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Biomedical subjects

P R Hutson

Publications and source records attributed to P R Hutson.

18 recordsLinked to original sources
PubMed1999

Methotrexate sequestration in an ovarian cyst.

OBJECTIVE: Methotrexate has been documented to accumulate in pleural effusions and ascitic fluid, resulting in severe local and systemic toxicity. In the following case report, we publish results of intraoperative measurements of methotrexate levels in serum and an ovarian cyst and attempt to determine if ovarian cysts similarly act as a depot for methotrexate. METHODS: After determining intraoperative measurements of serum and ovarian cystic levels of methotrexate, we compared demonstrated pharmacokinetics to those expected by using pharmacokinetic systems analysis software. RESULTS: Intraoperative measurement of methotrexate levels on day 3 of a 5-day methotrexate regimen revealed a serum methotrexate concentration of 1.6 x 10(-7) M and a concentration of 3.1 x 10(-7) M within the 166.4 ml ovarian cyst. CONCLUSIONS: The measured levels demonstrate that methotrexate is sequestered within an ovarian cyst resulting in higher local drug levels. Our pharmacokinetic analysis suggests that methotrexate doses less than 100 mg/m2 can be safely administered to patients with small ovarian cysts. However, computed simulations support the possibility of local and systemic toxicity arising from large ovarian cysts when using high doses of methotrexate.

Adult↗
PubMed1998

Renal clearance, tissue distribution, and CA-125 responses in a phase I trial of suramin.

Suramin was administered to 49 patients in a Phase I cancer trial with real-time pharmacokinetic monitoring and dose individualization to achieve targeted mean plasma concentrations of 210 and 155 mg/liter during the 7-day period between days 15 and 22. Pharmacokinetic sampling after doses on days 1, 3, 5, and 8 was used to modify weekly suramin doses, beginning on day 15, in an attempt to achieve specific averaged plasma concentrations of 210 and 155 mg/liter. A 200-mg test dose was not effective in prospectively determining individual pharmacokinetic parameters and dosage requirements. Patients with peak plasma suramin concentrations in excess of 350 mg/liter may be more likely to experience neurotoxicity (P = 0.06), but there was no statistically significant effect of peak suramin concentration or of cumulative dose. Biopsy and autopsy tissue samples demonstrated low penetration of suramin into brain tissue and muscle but good penetration into prostate and other visceral organs. Prospective use of surrogate substrates for CYP1A2, CYP3A3/4, and CYP2D6 showed no consistent effect of suramin on these enzymes. Although a correlation between creatinine clearance and suramin renal clearance was found (r2 = 0.38; P < 0.00005), there was no correlation between creatinine clearance and total suramin clearance (P = 0.21). No suramin dose modification for renal or hepatic dysfunction can be supported at this time. Three of four ovarian cancer patients demonstrated a drop in CA-125 serum concentrations during suramin treatment.

Adult↗
PubMed1997

Quantitation of beta-lapachone and 3-hydroxy-beta-lapachone in human plasma samples by reversed-phase high-performance liquid chromatography.

beta-Lapachone is an o-naphthoquinone found to have in vitro cytotoxicity in cancer cells, type I human immunodeficiency virus, and fungi. Analytical methods for evaluating beta-lapachone in biological fluids using high-performance liquid chromatography (HPLC) have not been published. The reversed-phase HPLC method described in this report utilizes liquid extraction of a 0.5-ml plasma sample with average recoveries of 67+/-10.8% and 70+/-10.3% for beta-lapachone and 3-hydroxy-beta-lapachone, respectively. Sensitivity of the assay using ultraviolet (UV) detection at 256 nm is 15 ng ml(-1) from a 100 microl injection. Plasma standards for beta-lapachone and 3-hydroxy-beta-lapachone are linear with no significant difference in slope between the compounds. The retention times of 2.7 min for 3-hydroxy-beta-lapachone and 5.9 min for beta-lapachone result in a clean separation permitting use of the same assay procedure without modification for both compounds. This assay offers the advantage that either beta-lapachone or 3-hydroxy-beta-lapachone can serve as the internal standard, depending on which compound is being analyzed.

Anti-Infective Agents↗
PubMed1994

Pharmacokinetics and short-term clinicopathologic changes after intravenous administration of a high dose of methimazole in dogs.

A bolus dose of methimazole (MMI) was administered IV over 1 minute to 5 healthy adult dogs at a dosage (40 mg/kg of body weight) known to impart protection against cisplatin-induced renal disease. Blood and urine samples for pharmacokinetic analysis were collected over a 24-hour period. Physical examination, CBC, determination of serum thyroid hormone concentrations, and serum biochemistry analysis were performed over a 10-day period to evaluate short-term toxicoses. At this dosage, MMI appears to be safe and well tolerated in dogs; only 1 of the 5 dogs had mild and transient increases in serum activity of hepatic enzymes. In addition, MMI did not alter serum thyroid hormone concentrations. Half-life of 8.82 hours and mean residence time of 12.18 hours were determined for MMI. Renal clearance of native MMI, along with sulfate and glucuronide conjugates, represented only 20% of total systemic clearance. Results of this study provide further information concerning clinical use of MMI in dogs and may contribute to better understanding of the mechanism of MMI protection against chemically induced nephrotoxicosis.

Alanine Transaminase↗
PubMed1993

Evidence of an absorption phase after short intravenous suramin infusions.

Suramin was given as an intravenous infusion to 16 cancer patients in a phase I trial. Individual pharmacokinetic parameters were calculated from a test dose given 1 week prior to the administration of a full-dose (350-700 mg/m2) regimen of 1-h loading and maintenance infusions. A distribution phase of 3.8 h was found. Plasma suramin concentrations were noted to increase following cessation of the intravenous test infusion in eight subjects. A model is proposed in which high-capacity, low-affinity binding of suramin to a shallow compartment adjacent to the intravascular space occurs rapidly during infusion, followed by absorption back into the measured blood pool with binding to plasma albumin. Despite the observable presence of this postinfusion peak shortly after the cessation of the brief suramin infusion, the pharmacokinetics of suramin were best characterized by a traditional two-compartment model. The dose-adjusted area under the concentration-time curve (AUC) increased with dose, supporting a hypothesis of sustained absorption of suramin to vascular endothelium but also raising the possibility of dose-dependent clearance.

Absorption↗
PubMed1992

Intradermal carboplatin and ifosfamide extravasation in the mouse.

BACKGROUND: Carboplatin and ifosfamide are new antineoplastic agents with vesicant properties that have not been determined. Vesicant activity was investigated in Balb-c mice by administering carboplatin or ifosfamide intradermally in clinically relevant concentrations. METHODS: Carboplatin concentrations tested were 15, 10, and 1 mg/ml; those of ifosfamide were 50, 20, and 1 mg/ml. Five female mice were tested with each concentration; and five animals were used as controls and received only saline. RESULTS: Carboplatin concentrations of 15 mg/ml and 10 mg/ml produced mean peak ulcer areas of 10 square millimeters (mm2) and 21 mm2 within 2-3 days of injection, respectively. The 1 mg/ml carboplatin injection was not associated with any ulcer formation. Ifosfamide at 50 mg/ml induced skin ulcerations in four of five mice, with maximal effect (19.6 mm2) by 1-2 days. Lower concentrations of ifosfamide produced no ulcerations. All ulcerative lesions healed completely within 21 days. CONCLUSIONS: These results suggest that extravasation of carboplatin at concentrations of greater than or equal to 10 mg/ml or ifosfamide at concentrations of greater than or equal to 50 mg/ml is likely to cause ulcers in humans.

Animals↗
PubMed1991

Levamisole in the adjuvant treatment of colon cancer.

The chemistry, pharmacology, pharmacokinetics, assay methodologies, adverse effects, and dosage of levamisole are described, and the clinical studies of levamisole therapy in patients with colorectal carcinoma are reviewed. Levamisole is a synthetic, orally active agent that has antihelmintic and immunomodulatory properties. It is capable of inducing T-cell differentiation and restoring depressed effector functions of peripheral lymphocytes and phagocytes to normal. The drug is well absorbed from the gastrointestinal tract after oral administration and is extensively metabolized by the liver. Gas chromatography and high-performance liquid chromatography are the most common methods used to measure concentrations of levamisole in biologic fluids. Levamisole combined with fluorouracil has been associated with a one-third reduction in recurrence and risk of death in patients with surgically resected Dukes stage C colon cancer; this combination is now recommended as standard therapy in these patients. Uses in patients with rectal carcinoma, Dukes stage B colon cancer, metastatic colon cancer, other malignancies, or nonmalignant disorders remain investigational. Common adverse effects include nausea, abdominal pain, vomiting, diarrhea, metallic or altered taste, flulike symptoms, mood elevation, insomnia, hyperalertness, dizziness, and headache. The most serious adverse effect associated with levamisole is granulocytopenia. The FDA-approved dosage of levamisole is 50 mg orally every eight hours for three days every two weeks. Levamisole therapy is to be initiated no earlier than 7 and no later than 30 days after surgery and is to be continued for one year. Levamisole combined with fluorouracil has been associated with a one-third reduction in recurrence and risk of death in patients with resected stage C colon cancer. Further research is needed to more clearly define the mechanism of action, optimum dose and scheduling, and clinical efficacy of levamisole in treating other malignancies.

Adenocarcinoma↗
PubMed1988

Efficacy of oral sucralfate suspension in prevention and treatment of chemotherapy-induced mucositis.

The efficacy of orally administered sucralfate suspension in preventing and treating chemotherapy-induced mucositis was evaluated in a double-blind trial. Forty-eight children and adolescents with newly diagnosed acute nonlymphocytic leukemia were randomized to receive suspensions of either sucralfate or placebo orally every 6 hours during the first 10 weeks of intensive remission-induction chemotherapy. Patients given sucralfate suspension were less likely than subjects receiving placebo to acquire colonization with potentially pathogenic microorganisms: 14 (58%) of 24 versus 22 (92%) of 24, respectively (p = 0.008). However, no effect on preexisting colonization was noted. Subjective reporting of discomfort, objective scoring of the severity of mucositis, and the maximal percent of body weight lost during therapy were similar; 58% of patients receiving sucralfate reported no oral pain compared with 25% receiving placebo (p = 0.06). Ten episodes of gastrointestinal bleeding, 25 documented infections, and 886 days with fever were also equally distributed between sucralfate and placebo groups. We conclude that sucralfate suspension is of limited, if any efficacy, in the prevention and treatment of chemotherapy-induced mucositis. Sucralfate administration can, however, reduce acquisition of alimentary colonization with potential pathogens, perhaps by interfering with adherence to mucosal membranes.

Administration, Oral↗
PubMed1983

Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion.

Twenty-nine children with acute lymphocytic leukemia were given 24-hr infusions of intermediate-dose methotrexate (MTX, 1000 mg/m2) with and without intrathecal (IT) MTX (12 mg/m2), followed by leucovorin rescue. There was substantial interpatient variability in MTX systemic clearance (98.3 +/- 51 ml/min/m2), inducing total steady-state serum MTX concentrations ranging from 5.4 to 33.7 microM. The cerebrospinal fluid (CSF) concentration at the end of the infusion was 0.27 (+/- 0.1) microM when no IT-MTX was given and correlated with total steady-state (24-hr) serum concentration of MTX. By stepwise regression, the CSF MTX concentration correlated better with the nonprotein bound (free) steady-state serum MTX concentration (r = 0.66, P less than 0.01) than with total steady-state serum MTX concentration. Mean CSF: serum MTX concentration ratio was 0.023 (+/- 0.04) when no IT MTX was given. When an IT MTX dose (12 mg/m2) was given at the start of the MTX infusion, the steady-state CSF MTX concentration was 1.1 (+/- 0.4) microM, leading to a mean CSF: serum ratio of 0.073 (+/- 0.05). Despite 7-hydroxy-MTX serum concentrations exceeding MTX concentrations immediately after infusion, 7-hydroxy-MTX was not detectable in CSF of most patients (21 of 29), and was less than 50% of the concurrent MTX concentration when detectable. These data establish the substantial interpatient variability in CSF distribution of MTX after intermediate-dose MTX infusions and establish a significant correlation between steady-state free concentration of MTX in serum and CSF MTX concentration.

Child↗
PubMed1982

Disposition of intermediate-dose methotrexate in children with acute lymphocytic leukemia.

Intermediate-dose methotrexate (MTX 200 mg/m2 iv in a bolus dose, followed by 800 mg/m2 iv, infused over 24 hours) is being used as a component of therapy for children with acute lymphocytic leukemia. To define the extent of interpatient variability in MTX disposition, with this dosage and schedule, the systemic clearance of MTX was measured in 69 children (total doses, 717; median, 10 doses per patient). The mean (+/- SD) systemic clearance was 91.6 (+/- 25.2) ml/min/m2 and ranged from 50-161 ml/min/m2. Renal clearance was measured in 16 of these patients and averaged 50.7 (+/- 14) ml/min/m2 during the MTX infusion (0-24 h), at which time mean systemic clearance was 8.7 (+/- 19) and nonrenal clearance was 31.1 (+/- 11.8) ml/min/m2. Measurement of 7-hydroxy-methotrexate in serum and urine was consistent with the substantial amount of nonrenal (metabolic) clearance observed in these patients. Cerebrospinal fluid MTX concentrations, measured at 24 hours, were 0.26 (+/- 0.1) microM when only the intravenous MTX was given and 1.08 (+/- 0.8) microM when an intrathecal dose (12 mg/m2) was also given at the start of the 24-hour infusion. This study establishes that there is substantial interpatient variability in MTX disposition in children and suggests a possible cause of variable patient response to MTX.

Adolescent↗
PubMedDate not supplied

Meperidine attenuates the secretion but not the transcription of interleukin 1 beta in human mononuclear leukocytes.

BACKGROUND: The infusion of amphotericin-B (AmB) often produces clinically distressing rigors and chills, which promptly abate with intravenous injection of meperidine, although its mechanism of action is unknown. OBJECTIVE: To examine the effects of meperidine on the transcription or secretion of Interleukin 1 beta (IL-1 beta) in human mononuclear leukocytes (MNL) exposed in vitro to the lipopolysaccharide (LPS) contained in Escherichia coli endotoxin or to AmB. METHODS: Blood was drawn from eight healthy adult volunteers. The blood was centrifuged, and the layer containing MNL was separated; incubated with various combinations of medium, meperidine, and AmB; then tested for IL-1 content to determine the effect of meperidine on MNL secretion of IL-1 beta. To determine the effect on MNL transcription of IL-1 beta, the RNA was extracted from cells and the IL-1 beta was measured using one of two different methods. RESULTS: Incubation of human MNL in the presence of LPS or AmB significantly increased transcription of IL-1 beta mRNA and secretion of IL-1 beta. Addition of meperidine to these cultures significantly reduced LPS-induced, but not AmB-induced, secretion of IL-1 beta in vitro. Meperidine did not alter IL-1 beta mRNA levels in MNL exposed to LPS or AmB. CONCLUSIONS: These data suggest that meperidine decreases rigors and chills in part by decreasing MNL secretion of IL-1 beta through a posttranscriptional mechanism.

Adult↗
PubMedDate not supplied

Meperidine attenuates the febrile response to endotoxin and interleukin-1 alpha in rats.

Intravenous meperidine is commonly used to treat rigors and chills in febrile patients, though its mechanism of action is unknown. Therefore a laboratory model of pyrogen-induced fever was used to evaluate the effects of meperidine on the febrile response of rats injected with bacterial endotoxin or IL-1 alpha. Fever was measured using a computerized biotelemetry system for the continuous monitoring of body temperature. Injection of meperidine blocked the onset of fever in rats injected with endotoxin and attenuated the febrile response in rats injected with IL-1 beta. Furthermore, incubation of human mononuclear leukocytes (MNL) in the presence of meperidine significantly reduced endotoxin-induced secretion of IL-1 beta in vitro. These data suggest that meperidine decreases rigors and chills by decreasing the "set point" for fever, perhaps by reducing MNL secretion of IL-1 beta.

Animals↗