Biomedical subjects
Publications and source records attributed to T Spector.
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OBJECTIVE: To outline the best available method of measurement for detecting progression of osteoarthritis (OA) of the hip especially in therapeutic trials. METHOD: A Medline search of articles related to progression of hip OA was performed. A group of experts met over a 1.5-day session to review available literature and new research. Specific questions were addressed in order to reach a consensus on measuring progression of OA of the hip. RESULTS: Of the available surrogate measures, a single yearly standing or reclined antero-posterior plain radiograph of the pelvis with feet internally rotated 15-20 degrees, can be evaluated with the use of an atlas for joint space width (JSW, interbone distance). There should be a minimum JSW upon baseline screening that may be 1 or 2 mm. Digitization of films offers a slight reduction in variability of measurements. Progression of OA can be calculated by measurement of the JSW on paired and blinded films. A reduction of > or = 0.5 mm is greater than the 'minimum perceptible difference' as well as the variation of most imaging techniques, and represents a clinically relevant and significant reduction in the JSW. Narrowing of the superomedial or superolateral JSW may tend to progress more rapidly than other changes. In clinical trials, patients who discontinue the study treatment need to be followed after discontinuation, and an imputation strategy which provides unbiased estimates of both the treatment effect and its variance is an appropriate technique for intent-to-treat analysis. CONCLUSION: For the development of new agents intended to prevent, retard, stabilize or reverse the progress of OA of the hip, the radiographic methodology presently available is adequate to detect changes in hip JSW of OA.
We used a twin study to investigate the genetic and environmental contributions to differences in musical pitch perception abilities in humans. We administered a Distorted Tunes Test (DTT), which requires subjects to judge whether simple popular melodies contain notes with incorrect pitch, to 136 monozygotic twin pairs and 148 dizygotic twin pairs. The correlation of DTT scores between twins was estimated at 0.67 for monozygotic pairs and 0.44 for dizygotic pairs. Genetic model-fitting techniques supported an additive genetic model, with heritability estimated at 0.71 to 0.80, depending on how subjects were categorized, and with no effect of shared environment. DTT scores were only weakly correlated with measures of peripheral hearing. This suggests that variation in musical pitch recognition is primarily due to highly heritable differences in auditory functions not tested by conventional audiologic methods.
OBJECTIVE: To construct a simple physiological model of leptin kinetics, based on measures of body size and composition, which is suitable for investigating the influence of genetic and other influences on circulating leptin levels in humans. METHODS: Consideration of the kinetics of the secretion and clearance of leptin led to a predicted linear relationship between ln(leptin), ln(fat mass), and a function of non-fat body compartments. Results obtained from this model were compared with those from two published empirical models based on adjustment for fat mass alone or for body mass index. Overnight fasted leptin levels, body composition data (dual-energy X-ray absorptiometry) and questionnaire responses were obtained from 527 twin pairs (127 monozygotic, 400 dizygotic; 37 male (age 18-68 y, BMI 18-32 kg/m2), 489 female (age 18-71, BMI 17-44) drawn from the St Thomas' UK Adult Twin Registry. RESULTS: In a partial correlation analysis ln(fat mass) and ln(height) (r=0.80, P<0.0001) and r=-0.22, P<0.0001 respectively) were independent predictors of ln(leptin) in females but ln(lean mass) was not (r=-0.01). A regression model incorporating ln(fat mass), ln(height) and a second order polynomial in age provided an adequate fit of the ln(leptin) data in females (r2=71%). ln(Leptin) values adjusted for body size and composition using the model were not significantly heritable (P=0.11), were significantly related to gender (r2=2.3%) and to ln(insulin) (r2=5.7%), but not to menopausal status (r2=0.7%), hormone replacement therapy (r2=0.4%), past or current smoking (r2=1.1%), or percentage trunk fat (r2=0.5%). Both empirical models found significant heritability (h2=36-42%), overestimated the effect of gender in the data (r2=14-16%), and produced significant relationships between adjusted ln(leptin) and percentage trunk fat (r2=4-12%). CONCLUSIONS: We conclude that our physiologically based model provides an adequate description of the relationship between leptin and body composition and provides a more reliable framework than current empirical approaches for the investigation of other influences on circulating leptin levels. Heritable variations in the control of leptin secretion are unlikely to contribute significantly to variations in leptin levels at the population level.
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We have shown previously that (R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of 5-fluorouracil (FUra) in rats bearing advanced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alanine (FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5-ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil-treated mice bearing MOPC-315 myeloma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also evaluated the effect of thymidylate synthase (TS) and thymidine kinase (TK) from tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the Eniluracil/FUra group than in the FUra-alone group at 120 hr. FBAL did not alter the effect of Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor FBAL affected the IC(50) of FUra in culture. Thus, the effect of FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established tumor.
Eniluracil (5-ethynyluracil, GW 776, 776C85) is being developed as a novel modulator of 5-fluorouracil (5-FU) for the treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), the first enzyme in the catabolic pathway of 5-FU. By temporarily eliminating this prevalent enzyme, eniluracil provides predictable dosing of 5-FU and enables oral administration of 5-FU to replace intravenous bolus and continuously infused dosing. New DPD is synthesized with a half-life of 2.6 days. It also eliminates the formation of problematic 5-FU catabolites. Most importantly, in laboratory animals, eniluracil increases the therapeutic index and absolute efficacy of 5-FU. Accompanying reports in this journal indicate that eniluracil has promising clinical potential.
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PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days. PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m(2) twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1. 35 to 1.8 mg/m(2) twice daily with an increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m(2) with eniluracil 20 mg twice daily was evaluated. RESULTS: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m(2) twice daily with eniluracil 20 mg twice daily. Mean (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m(2) (3.0 L/m(2)), and 51 mL/min/m(2) (13 mL/min/m(2)), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU C(SS,min) values achieved at the 1.0 mg/m(2) dose level were 22 ng/mL (8 to 38 ng/mL). CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.
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UNLABELLED: Noninvasive methods for measuring the pharmacokinetics of chemotherapeutic drugs such as 5-fluorouracil (FU) are needed for individualized optimization of treatment regimens. PET imaging of [18F]FU (PET/[18F]FU) is potentially useful in this context, but PET/[18F]FU is severely hampered by low tumor uptake of radiolabel and rapid catabolism of FU in vivo. Pretreatment with eniluracil (5-ethynyluracil) prevents catabolism of FU. Hypothesizing that suppression of catabolism would enhance PET/[18F]FU, we examined the effects of eniluracil on the short-term pharmacokinetics of the radiotracer. METHODS: Anesthetized rats bearing a subcutaneous rat colorectal tumor were given eniluracil or placebo and injected intravenously 1 h later with [18F]FU or [3H]FU. In the 18F studies, dynamic PET image sequences were obtained 0-2 h after injection. Tumors were excised and frozen at 2 h and then analyzed for labeled metabolites by high-performance liquid chromatography. Biodistribution of radiolabel was determined by direct tissue assay. RESULTS: Eniluracil improved tumor visualization in PET images. With eniluracil, tumor standardized uptake values ([activity/g]/[injected activity/g body weight]) increased from 0.72 +/- 0.06 (mean +/- SEM; n = 6) to 1.57 +/- 0.20 (n = 12; P < 0.01), and tumor uptake increased by factors of 2 or more relative to plasma (P < 0.05) and bone, liver, and kidney (P < 0.01). Without eniluracil (n = 5), 57% +/- 4% of recovered radiolabel in tumor at 2 h was on catabolites, with the rest divided among FU (2% +/- 1%), anabolites of FU (38% +/- 7%), and unidentified peaks (4% +/- 2%). With eniluracil (n = 8), catabolites, FU, and anabolites comprised 2% +/- 1%, 41% +/- 5%, and 57% +/- 4%, respectively, of the recovered radiolabel in tumors. CONCLUSION: Eniluracil increased tumor accumulation of 18F relative to host tissues and fundamentally changed the biochemical significance of that accumulation. With catabolism suppressed, tumor radioactivity reflected the therapeutically relevant aspect of FU pharmacokinetics--namely, uptake and anabolic activation of the drug. With this approach, it may be feasible to measure the transport and anabolism of [18F]FU in tumors by kinetic modeling and PET. Such information may be useful in predicting and increasing tumor response to FU.
Biochemical modulation of 5-fluorouracil (5-FU) has been used over the past 20 years to improve the therapeutic efficacy of this antineoplastic agent. Recently, modulation of the catabolic pathway of this fluoropyrimidine has been the focus of extensive preclinical and clinical investigation. Dihydropyrimidine dehydrogenase catalyzes the rate-limiting step in the catabolism of 5-FU and rapidly degrades 60-90% of the drug. An irreversible inactivating inhibitor of this enzyme, 5-ethynyluracil (EU), markedly improves the antitumor effect of 5-FU in animal models. Early clinical studies have shown a substantial alteration of the systemic disposition of 5-FU with an increase in 5-FU terminal half-life and have also indicated that EU allows safe oral administration of 5-FU by improving the oral bioavailability of the fluoropyrimidine, which is otherwise too erratic and unpredictable for a drug with such a limited therapeutic window. We evaluated the effect of EU on the metabolism of 5-FU in mice bearing colon 38 tumors using 19F nuclear magnetic resonance spectroscopy. Ex vivo measurements of tissue extracts from liver, kidney, and tumor indicated a >95% elimination of alpha-fluoro-beta-ureidopropionic acid and a-fluoro-beta-alanine signals in the tissues of mice that received 2 mg/kg of EU before administration of 5-FU. The spectra also showed an increased formation of fluoronucleotides in both normal and tumor tissues, a prolonged presence of 5-FU, and the accumulation of 5-fluorouridine that otherwise is undetectable, particularly in normal tissues. The in vivo NMR experiments on colon 38 tumors confirmed these findings, showing a complete elimination of the a-fluoro-beta-ureidopropionic acid and a-fluoro-beta-alanine signals in tumors treated with EU and a dramatic formation and accumulation of 5-fluorouridine mono-, di-, and triphosphates and 5-fluorouridine. Thus, by inactivating dihydropyrimidine dehydrogenase, EU prolonged the half-life for 5-FU, almost completely eliminated its catabolism for 4-6 h, which led to an increased accumulation of 5-fluorouridine mono-, di-, and triphosphates in both normal and tumor tissues.
Previous studies concerning the level of termination of the human spinal cord have been carried out in unselected cadavers. We have used magnetic resonance imaging to determine this level of termination, and that of the dural sac, in normal living subjects. We found a wider range of the level of termination of both the spinal cord and dural sac and a higher median level of termination of each than is commonly described. These anatomical findings are of clinical relevance to clinicians practicing regional anesthesia.
Because treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3-9.9], and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1-57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer.
Patients suffering from rheumatoid arthritis (RA) may experience a temporary reduction of disease symptoms during pregnancy. As indicated by the occurrence of RA-disease symptoms during pregnancy, three categories of patients were defined, namely, remission, relapse and unchanged. In all three categories changes in the plasma level and glycosylation of alpha1-acid glycoprotein (AGP) were determined longitudinally in comparison to those occurring in pregnancy of healthy women. In healthy pregnancy, we observed: (i) a peak in the plasma concentration at week 18 and a minimum at week 30; (ii) a continuous increase in the degree of branching of the glycans during the entire pregnancy period, and (iii) a decrease in the degree of alpha3-fucosylation of AGP-glycans with a minimum occurring at week 25. Comparable pregnancy-induced changes in glycosylation were found for two other acute-phase proteins alpha1-protease inhibitor (PI) and alpha1-antichymotrypsin (ACT). Increased oestrogen levels, known to occur during pregnancy, may be one of the factors that induce these changes, because the increased branching and decreased alpha3-fucosylation is in agreement with our earlier findings regarding an involvement of this hormone in the regulation of acute phase protein glycosylation in oestrogen-treated males as well as females. In all three clinical categories in RA, pregnancy also induced a continuous increase in the degree of branching of the glycans of AGP. However, similar changes in concentration and fucosylation were only found during remission of the disease symptoms. In the relapse and unchanged categories in RA, the degree of fucosylation and the plasma concentration of AGP remained constant throughout pregnancy. This indicates a relationship between changes in alpha3-fucosylation of AGP and RA disease activity.
Dihydropyrimidine dehydrogenase (DPD) is the key enzyme of the fluorouracil (FU) catabolic pathway. We have shown that tumor cells expressing a high DPD activity are resistant to FU (Eur J Cancer 30: 1517, 1994), and that 5-ethynyluracil (776C), a very potent DPD inactivator, markedly enhances the FU cytotoxic effect (Clin Cancer Res 1: 991, 1995). Both experimental background and clinical experience have demonstrated the role of folinic acid (FA) in increasing FU efficacy. The aim of the present study was to investigate the dual FU pharmacomodulation based on the combination of FU with 776C and/or FA on 7 human cancer cell lines (2 head and neck, 3 breast, 1 colon, 1 duodenum) expressing a spontaneous FU sensitivity. These cell lines were chosen according to their ability to respond to FU modulation by FA and/or 776C. The potency of FU modulation was evaluated by the ratio between FU IC50 and FU IC50 in the presence of the tested biomodulator(s), defined as factor F. In cell lines sensitive to FU modulation by 776C only (median F value with 1 microM of 776C = 2.5), the addition of FA did not enhance FU-776C cytotoxicity. In contrast, for cell lines resistant to FU modulation by 776C, the FU-FA-776C combination led to a significant cytotoxicity enhancement as compared to FU-FA (median F values were 3.6 and 2.6 respectively). In cell lines responsive to FU modulation by FA and 776C, the median F values were 2.3 and 1.8 with FA and 776C, respectively. Interestingly, the dual modulation by FA + 776C led to a median F value at 6.3, suggesting more than the additive effects of FA and 776C. This synergistic interaction was statistically confirmed by multivariate ANOVA (FA x 776C interaction). The present study points out that FA plus 776C could prove to be a very attractive combination for future strategies in FU biomodulation.
UNLABELLED: The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihydropyrimidine dehydrogenase (DPD) inactivator, 5-ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. METHOD: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. RESULTS: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL = 0.47B0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (Vc) increased proportionately with body weight (Vc = 0.58 B0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m2 of 5-FU, respectively. DISCUSSION: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85.
Patients with treated Wilson's disease and no residual impairments should have successful pregnancies. We report a case of a neurologically impaired patient with Wilson's disease who had a successful pregnancy with no complications. This is the first case to document that compliance with penicillamine therapy as low as 500 mg/day avoids placental and fetal copper accumulation.