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J M Collins

Publications and source records attributed to J M Collins.

At least 37 records · Page 2Linked to original sources
PubMed1998

Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone.

OBJECTIVE: To evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Ten women who had undergone surgical sterilization were enrolled in an open-label crossover study conducted in the Georgetown University Clinical Research Center. The pharmacokinetics of single doses of 0.07 mg ethinyl estradiol and 2 mg norethindrone were measured at baseline and after 3 weeks of 200 mg thalidomide. Compliance with the thalidomide regimen was assessed with use of Medication Event Monitoring System (MEMS) caps. RESULTS: No changes were observed in the pharmacokinetics of ethinyl estradiol or norethindrone with thalidomide therapy. The mean +/- SD area under the plasma concentration-time curve (AUC0-infinity) for ethinyl estradiol was 6580 +/- 1100 ng.h/L at baseline and 5970 +/- 1560 ng.h/L after the thalidomide regimen (paired t test, P > .05). The values for norethindrone were 103 +/- 54 micrograms.h/L and 107 +/- 58 micrograms.h/L (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for either ethinyl estradiol or norethindrone. No accumulation of thalidomide was seen after 21 days of therapy: day 1 AUC0-infinity 41.1 +/- 13.9 micrograms.h/mL; day 21 AUC0-infinity 59.6 +/- 27.3 micrograms.h/mL (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for thalidomide between days 1 and 21. Thalidomide was well tolerated but caused variable degrees of sedation. The average thalidomide compliance rate was 97%. CONCLUSIONS: The pharmacokinetics of thalidomide do not change with 3 weeks of daily dosing. Thalidomide does not alter the pharmacokinetics of ethinyl estradiol or norethindrone. Therefore there is no drug interaction between thalidomide and these 2 drugs. The efficacy of oral contraceptives containing ethinyl estradiol and norethindrone should not be affected by concomitant thalidomide therapy.

Adult↗
PubMed1998

Detailed interstitial temperature mapping during treatment with a novel transurethral microwave thermoablation system in patients with benign prostatic hyperplasia.

PURPOSE: To delineate in detail the temperature changes in the prostate gland and adjacent structures during treatment with a newly designed microwave thermoablation system in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Microwave thermoablation treatment was administered to 22 BPH patients at two centers in the U.S. and Argentina using the Urologix Targis targeted transurethral thermoablation system. Continuous temperature measurements were made with widely spatially dispersed fiber optic thermosensors at 11 to 24 prostatic sites in each patient using a recently described accurate stereotactic method. Urethral and rectal temperatures were also measured. RESULTS: Treatment using the microwave thermoablation system resulted in marked elevation of intraprostatic temperatures to as high as 80C in some patients with little or no elevation of urethral or rectal temperatures. Average temperature increased with radial distance from the urethra to a peak at 5 to 7 mm. and declined exponentially at greater distances. Higher maximum intraprostatic temperatures in individual patients were associated with a larger zone, up to 24.0 mm. in radius, of prostatic tissue exposed to thermoablative temperatures of 45C and higher. Along the longitudinal axis of the microwave treatment catheter, thermoablative temperatures were confined to a zone of 11.5 mm. from the microwave antenna midpoint apically and 11.3 mm. basally, that is, a range shorter than the length of the treatment catheter's microwave antenna (2.8 to 3.5 cm.). The mean temperature in the posterior sector of the prostate gland during treatment (43.6C; 95% CI, 41.1 to 46.1C) was significantly lower (p < 0.05) by 6.7C than that in the anterolateral prostate (50.3C; 95% CI, 48.3 to 52.3C), as a consequence of the preferential heating design of the treatment catheter. Intraprostatic mean temperature during treatment, as measured at all thermosensor sites without respect to spatial location, was 47.1C (95% CI, 44.2 to 50.0C), a value significantly higher (p < 0.05) than that measured in the urethra (39.6C; 95% CI, 36.6 to 42.6C) or rectum (37.7C; 95% CI, 36.7 to 38.7C). There was a strong correlation between the temporal pattern of fluctuation in urethral temperature and that of prostate temperature (r = 0.83; p < 0.001) during treatment. CONCLUSIONS: Treatment with the microwave thermoablation system fulfilled the requirements for an effective and safe microwave-based BPH treatment modality by exposing obstructive tissue to high temperatures without endangering vulnerable adjacent tissues.

Aged↗
PubMed1998

Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid.

Zidovudine (3'-azido-3'-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were > 100 and 8 micrograms/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 micrograms/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 micrograms/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.

Anti-HIV Agents↗
PubMed1998

Meniscal cysts: detection with high-resolution sonography.

OBJECTIVE: The purpose of this study was to determine the feasibility of high-resolution sonography for the detection of meniscal cysts and associated meniscal tears and for the differentiation of meniscal cysts from other masses at the knee joint. SUBJECTS AND METHODS: Fifty consecutive patients (51 knees) with a palpable mass at the knee joint were examined prospectively using a 7.5-MHz annular array transducer. Mass consistency and location and meniscal integrity were evaluated. Sonographic findings were correlated with surgery (46/51) and histopathology (15/51). Five patients did not undergo surgery. RESULTS: At surgery, 32 masses appeared to be meniscal cysts, whereas 19 were other types of masses. Sonographically, 31 of the 32 meniscal cysts were diagnosed correctly. Sonographic differentiation of the other types of masses from meniscal cysts could reliably be made in 17 of 19 cases; two masses were falsely interpreted as meniscal cysts. Sensitivity, specificity, and accuracy of sonography in the depiction of meniscal cysts were 97%, 86%, and 94%, respectively. The positive predictive value was 94% and the negative predictive value was 92%. Meniscal tears (31/46) and meniscal tears concomitant with meniscal cysts (26/32) were detected with an accuracy of 83% and 88%, respectively. CONCLUSION: Sonography is an accurate imaging technique for the detection of meniscal cysts and associated meniscal tears. Differentiation of meniscal cysts from other cystic and solid masses at the knee joint can be reliably made with sonography.

Adolescent↗
PubMed1998

Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues.

We reported previously that p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et al., Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at the maximum tolerable dose. We also evaluate IPdR metabolism in cytosolic extracts from normal human liver, normal human intestine, and human colorectal cancer specimens. Athymic mice tolerated a daily p.o. bolus of up to 2 g/kg IPdR for 6 days with minimal host toxicity (< or = 10% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 microM at 10 min following a p.o. IPdR bolus of 250-1500 mg/kg. The percentage IUdR-DNA in the HT29 s.c. human tumor xenografts increased 1.5 times (2.3-3.6%) with IPdR doses above 1 g/kg/day for 6 days, whereas the percentage IUdR-DNA incorporation in two proliferating normal tissues (4-4.5% in intestine; 1.6-2.2% in bone marrow) and a quiescent normal tissue (< or = 1% in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 g/kg/day for 6 days. In contrast, using a continuous infusion of IUdR at 100 mg/kg/day, significant systemic toxicity (> 20% body weight loss) was found by day 6 of the infusion. Steady-state plasma IUdR levels were 1.0-1.2 microM during the 6-day infusion, and percentage IUdR-DNA incorporations of 2.3, 8, 6, and 1% were measured in s.c. tumors, normal intestine, normal bone marrow, and normal liver, respectively, following the 6-day infusion. Thus, the p.o. IPdR schedule has an improved therapeutic index, based on percentage IUdR-DNA incorporation in normal and tumor tissues, compared to continuous infusion IUdR at the maximum tolerable dose in athymic mice with this human tumor xenograft. Additionally, a tumor regrowth assay to assess the radiation response of HT29 s.c. xenografts showed a 1.5-fold enhancement (time to regrow to 300% initial tumor volume) with IPdR (1000 mg/kg/day for 6 days) plus fractionated irradiation (XRT; 2 Gy/day for 4 days), compared to XRT (2 Gy/day for 4 days) alone. No enhancement in the radiation response of HT29 s.c. xenografts was found with continuous infusion IUdR (100 mg/kg/day for 6 days) plus XRT (2 Gy/day for 4 days), compared to XRT alone. Using cytosolic extracts from normal human liver specimens, we found a rapid (15-min) conversion of IPdR to IUdR. Coincubation of liver cytosol with IPdR and allopurinol, an inhibitor of xanthine oxidase, had no inhibitory effect on IPdR metabolism, whereas coincubation with IPdR and isovanillin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significantly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of IPdR was found in cytosolic extracts from colorectal liver metastases in two patients and from the HT29 human colon cancer xenografts in athymic mice. These additional data indicate that IPdR has the potential for clinical use as a p.o. prodrug for IUdR-mediated radiosensitization of resistant human cancers.

Animals↗
PubMed1997

Rifampin and rifabutin and their metabolism by human liver esterases.

1. The main metabolites of rifampin and rifabutin in man are their respective 25 deacetylated derivatives, but the enzyme(s) responsible for these biotransformations are not known. 2. In experiments with human liver slices and human liver microsomes, the 25 deacetylated derivatives of these drugs were the main metabolites observed. Slices and microsomes metabolized rifabutin 3-6-fold faster than rifampin, in agreement with their relative clearance in patients. Rifabutin partitioned into slices more avidly than rifampin. 3. In microsomal incubations, deacetylation did not require NADPH, but the amount of metabolite at the end of incubation was affected by NADPH. With NADPH the amount of 25 deacetyl rifabutin decreased, whereas the amount of 25 deacetyl rifampin increased slightly. A panel of liver microsomes from seven donors showed a 3-4-fold difference in the formation of 25 deacetyl rifabutin or 25 deacetyl rifampin, with strong correlation between the production of the two metabolites (r2 = 0.94). 4. The production of 25 deacetyl rifabutin and 25 deacetyl rifampin by human liver microsomes was not significantly affected by 1 microM 4 chloromercuricbenzoic acid or bis-(4-nitrophenyl) phosphate, but was completely inhibited by 1 microM paraoxon or 1 microM diisopropylfluorophosphate. These results indicate that in man rifampin and rifabutin are deacetylated to their main metabolites by B-esterases.

Acetylation↗
PubMed1997

Predicting drug interactions in vivo from experiments in vitro. Human studies with paclitaxel and ketoconazole.

This study was performed to evaluate whether concomitant treatment with ketoconazole could reduce the clearance of paclitaxel given to ovarian cancer patients. Paclitaxel, 175 mg/m2, was given as a 3-hour continuous intravenous infusion and repeated every 21 days. Initially, ketoconazole, 100 to 1600 mg, was given as a single oral dose 3 hours after paclitaxel. Later, ketoconazole, 200 mg, was given perorally 3 hours before paclitaxel. Plasma drug concentrations were measured by high-pressure liquid chromatography (HPLC), and cytochrome P450 3A (CYP3A) activity was measured with the erythromycin breath test (ERMBT). Ketoconazole did not alter plasma concentrations of paclitaxel or its principal metabolite, 6 alpha-hydroxypaclitaxel. Although there was marked inter- and intrapatient variability in ketoconazole pharmacokinetics, peak plasma concentrations in all but one course were below the 50% inhibitory concentration (IC50) point determined for inhibition of paclitaxel metabolism in vitro. Therefore, paclitaxel and ketoconazole can be coadministered safely without dose adjustments. There was no correlation between ERMBT measurements and serial plasma concentrations of paclitaxel. The erythromycin breath-test measurements did correlate with the corresponding ketoconazole plasma concentrations. The erythromycin breath test is a valuable tool for measuring instantaneous CYP3A activity in vivo. This clinical study confirms the results of prior studies with human-derived materials in vitro, reinforcing the notion that such studies are useful predictors of drug pharmacokinetics and interactions in vivo.

Antifungal Agents↗
PubMed1997

Stereoselective metabolism of fenoldopam and its metabolites in human liver microsomes, cytosol, and slices.

Fenoldopam is a racemic mixture (R-FEN, S-FEN) that is a selective dopamine (DA-1) receptor agonist with pronounced cardiovascular and renal effects in humans. Metabolism of fenoldopam in human liver microsomes, cytosol, and slices was stereoselective for glucuronidation, sulfation, and methylation. Microsomal and cytosolic fractions were supplemented with appropriate cofactors to obtain enzyme activity. There was no evidence of metabolism of fenoldopam by cytochrome P-450. R-FEN was metabolized to fenoldopam-8-sulfate (8-SO4), 7-methoxy fenoldopam (7-MeO), 8-methoxy fenoldopam (8-MeO), and two glucuronidated products. The 7-MeO formed with incubation of R-FEN in human liver slices was further metabolized to an unknown sulfated product. S-FEN was metabolized to fenoldopam-7-sulfate (7-SO4), a second unknown sulfated product, 7-MeO, 8-MeO, and two glucuronidated products. Metabolism of S-FEN and R-FEN in human liver slices to 7-MeO occurred at the same rate, whereas further metabolism of 7-MeO was stereospecific and slower for the S-isomer of 7-MeO. Fenoldopam has served as an excellent model compound for comparison of metabolism in human liver slices with metabolism in subcellular fractions. The parallel pathways of fenoldopam metabolism lessen the possible impact of drug-drug interactions.

Antihypertensive Agents↗
PubMed1997

Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole.

Rifabutin and fluconazole are often given concomitantly as therapy to prevent opportunistic infections in individuals infected with the human immunodeficiency virus. Recent reports have shown increased levels of rifabutin and its 25-desacetyl metabolite, LM565, in plasma when rifabutin is administered with fluconazole. Since fluconazole is known to inhibit microsomal enzymes, this study was undertaken to determine if this rifabutin-fluconazole interaction was due to an inhibition of human hepatic enzymes. The metabolism of both rifabutin and LM565 was evaluated in human liver microsomes and recombinant human cytochrome P-450 (CYP) 3A4 in the presence of fluconazole and other probe drugs known to inhibit CYP groups 1A2, 2C9, 2D6, 2E1, and 3A. The concentrations of rifabutin (1 microg/ml), LM565 (1 microg/ml), and fluconazole (10 and 100 microg/ml) used were equal to those observed in plasma after the administration of rifabutin and fluconazole at clinically relevant doses. High-performance liquid chromatography was used to assess the metabolism of rifabutin and LM565. Rifabutin was readily metabolized to LM565 by human microsomes, but the reaction was independent of NADPH and was not affected by the P-450 inhibitors. No rifabutin metabolism by recombinant CYP 3A4 was found to occur. LM565 was also metabolized by human microsomes to two products, but metabolism was dependent on NADPH and was affected by certain P-450 inhibitors. In addition, LM565 was readily metabolized by the recombinant CYP 3A4 to the same two products found with its metabolism by human microsomes. Therefore, rifabutin is metabolized by human microsomes but not via cytochrome P-450 enzymes, whereas LM565 is metabolized by CYP 3A4.

Anti-Bacterial Agents↗
PubMed1997

Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism.

Saquinavir is a HIV protease inhibitor used in the treatment of patients with acquired immunodeficiency syndrome, but its use is limited by low oral bioavailability. The potential of human intestinal tissue to metabolize saquinavir was assessed in 17 different human small-intestinal microsomal preparations. Saquinavir was metabolized by human small-intestinal microsomes to numerous mono- and dihydroxylated species with K(M) values of 0.3-0.5 microM. The major metabolites M-2 and M-7 were single hydroxylations on the octahydro-2-(1H)-isoquinolinyl and (1,1-dimethylethyl)amino groups, respectively. Ketoconazole and troleandomycin, selective inhibitors of cytochrome P4503A4 (CYP3A4), were potent inhibitors for all oxidative metabolites of saquinavir. The cytochrome P450-selective inhibitors furafylline, fluvoxamine, sulfaphenazole, mephenytoin, quinidine, and chlorzoxazone had little inhibitory effect. All saquinavir metabolites were highly correlated with testosterone 6beta-hydroxylation and with each other. Human hepatic microsomes and recombinant CYP3A4 oxidized saquinavir to the same metabolic profile observed with human small-intestinal microsomes. Indinavir, a potent HIV protease inhibitor and a substrate for human hepatic CYP3A4, was a comparatively poor substrate for human intestinal microsomes and inhibited the oxidative metabolism of saquinavir to all metabolites with a Ki of 0.2 microM. In addition, saquinavir inhibited the human, small-intestinal, microsomal CYP3A4-dependent detoxication pathway of terfenadine to its alcohol metabolite with a Ki value of 0.7 microM. These data indicate that saquinavir is metabolized by human intestinal CYP3A4, that this metabolism may contribute to its poor oral bioavailability, and that combination therapy with indinavir or other protease inhibitors may attenuate its low relative bioavailability.

Anti-HIV Agents↗
PubMed1997

Effect of albumin on the estimation, in vitro, of phenytoin Vmax and Km values: implications for clinical correlation.

The effect of bovine serum albumin (BSA) on human liver metabolism, in vitro, of 14C-phenytoin (PHT) was studied. Michaelis Menten parameters were determined for the conversion of PHT to p-hydroxy phenytoin in seven different microsomal preparations with the addition of 0, 2, and 4% BSA. The unbound Km (Kmu) values were 30.8 +/- 18.6, 1.57 +/- 0.21 and 1.50 +/- 0.17 microM (mean +/- S.D.), respectively; however, there was excellent agreement among the Vmax values (29.1, 31.8 and 31.5 pmol/min/mg). With intact tissue slices, BSA (4%) added to incubations of PHT had a minimal effect on the Vmax values in two of the four livers studied and resulted in a mean Kmu value of 2.20 +/- 0.59 microM, although the Kmu in the absence of BSA was 6.64 +/- 3.17. In scaling-up to the whole body, Vmax values were 3.9 and 1.0 mg/kg/day for microsomes and slices, respectively, compared to 5.9 mg/kg/day, in vivo. The Kmu values determined in the presence of albumin in both microsomes and slices were similar to those based on in vivo human steady state data (Kmu = 2-3 microM), and the intersubject variation, in vitro, was decreased in the presence of BSA. These findings for phenytoin metabolism suggest that the addition of albumin to incubation media for slices or microsome experiments may yield Km estimates that are more representative of in vivo values.

Anticonvulsants↗
PubMed1997

The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone.

The N-demethylation of LAAM, norLAAM, and methadone has been investigated in human liver microsomes and microsomes containing cDNA-expressed human P450s. Gas chromatography/mass spectrometry methods allowed detection of norLAAM and dinorLAAM formation from LAAM, dinorLAAM formation from norLAAM, and EDDP and EMDP formation from methadone. The rates of N-demethylation varied 4- to 7-fold in microsomes from four different donors with activities for LAAM and norLAAM consistently greater (5- to 14-fold) than for methadone. The N-demethylation of LAAM, norLAAM, and methadone were significantly inhibited by ketoconazole. IC50s could be determined for ketoconazole inhibition of LAAM and norLAAM N-demethylation of 1.6 and 1.1 microM, respectively. The ability of ketoconazole to reduce methadone N-demethylation below 40% varied in regard to liver donor. No other P450-selective inhibitors reduced the average activities more than 43%. cDNA-expressed P450 3A4 N-demethylated LAAM, norLAAM, and methadone at greater rates than the other cDNA-expressed P450s studied (1A2, 2C9, 2D6, or 2E1). P450 3A N-demethylation of LAAM, norLAAM, and methadone exceeded the next most active P450, respectively, by at least 2.5, 9.6, and 13.4 times when expressed per milligram protein and by 18.2, 6.0, and 6.1 times when expressed per nanomole P450. These results suggest that P450 3A4 is the primary site of N-demethylation of LAAM, norLAAM, and methadone in human liver. Although other enzymes may also be capable of N-demethylating these compounds, identification of specific enzymes, except P450 3A4, has yet to be established. Knowledge of these enzymatic pathways is essential for assessment of the impact of metabolic drug-drug interactions on therapeutic success and/or adverse events.

Cytochrome P-450 CYP3A↗
PubMed1996

Detailed prostatic interstitial thermal mapping during transurethral grooved rollerball electrovaporization and loop electrosurgery for benign prostatic hyperplasia.

OBJECTIVES: To determine the detailed pattern of prostatic interstitial temperature change during rollerball electrovaporization and loop electrosurgery in patients with benign prostatic hyperplasia (BPH). METHODS: Four patients with symptomatic BPH necessitating prostate surgery were subjected to rollerball electrovaporization on one side of their prostate glands, as well as contralateral loop electrosurgery. Continuous temperature readings were recorded from 20 to 24 interstitially implanted fiber-optic thermosensors using a novel stereotactic thermal mapping technique. Ultrasound and video endoscopic visualization were used to evaluate and quantify the spatial relationship between the thermosensors and the rollerball or loop. RESULTS: The patterns of temperature change during rollerbal electrovaporization and loop electrosurgery were substantially similar. Temperatures decreased steeply and significantly with increasing distance from both the rollerball (P < 0.001) and loop (P < 0.001). Marked mean temperature increases occurred at 1 to 2 mm from both the rollerball (30.8 degrees C, 95% confidence interval [CI] 27.8 to 33.8 degrees C) and loop (34.8 degrees C, 95% CI 24.0 to 45.6 degrees C), and temperatures at this distance were significantly higher than those at greater distances (P < 0.05). At 3 to 5 mm, the mean temperature increases declined by 58% for the rollerball and 68% for the loop. Further declines of 68% and 63%, respectively, were observed at 6 to 10 mm, and at distances exceeding 10 mm the temperature changes were minimal (0.5 degree C [95% CI 0.3 to 0.8 degree C] for the rollerball and 0.5 degree C [95% CI 0.1 to 0.8 degree C] for the loop). There was no change in temperature at any of the thermosensors near the neurovascular bundles and rectum. CONCLUSIONS: The patterns of temperature change with rollerball electrovaporization and loop electrosurgery are closely similar. Interstitial temperature changes during use of the rollerball and loop are transient and highly localized, posing minimal risk of unintended thermal damage to adjacent tissues, including the neurovascular bundles and rectum.

Aged↗
PubMed1996

Identification of 2,6-xylidine as a major lidocaine metabolite in human liver slices.

Human liver slices, in vitro, were used to establish whether lidocaine (LIDO) can be converted by human liver tissue to 2,6-xylidine (XYL), a compound shown to be carcinogenic in rodents. XYL was identified by GC/MS as a major metabolite in human liver slices from five individual donors after incubation with either LIDO (100 microM) or its deethylated metabolite, monoethylglycinexylidide (MEGX; 100 microM). Similar media XYL concentrations (9.8 microM +/- 2.1 SD and 7.9 microM +/- 2.1 SD) were achieved after either LIDO or MEGX incubation for 4 hr, respectively. With LIDO, the mean media XYL to MEGX ratios were 1.1 at 1-hr and 1.0 at 4-hr incubation times. In contrast, when LIDO (> 500 microM) was incubated with human liver microsomes for 1 hr, the XYL to MEGX ratio was approximately 0.01. No XYL was detected when LIDO (100 microM) was incubated with either human liver S9 fractions or whole liver homogenates. These results suggest that the enzyme primarily responsible for hydrolysis of LIDO may be labile in subcellular fractions. Kinetic analysis of the data suggests that XYL can be produced from either LIDO directly, or sequentially through MEGX. Although these metabolic data are helpful in addressing issues of LIDO toxicity, the overall risk assessment for LIDO is determined in large part by other factors, including the relative rates of activation to other potentially toxic species such as 4-HO-2,6-XYL as well as inactivation by detoxification pathways. The results presented emphasize the important role human liver slices can play in drug metabolism studies.

Aniline Compounds↗
PubMed1996

Murine and human in vivo penclomedine metabolism.

Penclomedine is a multichlorinated alpha-picoline derivative which has shown prominent activity in murine breast cancer models and is currently undergoing clinical development. Previous in vitro research has identified several penclomedine metabolites. In this study, human and murine in vivo penclomedine metabolism was examined. Upon i.v. administration to mice, no penclomedine was detectable in plasma at time points as early as 1 h postinfusion. The principle metabolite was demethyl-penclomedine [3, 5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine]. Both penclomedine and demethyl-penclomedine could be recovered from tissues. Greater than 60% of the penclomedine dose remaining in the body at 22 h was indelibly bound to tissue and plasma proteins. Urinary metabolites of penclomedine consisted mainly of penclomic acid and additional polar metabolites. The results obtained after p. o. administration were nearly identical to i.v. administration with respect to the extent, level, and type of metabolites found in the plasma, tissues, and urine and with respect to the extent of protein binding. In human subjects administered penclomedine daily for 5 consecutive days, demethyl-penclomedine could be detected in plasma and accumulated with successive doses of penclomedine, reaching peak plasma concentrations of up to 10 times that of penclomedine itself and plasma exposures of nearly 400 times that of the parent drug. It appears that patients eliminate penclomedine largely through metabolism and that this drug may be amenable to p.o. administration.

Animals↗
PubMed1996

Cyclophosphamide and 4-Hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy.

Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P < 0.001). In contrast, the AUC4HOCP (27 micrometer . h/g/m2 +/- 25% CV) determined for the first course was 29% higher than the AUC4HOCP (21 micrometer . h/g/m2 +/- 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m2) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC50 values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 micrometer. However, the clinical relevance of this observation has not been established.

Adolescent↗
PubMed1995

Receptor binding of PDGF-AA and PDGF-BB, and the modulation of PDGF receptors by TGF-beta, in human periodontal ligament cells.

The growth factors PDGF-AA and PDGF-BB have previously been shown to be potent mitogens for human periodontal ligament (hPDL) cells in vitro. Additionally, the mitogenic response to PDGF-AA has been shown to be specifically inhibited by TGF-beta. The purpose of the present investigation was to examine the binding of PDGF-AA and PDGF-BB, and the modulation of PDGF binding by TGF-beta, in hPDL cells. Scatchard analysis identified an average of 32,000 PDGF-AA high-affinity binding sites per cell with a dissociation constant (Kd) of 0.66 nM and an average of 36,000 PDGF-BB binding sites per cell with a dissociation constant (kd) of 0.44 nM. After treatment with TGF-beta, the receptor number for PDGF-AA was found to specifically decrease by approximately 50%, with no change in binding affinity. This reduced number of binding sites was shown to correlate with both a decrease in levels of receptor tyrosine phosphorylation and a decreased number of alpha receptor subunits. Northern blot analysis identified the TGF-beta-mediated decrease in PDGF alpha receptor subunit mRNA levels. PDGF-BB showed little change in the number of binding sites or in the binding affinity with TGF-beta treatment, and the data were consistent with an increase in the number of beta receptor subunits. These results demonstrate nearly equivalent numbers of receptors for both PDGF-AA and PDGF-BB in hPDL cells. Also, modulation of PDGF binding, by TGF-beta, was shown to result in a reduced number of alpha receptor subunits with an increase in the number of beta receptor subunits.

Cells, Cultured↗