Biomedical subjects

J A Dunn

Publications and source records attributed to J A Dunn.

At least 19 recordsLinked to original sources

PubMed2001

Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial.

BACKGROUND: The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. METHODS: After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat. Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005). Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

Adenocarcinoma↗

PubMed2001

Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma.

Oral clodronate (1600 mg/d) has been shown to significantly reduce the incidence of skeletal complications in multiple myeloma. Preliminary analysis of a double-blind placebo-controlled trial of this treatment indicated that clodronate might prolong survival in patients without vertebral fractures at presentation. This issue was re-examined after further follow-up of the patients recruited into the Medical Research Council (MRC) VIth Myeloma Study. The trial examined the effects of clodronate on the natural history of skeletal disease in multiple myeloma; 619 patients were randomized between June 1986 and May 1992 commencing 15 d after the start of ABCM [adriamycin, BCNU (carmustine), cyclophosphamide, melphalan] chemotherapy or 43 d after ABCMP (ABCM + prenisolone); 535 patients who received clodronate or placebo were included in the analysis. The presence or absence of spinal fractures was assessed centrally from spinal X-rays; long-bone fractures were assessed locally. With a median follow-up of 8.6 years, there was no overall significant difference in survival between the two treatment groups (O/E, chi2 = 0.78, P = 0.38). Among the subgroup of 153 patients with no skeletal fractures at presentation there was a significant survival advantage (O/E, chi2 = 7.52, P = 0.006) in favour of the 73 patients receiving clodronate, with median survivals being, respectively, 59 months (95% CI 43-71 months) and 37 months (95% CI 31-52 months), and 5-year survivals being 46% and 35%. The original analysis of this study shows that there is a benefit in taking 1600 mg clodronate daily for patients with myelomatosis to prevent the development of new skeletal disease. Bearing in mind the limitations of subgroup analysis, the present study indicates that treatment may prolong survival in patients without overt skeletal disease at diagnosis. These observations, however, require confirmation in prospective clinical trials.

Aged↗

PubMed2001

Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial.

OBJECTIVE: To assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. SUMMARY BACKGROUND DATA: Pancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. METHODS: ESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. RESULTS: Of 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. CONCLUSIONS: Resection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

Adenocarcinoma↗

PubMed2001

The single umbilical artery in a high-risk patient population: what should be offered?

OBJECTIVE: To determine whether fetal echocardiography is warranted in cases of single umbilical artery in a population at risk for aneuploidy. METHODS: All cases of fetal single umbilical artery identified over a 2-year period were reviewed for other sonographically detected abnormalities, fetal echocardiographic results, and karyotype. RESULTS: Sixty-five cases of single umbilical artery were diagnosed on the basis of initial sonograms. Five were subsequently shown to have 3-vessel cords (8% false-positive diagnosis; incidence, 1.2%). Excluding 3 from twin gestations, 57 cases formed the study population. Thirty-one fetuses (54%) were initially thought to have isolated single umbilical arteries, and 26 (46%) had nonisolated single umbilical arteries. Fetal echocardiography was performed in 29 cases (51%), 24 (83%) with normal findings and 5 (17%) with abnormal findings. Four (50%) of 8 nonisolated single umbilical arteries had abnormal echocardiographic findings versus 1 (5%) of 21 apparently isolated single umbilical arteries (P < .05; odds ratio, 20). Karyotypes in 36 cases (63%) showed 25 (69%) euploid and 11 (31%) aneuploid fetuses. An apparently isolated single umbilical artery was never associated with an abnormal karyotype. Eleven (50%) of 22 fetuses with nonisolated single umbilical arteries had aneuploidy (P < .005). The side of the missing umbilical artery did not correlate with other sonographically detected abnormalities, abnormal fetal echocardiographic findings, or aneuploidy. CONCLUSIONS: The rate of cardiac malformations seen with apparently isolated single umbilical arteries is significant, and fetal echocardiography should be performed.

Female↗

PubMed2000

Simultaneous determination of lamivudine and zidovudine concentrations in human seminal plasma using high-performance liquid chromatography and tandem mass spectrometry.

A HPLC-MS-MS method was developed and validated to measure lamivudine and zidovudine simultaneously in small volumes of human seminal plasma. Sample preparation was simple and rapid, requiring 25 microl of sample, the use of isotopically labeled lamivudine and zidovudine as internal standards and ultrafiltration through a molecular mass cut-off membrane. Lamivudine and its internal standard were separated from zidovudine and its internal standard with isocratic HPLC. Detection was carried out using tandem mass spectrometry. This validated method was used to analyze seminal samples obtained from six HIV-positive patients prescribed lamivudine and zidovudine.

Anti-HIV Agents↗

PubMed2000

Simultaneous determination of zidovudine and lamivudine in human serum using HPLC with tandem mass spectrometry.

A method employing high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS) has been developed and validated for the simultaneous determination of clinically relevant levels of zidovudine (AZT) and lamivudine (3TC) in human serum. The method incorporates a fully automated ultrafiltration sample preparation step that replaces the solid-phase extraction step typically used for HPLC with UV detection. The calibration range of the dual-analyte LC-MS/MS method is 2.5-2,500 and 2.5-5,000 ng ml-1 for AZT and 3TC, respectively, using 0.25 ml of human serum. The lower limit of quantification was 2.5 ng ml-1 for each analyte, with a chromatographic run time of approximately 6 min. Overall accuracy, expressed as bias, and inter- and intra-assay precision are < +/- 7 and < 10% for AZT, and < +/- 5 and < 12.1% for 3TC over the full concentration ranges. A cross-validation study demonstrated that the LC-MS/MS method afforded equivalent results to established methods consisting of a radioimmuno-assay for AZT and an HPLC-UV method for 3TC. Moreover, the LC-MS/MS was more sensitive, allowed markedly higher-throughput, and required smaller sample volumes (for 3TC only). The validated method has been used to support post-marketing clinical studies for Combivir a combination tablet containing AZT and 3TC.

Anti-HIV Agents↗

PubMed2000

Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer.

OBJECTIVES: To establish the long-term outcome for muscle-invasive transitional cell carcinoma of the bladder treated by radiotherapy with or without neoadjuvant cisplatin. METHODS: 159 patients with T2-T4a NX M0 bladder cancer were entered into a prospective randomized trial between June 1984 and June 1988. Follow-up was by 3-monthly cystoscopy in the first year, 6-monthly the next 2 years and yearly thereafter. Salvage surgery was performed at the discretion of the participating clinician. RESULTS: Minimum follow-up was 9 (median 11) years, at which time 29 patients (18%) remain alive. Median survival was 24 months with no difference between the treatment groups (chi(2) = 0.08, p = 0.77). Overall cystectomy rate was 24% (radiotherapy alone 20%, combined therapy 28%; p = 0.24). Median time to cystectomy from primary treatment was 12 months; range 56 days to 10 years. The risk of cystectomy was 11, 10 and 7% for the first, second and third years after radiotherapy respectively, and 8% in total after the third year. The proportion of patients alive in each successive year who had required a cystectomy was between 20 and 30% for 5 of the first 8 years after treatment. CONCLUSIONS: Salvage cystectomy is necessary in a quarter of patients after radiotherapy and this can be needed up to 10 years after treatment. During this time, multiple invasive procedures are likely to be performed, resulting in significant patient morbidity and cost. Patients should be fully counselled about the need for prolonged surveillance and the persisting risk of salvage surgery when deciding between primary cystectomy and radiotherapy.

Adult↗

PubMed1999

Liquid chromatographic-tandem mass spectrometric method for the determination of the neuraminidase inhibitor zanamivir (GG167) in human serum.

An LC-MS-MS method for the analysis of the neuraminidase inhibitor, zanamivir, in human serum is described. Zanamivir was extracted from protein precipitated human serum samples using Isolute SCX solid-phase extraction cartridges and analysed using reversed-phase chromatography with TurboIonSpray atmospheric pressure ionisation followed by mass spectrometric detection. The method uses a stable isotope internal standard, is highly specific and sensitive for a compound of this type and has been used for the analysis of human serum and urine samples from clinical studies. The method was extended to the analysis of serum and plasma samples from pre-clinical studies involving the rat, ferret and cell culture media. The method has been shown to be robust and valid over a concentration range of 10-5000 ng/ml using a 0.2-ml sample volume. The main advantages of this method compared to earlier procedures are primarily specificity, sensitivity, ease of sample preparation, small sample volume and short analysis time (ca. 5 min).

Animals↗

PubMed1999

Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer. British Stomach Cancer Group.

Cimetidine is thought to inhibit suppressor T-lymphocyte function and preliminary evidence from a randomized trial indicated that it might prolong survival for patients with operable and inoperable gastric cancer. The British Stomach Cancer Group conducted a randomized, double-blind, placebo-controlled trial examining the effects of cimetidine (400 mg or 800 mg twice a day) on the survival of patients with early (stages I, II and III: n = 229) and advanced (stages IVa and IVb: n = 201) gastric cancer. The primary end point was death. A total of 442 patients were randomized by 59 consultants in 39 hospitals between February 1990 and March 1995. Log-rank survival analysis was used to assess differences between the groups. Three hundred and forty patients died during the study: 166 (49%) in the cimetidine treatment groups and 174 (51%) in the placebo groups. Median survival for patients receiving cimetidine was 13 months (95% confidence interval (CI) 9-16 months) and 11 months in the placebo arm (95% CI 9-14 months). There was no significant difference in survival between the two treatment groups (P = 0.42) or between different doses of cimetidine tablets (P = 0.46). Five-year survival of those patients randomized to cimetidine was 21% compared to 18% for those patients randomized to placebo. Cimetidine at a dose of 400 mg or 800 mg twice a day does not have a significant influence on the survival of patients with gastric cancer compared to placebo.

Adult↗

PubMed1999

Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden.

Human immunodeficiency virus (HIV) can be transmitted in semen from a man to his sexual partners. Antiretroviral drugs are likely to affect the amount of HIV-1 in semen and perhaps transmission of the virus. The concentrations of zidovudine, lamivudine, and HIV-1 RNA in blood and seminal plasma were measured in 9 HIV-positive men over </=2 years. Median (25th-75th percentiles) zidovudine blood and seminal plasma concentrations were 64.2 (range, 48.4-206.9; n=82) and 292.5 (range, 194.3-438.4; n=79) ng/mL, respectively. Median lamivudine blood and seminal plasma concentrations were 391.3 (range, 175.3-793.8; n=82) and 2701.8 (range, 1460.5-4320.2; n=79) ng/mL, respectively. The concentration of HIV-1 RNA in seminal plasma was monitored as a potential surrogate marker for infectiousness. RNA became undetectable (<400 copies/mL) in the blood and seminal plasma of 8/9 subjects after initiation of therapy and remained undetectable in 6/9 subjects. These data show that zidovudine and lamivudine achieve high concentrations in seminal plasma and significantly reduce HIV-1 RNA. The effects of antiviral therapy on HIV-1 in semen and on the sexual transmission of HIV-1 require further study.

Adult↗

PubMed1998

MRC trial of alpha2b-interferon maintenance therapy in first plateau phase of multiple myeloma. MRC Working Party on Leukaemia in Adults.

Plateau phase has been achieved in 64% of all newly diagnosed patients with multiple myeloma treated with the ABCM (adriamycin, BiCNU, cyclophosphamide and melphalan) regimen in the Medical Research Council (MRC) trials; this stable clinical stage of the disease is associated with no more than minimal symptoms. Several studies have found that alpha-interferon (alpha-IFN) maintenance therapy increases the duration of plateau phase, but it is less clear if this translates into prolonged survival. We report the effect of alpha-IFN on the duration of plateau phase and overall survival in a trial with 284 patients who were randomized to receive alpha2b-IFN (Intron-A) or no maintenance therapy during first plateau phase. The minimum follow-up after randomization was 21 months. There was no significant difference in the overall survival between the two treatment groups (X2=0.32, P=0.57). There was a trend towards longer relapse-free survival in the patients allocated alpha-IFN, but this trend to longer plateau phase was not statistically significant (X2 = 1.62, P = 0.2). Disease progression at relapse on alpha-IFN appears to be more severe with greater elevations from plateau levels of serum paraprotein (P = 0.06) and beta2-microglobulin (P= 0.03) levels. Physicians tended to start chemotherapy sooner after diagnosis of relapse when patients had received alpha-IFN (P = 0.16). Although, in common with most other studies, there is a trend for patients treated with alpha-IFN to have a longer plateau phase, this is counteracted by morbidity attributable to the treatment and a somewhat shortened survival post relapse. Meta-analysis of interferon trials is required to assess whether the minor trend for longer survival in patients maintained on alpha-IFN found in some studies is significant and, if so, the extent of this advantage.

Adult↗

PubMed1997

Immunoglobulin molecules are present in early-generated neuronal populations in the rat cerebral cortex and retina.

Immunoglobulin-like antigens have been identified in neuronal subsets restricted to deeper layers of the developing mammalian cerebral cortex. The pattern is suggestive of selective uptake of immunoglobulin (Ig) from serum or synthesis of Ig or a molecule with Ig-like motifs. To distinguish between these alternatives, biochemical, immunocytochemical, and birthdating analyses were conducted. In neonatal rat cerebral cortex, immunoglobulin-like immunoreactivity was chiefly in subplate neurons, marginal zone neuropil, and processes spanning the cortical plate. Isolated staining was also observed within the ventricular zone. Although most staining in the cortical plate was absent several days after birth, subplate neuron staining persisted until the end of the second postnatal week. Quantitative immunoassays showed that the antigen concentration dropped from 130 ng/mg in cortical cytosol at birth to approximately 80 ng/mg by postnatal day 7 (P7) and remained low thereafter. Two Ig-immunoreactive polypeptides with mobilities similar to heavy and light chains of serum IgG, were identified by Western blotting. The larger band was purified, partially sequenced by Edman degradation, and found to match rat IgG heavy chain. Bromodeoxyuridine birthdating and anti-IgG double-labeling studies showed that most of the Ig-containing cells were early-generated neurons. Outside of the cortex, transient IgG staining was also detected in neurons of the retina and cerebellum. These studies suggest that subplate and other early-generated neurons selectively take up Ig from serum. The IgG may then either be degraded or lost from the central nervous system (CNS) during developmentally regulated cell death.

Amino Acid Sequence↗

PubMed1997

Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers.

Bupropion is an antidepressant agent that is also effective as an aid to quit cigarette smoking. A single 150-mg tablet of sustained-release bupropion hydrochloride was administered to two groups of volunteers, cigarette smokers and nonsmokers, who were matched for race, gender, body frame, age, and weight. Pharmacokinetic parameters were calculated for bupropion, and three major metabolites (hydroxybupropion and the aminoalcohol isomers, threohydrobupropion and erythrohydrobupropion, expressed as a composite total). Mean (+/-SD) values of area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity), maximum concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2) of bupropion in smokers and nonsmokers, respectively, were 1,164 +/- 220 ng.hr/mL and 1,161 +/- 292 ng.hr/mL; 144 +/- 28 ng/mL and 143 +/- 39 ng/mL; 3.00 +/- 0.50 hours and 2.88 +/- 0.49 hours; and 19 +/- 5 hours and 18 +/- 3 hours. No clinically significant differences between smokers and nonsmokers or between male and female volunteers were observed for the pharmacokinetics of bupropion or its metabolites. The absence of pharmacokinetic differences indicates that dosage adjustments are not necessary when bupropion is prescribed to male and female cigarette smokers.

Adolescent↗

PubMed1997

Randomised trial of immediate versus deferred treatment strategies for the management of minor cervical cytological abnormalities.

OBJECTIVE: To compare immediate and deferred treatment in women with cervical smears showing borderline nuclear abnormalities or mild dyskaryosis. DESIGN: Prospective randomised trial. SETTING: Colposcopy clinics at Birmingham and Midland Hospital for Women and the City Hospital NHS Trust, Dudley Road, Birmingham. PARTICIPANTS: Four hundred and thirty-five women with minor cytological abnormality younger than 35 years of age, of whom 353 were randomised to immediate treatment or deferred treatment. MAIN OUTCOME MEASURES: Comparison of histologies in the subsequent two years in the immediate and deferred treatment groups. RESULTS: Thirty-six women (21%) defaulted from follow up. The percentage of high grade abnormalities (CIN II and III) in the deferred treatment arm at two years is similar to that in the immediate treated arm at first colposcopy (25% vs 24%). Cytology failed to pick up two cases of CIN III and there was one case of early invasive carcinoma at the six month follow up. If treatment is deferred, the proportion with CIN I is almost halved (25% vs 13%); the proportion with koilocytic atypia is slightly reduced (51% vs 42%) and the proportion with no abnormality is substantially increased (0.6% vs 20%). CONCLUSION: Immediate referral and a select-and-treat management strategy of all women with any degree of dyskaryosis is recommended based on the case of invasive cervical cancer, high default rate and the failure of cytology to pick up two cases of CIN III.

Adolescent↗

PubMed1997

Therapeutic modification of nuclear factor kappa B binding activity and tumor necrosis factor-alpha gene expression during acute biliary pancreatitis.

The role of cytokines has been well documented in the pathogenesis of acute pancreatitis. Antibodies against specific cytokines have been used to treat pancreatitis, with mixed results. The transcription factor nuclear factor (NF)-kappa B is a pleiotropic regulator of many genes involved in stress and inflammatory responses. The aim of this study was to prevent the NF-kappa B binding activity and tumor necrosis factor (TNF)-alpha gene overexpression as a possible therapeutic intervention for acute pancreatitis. Reversible acute biliary pancreatitis was induced in male Sprague Dawley rats as established in this laboratory. The animals were sacrificed at 0, 5, 15, 30 min and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after the induction of pancreatitis. NF-kappa B binding activity was determined by electrophoretic mobility shift assay, and TNF-alpha gene expression was assayed by reverse transcription-PCR. NF-kappa B binding activity was markedly higher around 4 hours and persisted up to 24 hours after pancreatitis induction in animals with acute pancreatitis, whereas TNF-alpha mRNA levels peaked at 24 hours. When amobarbital (to block NF-kappa B activation) was given (60 mg/kg body weight, I.P.) 3 hours before induction of pancreatitis, the activation of NF-kappa B and the overexpression of TNF-alpha gene was prevented, with significantly decreased severity of pancreatitis as assessed by amylase and clinical recovery. We conclude that 1) preventing the activation of NF-kappa B eliminates the induced overexpression of inflammatory cytokines (TNF-alpha) in acute pancreatitis, 2) such intervention correlates with clinical improvement in pancreatitis, and 3) this genetic modification offers a possible therapeutic intervention in acute pancreatitis.

Acute Disease↗

PubMed1996

Validation of a high-performance liquid chromatographic-mass spectrometric method for the measurement of 5-chloro-2',3'-dideoxy-3' -fluorouridine (935U83) in human plasma.

An isocratic reversed-phase LC-MS method for measuring concentrations of 5-chloro-2',3'-dideoxy-3'-fluorouridine (935U83; I) directly and its 5'-glucuronide metabolite (5-chloro-2',3'-dideoxy-5'-O-beta-D-glucopyranuronosyl-3'-fluorour idine) indirectly in human plasma was developed, validated, and applied to a Phase I clinical study. The pyrimidine nucleoside, I, was extracted from human plasma by using anionic solid-phase extraction. The concentration of the glucuronide conjugate was determined from the difference between the molar concentration of I in a sample hydrolyzed with beta-glucuronidase and the nonhydrolyzed sample. Recovery of I from human plasma averaged 90%. The bias of the assay for I ranged from -5.5 to 7.1% during the validation and from -6.0 to 1.4% during application of the assay to the Phase I single-dose escalation study. The intra- and inter-day precision was less than 8% for I and its glucuronide conjugate. The lower and upper limits of quantitation for a 50-microliters sample were 4 ng/ml and 3000 ng/ml, respectively. No significant endogenous interferences were noted in human plasma obtained from drug-free volunteers nor from predose samples of HIV-infected patients.

Antiviral Agents↗

PubMed1996

In vitro characterization of a novel series of platelet-derived growth factor receptor tyrosine kinase inhibitors.

In this report, we describe the discovery and characterization of a novel biarylhydrazone series of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors typified by the prototype WIN 41662 (3-phenyl-N1-[1-(4-pytidyl)pyrimidine]hydrazone). WIN 41662 inhibited PDGF-stimulated autophosphorylation of PDGF receptors from human vascular smooth muscle cells (hVSMC) with an IC50 value of 60 nM. The inhibitor appeared to be competitive with respect to substrate (Mn(2+)-ATP), having a calculated Ki of 15 +/- 5 nM. WIN 41662 was approximately 500-fold more potent in inhibiting the PDGF receptor tyrosine kinase than the p56lck tyrosine kinase. It was inactive against other serine/threonine and tyrosine kinases tested. WIN 41662 produced concentration-dependent inhibition of PDGF-stimulated receptor autophosphorylation in intact hVSMC with an IC50 < 100 nM. Intracellular Ca2+ mobilization and cell proliferation were events that occurred in hVSMC subsequent to PDGF receptor activation. WIN 41662 inhibited PDGF-stimulated Ca2+ mobilization and cell proliferation ([3H]TdR incorporation) with IC50 values of 430 nM and 2.3 microM, respectively. These effects appeared to be specifically related to PDGF receptor tyrosine kinase inhibition since WIN 41662 was not cytotoxic (in vitro) and since WIN 72039, a close structural analog that does not inhibit PDGF receptor tyrosine kinase, also did not inhibit PDGF-stimulated receptor autophosphorylation, Ca2+ mobilization, or hVSMC proliferation. Thus, WIN 41662 is representative of a novel class of selective PDGF receptor tyrosine kinase inhibitors that inhibit PDGF-regulated secondary events in intact cells.

Adenosine Triphosphate↗

PubMed1996

Safety and pharmacokinetics of 5-chloro-2',3'-dideoxy-3'-fluorouridine (935U83) following oral administration of escalating single doses in human immunodeficiency virus-infected adults.

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a nucleoside analog reverse transcriptase inhibitor that has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. A phase I study was conducted to evaluate the safety and pharmacokinetics of six escalating single oral doses of 935U83 in 12 HIV-infected adults. The effect of a high-fat meal on the oral bioavailability of 935U83 was also assessed. The volunteers enrolled had CD4+ cell counts ranging from < 50 to 753 cells per mm3 (median, 198). In the dose range of 100 to 1,500 mg 935U83 was well tolerated by all subjects with no drug-related adverse events reported. No significant clinical or laboratory abnormalities were observed throughout the study. 935U83 was rapidly and well absorbed following oral administration with peak plasma concentrations (Cmax) occurring at 0.8 to 1.3 h postdosing. Mean Cmax and AUC0-infinity values of 935U83 were nearly dose proportional in the 100- to 1,500-mg dose range (from 2.4 to 30 micrograms/ml and from 3.4 to 59 h.micrograms/ml, respectively). Elimination of 935U83 from the plasma was rapid, with an apparent half-life of 1.3 to 1.7 h which was independent of the dose level. Administration of 935U83 with a high-fat meal decreased the rate of 935U83 absorption (mean Cmax decreased by approximately 50% and mean time to Cmax increased by approximately 1 h) but did not affect the extent of oral bioavailability (AUC0-infinity) of 935U83. The 5'-O-glucuronide conjugate was the principal metabolite of 935U83 and was present in the plasma of all volunteers at concentrations lower than 935U83. The molar AUC0-infinity ratio (935U83 glucuronide to the parent compound) was similar across all dose levels (mean, 21 to 27%). At least 60% of the 935U83 dose was absorbed, and approximately an equal percentage of the dose (approximately 30%) was excreted as unchanged 935U83 and as 935U83 glucuronide. Systemic exposure to 935U83 at levels exceeding its average in vitro antiretroviral 50% inhibitory concentration (approximately 0.5 microgram/ml or 1.8 microM) can be achieved after a single oral dose.

Administration, Oral↗