PubMed2001

Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment.

Despite intensive study, the relation between insulin's action on blood flow and glucose metabolism remains unclear. Insulin-induced changes in microvascular perfusion, independent from effects on total blood flow, could be an important variable contributing to insulin's metabolic action. We hypothesized that modest, physiologic increments in plasma insulin concentration alter microvascular perfusion in human skeletal muscle and that these changes can be assessed using contrast-enhanced ultrasound (CEU), a validated method for quantifying flow by measurement of microvascular blood volume (MBV) and microvascular flow velocity (MFV). In the first protocol, 10 healthy, fasting adults received insulin (0.05 mU. kg(-1). min(-1)) via a brachial artery for 4 h under euglycemic conditions. At baseline and after insulin infusion, MBV and MFV were measured by CEU during continuous intravenous infusion of albumin microbubbles with intermittent harmonic ultrasound imaging of the forearm deep flexor muscles. In the second protocol, 17 healthy, fasting adults received a 4-h infusion of either insulin (0.1 mU. kg(-1). min(-1), n = 9) or saline (n = 8) via a brachial artery. Microvascular volume was assessed in these subjects by an alternate CEU technique using an intra-arterial bolus injection of albumin microbubbles at baseline and after the 4-h infusion. With both protocols, muscle glucose uptake, plasma insulin concentration, and total blood flow to the forearm were measured at each stage. In protocol 2 subjects, tissue extraction of 1-methylxanthine (1-MX) was measured as an index of perfused capillary volume. Caffeine, which produces 1-MX as a metabolite, was administered to these subjects before the study to raise plasma 1-MX levels. In protocol 1 subjects, insulin increased muscle glucose uptake (180%, P < 0.05) and MBV (54%, P < 0.01) and decreased MFV (-42%, P = 0.07) in the absence of significant changes in total forearm blood flow. In protocol 2 subjects, insulin increased glucose uptake (220%, P < 0.01) and microvascular volume (45%, P < 0.05) with an associated moderate increase in total forearm blood flow (P < 0.05). Using forearm 1-MX extraction, we observed a trend, though not significant, toward increasing capillary volume in the insulin-treated subjects. In conclusion, modest physiologic increments in plasma insulin concentration increased microvascular blood volume, indicating altered microvascular perfusion consistent with a mechanism of capillary recruitment. The increases in microvascular (capillary) volume (despite unchanged total blood flow) indicate that the relation between insulin's vascular and metabolic actions cannot be fully understood using measurements of bulk blood flow alone.

Adult↗
PubMed2001

[Mediator release assay of rat basophil leukemia cells as alternative for passive cutaneous anaphylaxis testing (PCA) in laboratory animals].

Passive cutaneous anaphylaxis (PCA) is an animal model for inflammatory reactions in Type I allergy. An in vitro assay based on IgE dependent and allergen-induced mediator release of RBL-2H3 cells is presented as an alternative for PCA. The assay has been adopted to the special needs of examining allergen extracts and has been proven to be practicable and reliable. A high number of samples can be processed quickly in one assay, with intra-assay variations below 10%. The first successful applications are the measurement of biologic potencies in allergenic extracts and the determination of murine serum IgE antibodies. Further studies will show whether this assay is suited to evaluate the efficiency of anti-inflammatory and anti-allergic drugs.

Allergens↗
PubMed2001

Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients.

UFT is composed of tegafur (FT), a prodrug of 5-fluorouracil (5-FU), and uracil in a fixed combination (1:4). In conjunction with leucovorin, UFT is being developed for the first-line oral treatment of metastatic colorectal cancer. The effect of food on the oral bioavailability of UFT (2 x 100 mg capsules; dose in terms of FT) and leucovorin (2 x 15 mg tablets) was evaluated in a single-dose, randomized, two-way crossover study. Patients (n = 25) were assigned to receive both drugs after an overnight fast or 5 min after completion of a high-fat meal (721 calories) with a 3-day washout period between treatments; then they were permitted to continue on oral UFT/leucovorin therapy for safety assessment. UFT (300 mg/m2/day as three divided doses) and leucovorin (90 mg/day as three divided doses) were given for 28 days. After a 7-day rest, the 28-day cycle was repeated. Pharmacokinetics (n = 22 patients) were determined for FT, 5-FU, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). The absence of food-effect on peak plasma concentration (CMAX) and the area under the curve (AUC) was concluded if the 90% confidence interval for the ratio of the treatment means was entirely contained in 0.75-1.33. Administration of UFT with food resulted in a 34% decrease in CMAX of FT, whereas the AUC of FT remained unchanged. Food decreased the CMAX and AUC values of uracil and 5-FU by 37-76%. On the contrary, the CMAX and AUC values of leucovorin and 5-methyltetrahydrofolate were increased by 14-60% with food. Time to reach CMAX for all analytes was significantly (P < or = 0.001) delayed by food. Except for the AUCs of FT, the statistical criterion for concluding a lack of food-effect was not met. These data suggest that UFT/leucovorin should not be dosed simultaneously with food. It is recommended that food should not be consumed for 1 h before and after an oral dose of UFT and leucovorin in a manner similar to pivotal Phase III trials. The 28-day oral regimen of UFT and leucovorin was generally well tolerated in the population studied.

Administration, Oral↗