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K S Godwin

Publications and source records attributed to K S Godwin.

11 recordsLinked to original sources
PubMed2003

Long-term trends in sodium and chloride in the Mohawk River, New York: the effect of fifty years of road-salt application.

Ecological studies have demonstrated the adverse effects of road-salt, primarily NaCl, on water quality, flora, and fauna. In this study, we quantified changes in ionic composition and solute flux of water draining the Mohawk River Basin (9103 km(2)) in New York State, from 1952 to 1998. Using various statistical, graphical, and modeling techniques, we showed that concentrations ofNa+ and Cl- have increased by 130 and 243%, respectively, while other constituents have decreased or remained constant. The use of de-icing salt on roads within the watershed, which we estimate at 39 kg km(-2) day(-1), appears to be the primary mechanism responsible for reported increases, accounting for the increase in NaCl export from 16 to 46 kg km(-2) day(-1) over the 47-year period.Moreover, despite population decline within this rural upstate watershed, increased environmental stewardship, and The Clean Water Act, concentrations of Na+ and Cl- still increased during the 1990s.

Chlorides↗
PubMed1999

The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex) in a nonhuman primate model.

PURPOSE: Raltitrexed (Tomudex), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. METHODS: Animals received 3 mg/m(2) (n = 1), 6 mg/m(2) (n = 3), or 10 mg/m(2) (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 microM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. RESULTS: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing >20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m(2) doses were 1.5, 2.4 and 4.8 microM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m(2), and the steady-state volume of distribution exceeded 200 l/m(2). The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m(2 )dose. CONCLUSIONS: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.

Animals↗
PubMed1999

Gastropathy induced by nonsteroidal anti-inflammatory drugs: prescribing patterns among geriatric practitioners.

The objective of this study was to determine patterns among geriatric practitioners in prescribing agents that protect the gastrointestinal tract when nonsteroidal anti-inflammatory drug (NSAID) treatment is started for elderly patients. A questionnaire describing five scenarios of elderly patients requiring NSAID therapy asked respondents to choose gastrointestinal-protective agents for each scenario. Respondents were then asked to what extent four established risk factors for NSAID gastropathy (age, previous peptic ulcer, previous gastrointestinal bleeding, and heart disease) affected their choices. The choice of gastrointestinal-protective agent was compared with the training and experience of the respondents. This self-administered survey was provided to 821 randomly selected physicians from the membership of the American Geriatrics Society throughout the United States and Puerto Rico. Statistical Package for the Social Sciences (SPSS), version 6.1.4, was used to obtain frequencies. Of 821 surveys, 229 (28%) were returned. It was found that well elderly patients and nursing home residents were not treated with any gastrointestinal-protective agent by 64% (well elderly patients) and 32% (nursing home residents) of respondents. Among respondents who would prescribe, about half would choose misoprostol for a well elderly patient or a nursing home resident, whereas half or more preferred histamine H2-receptor antagonists. Twenty-three percent would not prescribe misoprostol when NSAID therapy was resumed after an active ulcer had healed, and 68% preferred H2 antagonists in that setting. The difference in response attributable to training/experience was less than 9%. Factors that did not affect prescribing patterns included the patient's age (15% to 62%) and heart disease (44% to 50%). The study concluded that age and heart disease are risk factors to which physicians give less consideration when choosing gastrointestinal-protective agents. Although misoprostol is the only agent approved by the Food and Drug Administration for prophylaxis against NSAID gastropathy, 23% of respondents chose not to prescribe misoprostol when NSAID therapy was resumed after an active ulcer had healed. Histamine H2-receptor antagonists were preferred over misoprostol for well elderly patients and nursing home residents. Training and experience were not responsible for differences among respondents' prescribing patterns.

Aged↗
PubMed1995

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddA), didanosine, 2',3'-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 microM.h) and the 6-halogenated-ddG prodrugs (18.8 microM.h for 6-chloro-ddG, 9.3 microM.h for 6-iodo-ddG).6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.

Animals↗
PubMed1994

Cerebral subarachnoid sampling of cerebrospinal fluid in the rhesus monkey.

A previously described rhesus monkey model with two intraventricular catheter systems was expanded to provide a means of studying drug concentrations of chemotherapeutic agents such as methotrexate (MTX) in the cerebral subarachnoid cerebrospinal fluid (CSF) following intrathecal drug injection. A continuous intraventricular infusion of MTX was started through the lateral ventricular catheter 44 h before surgical placement of the cerebral subarachnoid catheter to allow for steady-state concentrations to be attained throughout the subarachnoid space. Monkeys were anesthetized intramuscularly with ketamine hydrochloride (7 mg/kg) and xylazine (6 mg/kg) to allow placement of a temporary lumbar catheter for sampling of lumbar CSF Sodium thiopental (2.5%) was given intravenously if needed for intubation and anesthesia was maintained with isoflurane (0.5 to 1.5%) and oxygen during the surgical placement and sampling of the cerebral subarachnoid catheter. A midline incision was made over the frontal bone and a 3/8-inch trephine was used to expose the dura adjacent to the lateral midline. Following puncture of the dura with an 18-gauge spinal needle, the cerebral subarachnoid catheter (0.025-inch [i.d.] x 0.047-inch [o.d.] Silastic tube) was passed into the subarachnoid space for approximately 10 to 17 mm. The CSF from the cerebral subarachnoid catheter was collected by gravity flow Ventricular, lumbar subarachnoid, and cerebral subarachnoid CSF were collected concurrently at 44, 46, and 48 h after the start of MTX infusion. Mean ventricular, lumbar subarachnoid, and cerebral subarachnoid CSF methotrexate concentrations at steady state were 5.8, 1.0, and 1.5 mumol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Pharmacokinetics of PEG-L-asparaginase and plasma and cerebrospinal fluid L-asparagine concentrations in the rhesus monkey.

The pharmacokinetics of the polyethylene glycol-conjugated form of the enzyme L-asparaginase and the depletion of L-asparagine from the plasma and cerebrospinal fluid (CSF) following an i.m. dose of 2500 IU/m2 PEG-L-asparaginase was studied in rhesus monkeys. PEG-L-asparaginase activity in plasma was detectable by 1 h after injection and maintained a plateau of approximately 4 IU/ml for more than 5 days. Subsequent elimination from plasma was monoexponential with a half-life of 6 +/- 1 days. Plasma L-asparagine concentrations fell from pretreatment levels of 14-47 microM to < 2 microM by 24 h after injection in all animals and remained undetectable for the duration of the 25-day observation period in four of six animals. In two animals, plasma L-asparagine became detectable when the PEG-L-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSF L-asparagine levels ranged from 4.7 to 13.6 microM and fell to < 0.25 microM by 48 h in five of six animals. CSF L-asparagine concentrations remained below 0.25 microM for 10-14 days in four animals. One animal had detectable CSF L-asparagine concentrations within 24 h and another had detectable concentrations within 1 week of drug administration despite a plasma PEG-L-asparaginase activity profile that did not differ from that of the other animals. These observations may be useful in the design of clinical trials with PEG-L-asparaginase in which correlations among PEG-L-asparaginase pharmacokinetics, depletion of L-asparagine, and clinical outcome should be sought.

Aminolevulinic Acid↗
PubMed1993

Pharmacokinetics, cerebrospinal fluid penetration, and metabolism of piroxantrone in the rhesus monkey.

Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activity in vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluated in vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m2 given over 60 minutes was biexponential with mean t1/2 alpha of 1.0 minutes and a mean t1/2 beta of 180 minutes. The mean area under the curve was 220 microM.min and the clearance was 1420 ml/min/m2. Piroxantrone was not detectable in the cerebrospinal fluid. Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cells in vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite. The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.

Animals↗
PubMed1992

Methotrexate pharmacokinetics following administration of recombinant carboxypeptidase-G2 in rhesus monkeys.

PURPOSE: Carboxypeptidase-G2 (CPDG2) is a bacterial enzyme that rapidly hydrolyzes methotrexate (MTX) into inactive metabolites. As an alternative form of rescue after high-dose MTX (HDMTX), CPDG2 has more potential advantages than standard leucovorin (LV) rescue. In this study, the plasma pharmacokinetics of MTX with and without CPDG2 were evaluated in adult rhesus monkeys. MATERIALS AND METHODS: The plasma pharmacokinetics of MTX were determined in groups of animals that had received a 300-mg/m2 loading dose of MTX followed by a 60-mg/m2/h infusion during an 18-hour period. One group received CPDG2 at the end of the infusion, and the other group served as a control. Two additional animals with high titers of anti-CPDG2 antibody also were studied. RESULTS: During infusion, the steady-state MTX plasma concentration was 11.3 +/- 4.8 mumol/L. Without CPDG2, the postinfusion plasma MTX concentration remained above 0.1 mumol/L for more than 6 hours. After the administration of 50 U/kg of CPDG2, plasma MTX concentrations decreased to nontoxic levels (less than 0.05 mumol/L) within 30 minutes. The initial half-life (t1/2 alpha) of MTX decreased from 5.8 +/- 2.1 minutes to 0.7 +/- 0.02 minutes after enzyme administration. The postinfusion area under the plasma concentration time curve of MTX was 301 +/- 171 mumol/L/min without CPDG2 compared with 19.6 +/- 6.1 mumol/L/min with CPDG2. The immunogenicity studies performed indicated that although animals developed anti-CPDG2 antibodies, none of them manifested allergic symptoms. The effectiveness of CPDG2 was diminished but not eliminated in animals with high titers of anti-CPDG2 antibody. CONCLUSIONS: CPDG2 is capable of rapidly decreasing plasma MTX concentrations to nontoxic levels. The administration of CPDG2 seems safe, well tolerated, and it may be useful as an alternative to LV rescue.

Animals↗
PubMed1991

Pharmacokinetics of pyrazoloacridine in the rhesus monkey.

Pyrazoloacridine is a rationally synthesized acridine derivative with in vitro activity against solid tumor cell lines, noncycling and hypoxic cells, and tumor cell lines that exhibit the multidrug resistance phenotype. The pharmacokinetic behavior of pyrazoloacridine after a 1- or 24-h i.v. infusion was studied in 5 rhesus monkeys that received a total of 10 courses of pyrazoloacridine at 300 or 600 mg/m2. Pyrazoloacridine levels in plasma and cerebrospinal fluid were measured by high-pressure liquid chromatography. For 1-h infusions, the plasma disappearance was biexponential with a t 1/2 alpha of 31 min and t 1/2 beta of 11 h. The mean volume of distribution at steady state was 1380 liters/m2. The clearance was 1660 ml/min/m2. For the 300 mg/m2 dose, the mean area under the concentration-time curve was 759 microM.min, and the mean peak concentration was 1.3 microM. For the 600 mg/m2 dose, the area under the concentration-time curve was 1330 microM.min, and the peak concentration was 2.5 microM. The steady-state plasma concentrations during the 24-h continuous infusions were 0.27 microM for the 300 mg/m2 dose and 0.45 microM for the 600 mg/m2 dose. The mean clearance calculated from these steady-state concentrations was 2420 ml/min/m2. Cerebrospinal fluid levels were less than 0.1 microM for all doses and schedules. There was no evidence of toxicity at any dose or schedule. These results contrast strikingly with those obtained in mice and dogs in which, despite a more rapid clearance of pyrazoloacridine, significant toxicities were observed at doses that were nontoxic in the monkey. These interspecies differences in the pharmacokinetic and pharmacodynamic behavior of pyrazoloacridine have important implications for the design of Phase I trials in humans.

Acridines↗
PubMed1991

Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2.

The carboxypeptidase G class of enzymes rapidly hydrolyze methotrexate (MTX) into the inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. This study evaluated the use of carboxypeptidase-G2 (CPDG2) as a potential intrathecal (IT) rescue agent for massive IT MTX overdose. The CSF pharmacokinetics of MTX with and without CPDG2 rescue was studied in adult rhesus monkeys (Macaca mulatta) using a nontoxic IT 5 mg dose (equivalent to 50 mg in humans). Without CPDG2 rescue, peak CSF MTX concentration was 2,904 +/- 340 mumol/L. Within 5 minutes of administration of 30 U IT CPDG2, CSF MTX concentrations decreased greater than 400-fold to 6.55 +/- 6.7 microM. Subsequently, groups of three monkeys received either 25 mg IT MTX (equivalent to 250 mg in humans) followed by 150 U IT CPDG2 or 50 mg IT MTX (equivalent to 500 mg in humans) followed by 300 U IT CPDG2. All animals survived without neurotoxicity. Our studies suggest that CPDG2 may prove to be an important addition to the currently recommended strategy for the management of IT MTX overdose.

Animals↗