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Biomedical subjects

R A Carr

Publications and source records attributed to R A Carr.

At least 19 recordsLinked to original sources
PubMed2006

A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors.

BACKGROUND: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine-cisplatin chemotherapy in patients with solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors received gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of a 3-week cycle in combination with ABT-510. ABT-510 was administered subcutaneously twice daily at doses of 50 mg or 100 mg. Plasma samples for pharmacokinetics were obtained on days 1 (gemcitabine, cisplatin as single agents), 15 (ABT-510 as single agent) and 22 (gemcitabine, cisplatin and ABT-510 as combination). RESULTS: Thirteen patients received ABT-510 as either 50 mg b.i.d. (seven patients) or 100 mg b.i.d. (six patients) in combination with gemcitabine-cisplatin. The most common reported adverse events reflected the known toxicity profile induced by gemcitabine-cisplatin without ABT-510. One episode of hemoptysis occurred in a patient with non-small-cell lung cancer (NSCLC) after 13 days of treatment. No clinically significant pharmacokinetic interactions between ABT-510, gemcitabine and platinum were observed. Three partial responses were observed in 12 evaluable patients (one head and neck cancer, one melanoma and one NSCLC). CONCLUSIONS: Combining ABT-510 at doses of 50 mg and 100 mg with gemcitabine-cisplatin is feasible. Pharmacokinetic interactions were not observed and adding ABT-510 does not appear to increase toxicity.

Adult↗
PubMed2006

The Warwick system of prospective workload allocation in cellular pathology--an aid to subspecialisation: a comparison with the Royal College of Pathologists' system.

BACKGROUND: Guidelines on staffing and workload for histopathology and cytopathology departments was published by the Royal College of Pathologists (RCPath) in July 2003. In this document, a system is provided whereby the workload of a cellular pathology department and individual pathologists can be assessed with a scoring system based on specialty and complexity of the specimens. A similar, but simplified, system of scoring specimens by specialty was developed in the Warwick District General Hospital. The system was based on the specimen type and suggested clinical diagnosis, so that specimens could be allocated prospectively by the laboratory technical staff to even out workload and support subspecialisation in a department staffed by 4.6 whole-time equivalent consultant pathologists. METHODS: The pathologists were asked to indicate their reporting preferences to determine specialist reporting teams. The workload was allocated according to the "prospective" Warwick system (based on specimen type and suggested clinical diagnosis, not affected by final diagnosis or individual pathologist variation in reference to numbers of blocks, sections and special stains examined) for October 2003. The cumulative Warwick score was compared with the "retrospective" RCPath scoring system for each pathologist and between specialties. Four pathologists recorded their time for cut-up and reporting for the month audited. RESULTS: The equitable distribution of work between pathologists was ensured by the Warwick allocation and workload system, hence facilitating specialist reporting. Less variation was observed in points reported per hour by the Warwick system (6.3 (range 5.5-6.9)) than by the RCPath system (11.5 (range 9.3-15)). CONCLUSIONS: The RCPath system of scoring is inherently complex, is applied retrospectively and is not consistent across subspecialities. The Warwick system is simpler, prospective and can be run by technical staff; it facilitates even workload distribution throughout the day. Subspecialisation within a small-sized or medium-sized department with fair distribution of work between pathologists is also allowed for by this system. Reporting times among pathologists were shown by time and motion studies to be more consistent with Warwick points per hour than with RCPath points per hour.

Cytodiagnosis↗
PubMed2006

Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

Aged↗
PubMed2006

Subspecialisation in cellular pathology in the DGH setting: the Warwick experience.

A successful move towards subspecialised reporting in cellular pathology in the setting of a small to medium-sized district general hospital staffed by five consultant pathologists is described. This move has been facilitated by implementation of a prospective workload allocation system. Perceived benefits in service delivery and career progression are highlighted.

Cytodiagnosis↗
PubMed2004

Multiple congenital melanocytic naevi presenting with neurofibroma-like lesions complicated by malignant melanoma.

Giant congenital pigmented naevi and neurofibromatosis (NF-1) may rarely occur together. We report an unusual case where extensive congenital melanocytic naevi were associated with neurofibroma-like lesions that were clinically and histologically confused with neurofibromatosis. The development of malignant melanomas within the pigmented and pendulous lesions representing multiple congenital melanocytic naevi highlights the importance of an accurate diagnosis and a close follow-up of such patients.

Diagnosis, Differential↗
PubMed2001

Single bead characterization using analytical constructs: application to quality control of libraries.

Analytical construct technology has been successfully applied to the single-bead analysis of a split-mix combinatorial library. Substrates can be released from the resin by conventional cleavage for biological screening. Alternatively, for the purpose of analysis and quality control, cleavage at an orthogonal construct linker produces an analytical fragment incorporating the substrate. This analytical fragmnent is highly sensitized to electrospray mass spectrometry (ESI-MS) and is easily identified by isotope labeling. The construct cleavage rendered readily visible even those compounds that clearly could not be seen by conventional cleavage and mass spectrometry analysis. A 1H NMR control experiment proved that the compounds cleaved conventionally were, however, present in the sample in good yield and purity. In view of the data obtained, we think that this is a significant and important step toward solving our current quality control problems.

Amino Acids↗
PubMed2001

Reporter resins for solid-phase chemistry.

[reaction: see text] An analytical construct resin, designed to aid the analysis of solid-phase chemistry, has been mixed in a small proportion with a conventional resin. The analytical construct ("reporter resin") contains two orthogonal linkers that allow cleavage of either the synthetic intermediates (at linker 2) or their analytically enhanced derivatives (at linker 1). The convenient and rapid monitoring of each step in the syntheses of representative library compounds was possible using small resin aliquots.

Chemistry, Pharmaceutical↗
PubMed2000

Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.

Animals↗
PubMed1999

Sclerosing mesenteritis involving the pancreas: two cases of a rare cause of abdominal mass mimicking malignancy.

Two patients presented with abdominal pain and weight loss and each was found to have an abdominal mass involving the pancreas and small bowel mesentery. In both cases a malignant process was suspected clinically, radiologically and surgically. Multiple biopsy specimens in both patients showed dense fibrosis, chronic inflammation and fat necrosis with pancreatic infiltration. Histological opinions included the differential diagnosis of retroperitoneal fibrosis but, with the knowledge of the presence of localized masses, these cases were eventually considered to be due to sclerosing mesenteritis. Direct involvement of the pancreas has not previously been highlighted and led to diagnostic difficulty. Both patients have responded to treatment with corticosteroids. Interestingly, one of the patients subsequently developed a tubulo-interstitial nephritis, which has not previously been reported as associated with sclerosing mesenteritis. This has also responded to corticosteroid treatment.

Adult↗
PubMed1998

Steady-state pharmacokinetics and electrocardiographic pharmacodynamics of clarithromycin and loratadine after individual or concomitant administration.

To evaluate the potential for an interaction between clarithromycin and loratadine, healthy male volunteers (n = 24) received each of the following regimens according to a randomized crossover design: 500 mg of clarithromycin orally every 12 h (q12h) for 10 days, 10 mg of loratadine orally q24h for 10 days, and the combination of clarithromycin and loratadine. A washout interval of 14 days separated regimens. The addition of loratadine did not statistically significantly affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxy-clarithromycin. However, the addition of clarithromycin statistically significantly altered the steady-state maximum observed plasma concentration and the area under the plasma concentration-time curve over a dosing interval for loratadine (+36 and +76%, respectively) and for descarboethoxyloratadine (DCL), the active metabolite of loratadine (+69 and +49%, respectively). Clarithromycin probably inhibits the oxidative metabolism of loratadine and DCL by the cytochrome P-450 3A subfamily. Electrocardiograms (n = 12) were obtained over 24-h periods at baseline and steady state (day 10). The mean maximum QTc interval and area under the QTc interval-time curve on day 10 were modestly increased (<3%) from baseline for all three regimens, but no QTc interval exceeded 439 ms for any subject. Elevated steady-state concentrations of loratadine and DCL do not appear to be associated with adverse cardiovascular effects related to prolongation of the QTc interval. Loratadine and clarithromycin were well tolerated, alone and in combination.

Adolescent↗
PubMed1997

Lesions produced by the extravasation of urine from the upper urinary tract.

We present six cases which illustrate the spectrum of clinical features, macroscopic findings and light microscopic findings of urine extravasation from the upper urinary tract. The early lesions are characterized macroscopically by an oedematous, glistening or gelatinous appearance to the renal perihilar and peripelvic fat. Light microscopically there is lipolysis with associated foamy macrophages, multinucleate giant cells and lymphocytes. Immunohistochemical staining for Tamm-Horsfall protein is strongly positive in the extracellular space and in the foamy macrophages confirming urine extravazation. Later lesions are characterized by cicatrization of fibrous tissue around the renal pelvis and hydronephrosis. Microscopically there is relatively bland fibrosis with occasional lymphocytes and histiocytic cells. The late lesions are also characterized by extracellular deposits of weakly eosinophilic, granular or hyaline material, the so called 'urinary precipitates'. These deposits stain strongly with diastase PAS and weakly positive for Tamm-Horsfall protein. The staining of these urinary precipitates is analogous to renal tubular hyaline casts, thus supporting the theory that they are derived from uroproteins. We consider that these deposits are pathognomic of past urine extravasation.

Adolescent↗
PubMed1996

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger".

Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.

Amino Acid Sequence↗
PubMed1996

Influence of cimetidine coadministration on the pharmacokinetics of sotalol enantiomers in an anaesthetized rat model: evidence supporting active renal excretion of sotalol.

Sotalol (STL) is an amphoteric, chiral beta-adrenergic blocking drug useful in the treatment of both hypertension and ventricular arrhythmias. In the human and rat, STL enantiomers are predominantly cleared from the body by the kidney as intact drug. The renal clearance (Clr) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL enantiomers are excreted by an active renal transport system was investigated in the rat by coadministering racemic STL (10 mg kg-1) with cimetidine, an inhibitor of renal tubular secretion of organic cations. To compare the effects of short-term and sustained cimetidine exposure on STL enantiomer disposition, cimetidine was administered either as a single bolus (30 mg kg-1, n = 7) immediately prior to the STL dose, or as a 30 mg kg-1 bolus plus a 50 mg kg-1 infusion over the 6 h study period (n = 7). Blood and urine samples were collected over 6 h, during which time anaesthesia was maintained via intraperitoneal administration of pentobarbital. Cimetidine bolus and cimetidine infusion reduced STL enantiomer Clr by 43 and 59%, respectively, compared with respective saline controls. Significant stereoselectivity was observed in the cimetidine infusion group: systemic clearance, Clr (R > S), and AUC (S > R), although the magnitude of stereoselectivity was less than 5%. This study supports the hypothesis that STL enantiomers are predominantly cleared from the rat via a renal cationic transport mechanism and that this system can be competitively inhibited by the presence of cimetidine.

Adrenergic beta-Antagonists↗
PubMed1996

Renal, biliary and intestinal clearance of sotalol enantiomers in rat model: evidence of intestinal exsorption.

Biliary clearance (Clb) of sotalol (STL) enantiomers was assessed in anaesthetized Sprague-Dawley rats (419 +/- 9 g, mean +/- SEM, n = 4) following administration of a 10 mg kg-1 i.v. dose of the racemate. Clb for S- and R-STL (0.0675 +/- 0.0090 and 0.0662 +/- 0.0089 mL min-1 kg-1, respectively) represented approximately 0.3% of systemic clearance (Cls) values for S- and R-STL (20.4 +/- 2.2 and 20.7 +/- 2.0 mL min-1 kg-1, respectively). Bile:plasma concentration ratios at 1, 2, and 3 h post-dose were approximately 1.4, 1.3, and 1.2 for both STL enantiomers. Renal clearance (Clr) and intestinal clearance (Cli) of STL enantiomers were assessed in conscious Sprague-Dawley rats (325 g, n = 4) following administration of a 10 mg kg-1 i.v. dose of the racemate. STL enantiomers were predominantly eliminated intact in the urine: Clr for S- and R-STL (26.3 +/- 3.2 and 28.7 +/- 4.2 mL min-1 kg-1 respectively) accounted for approximately 96% of Cls for S- and R-STL (27.5 +/- 3.3 and 29.9 +/- 4.2 mL min-1 kg-1, respectively). Approximately 4% of the dose was recovered in the faeces, corresponding to Cli values of 1.16 +/- 0.17 and 1.26 +/- 0.19 mL min-1 kg-1 for S- and R-STL, respectively. Total recovery of the administered dose in urine and faeces was 99.7 +/- 0.2 and 99.8 +/- 0.5% for S- and R-STL, respectively. It is concluded from these results in the rat model that (i) STL enantiomers are predominantly eliminated intact in urine; (ii) STL enantiomers are excreted intact in bile, and to a much larger extent in the faeces, thus suggesting the presence of intestinal exsorption of STL; (iii) STL does not appear to be metabolized; and (iv) Cls, Clr, Clb, and Cli are negligibly stereoselective.

Adrenergic beta-Antagonists↗