Impact of choice of volumetry software and nodule management guidelines on recall rates in lung cancer screening.

PURPOSE: Appropriate lung nodule management is essential to minimizing unnecessary patient recall in lung cancer screening. Two European guidelines provide differing recommendations in that participants with nodules ≥100 mm3 or ≥80 mm3 respectively should be recalled, at baseline. Nodule size estimation is known to vary between volumetry software packages (VSPs). The aim of this study was to examine the impact of choice of VSP on participant recall rates, when applying different European nodule management guidelines. An additional aim was to compare recall rates between 7 VSPs and manual diameter measurements. METHODS: 156 small-sized lung nodules (50-150 mm3) from the UK Lung Screening trial were measured using 7 different VSPs (VSP1-7) and also using manual diameter. The type of VSP used in the NELSON study (VSP1), on which European nodule management guidelines are based, provided the reference standard. Nodule size was compared using Bland Altman, and recall rates by Mcnemar's test. RESULTS: Compared to the reference standard, a 100 mm3 threshold for recall, resulted in no difference in recall rates only for VSP 5 & 7. Using an 80mm3 threshold resulted in no difference in recall rates for VSP2 & 6. Recall rates were significantly higher for VSP 4 regardless of threshold and when using manual diameter measurements. CONCLUSIONS: Appropriate nodule size thresholds for recall in screening depend on the type of volumetry software used. The results highlight the importance of benchmarking of volumetry packages.

Idiopathic pulmonary fibrosis: current and future directions.

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and is increasingly recognised. Prior to the advent of effective therapies, achieving an early diagnosis was arguably of little prognostic consequence given IPF was considered an untreatable and uniformly fatal disease. The advent of new drug treatments has given hope for the future and raised the profile of IPF. International management guidelines highlight the critical role of radiology as part of an interstitial lung disease multidisciplinary team approach in reaching an accurate and early diagnosis of IPF. The diagnostic criteria and levels of diagnostic confidence for the radio-pathological pattern associated with the clinical syndrome of IPF, usual interstitial pneumonia (UIP), appear seemingly straightforward; however, with increasing research and recognition of radiopathological interobserver variability, limitations of this classification model are becoming increasingly apparent. This review describes ancillary radiological features, comorbidities, and emerging new entities that potentially co-exist with IPF. Beyond diagnosis radiology is developing as a key prognostic tool to inform longitudinal patient evaluation. These diagnostic and prognostic clinical challenges and the future role of radiology in IPF are discussed.

Anti-platelet and anti-hypertension medication use in patients with fibromuscular dysplasia: Results from the United States Registry for Fibromuscular Dysplasia.

Fibromuscular dysplasia (FMD), a non-inflammatory arterial disease, may lead to renovascular hypertension (HTN) and cerebrovascular disease. Little is known about medication use in FMD. Clinical features and medication use were reviewed in a national FMD registry (12 US sites). Medication usage was assessed in raw and adjusted analyses. Covariates included demographic characteristics, co-morbid conditions and vascular bed involvement. A total of 874 subjects (93.6% female) were included in the analysis. Mean age was 55.6±13.1 years, 74.5% had HTN, 25.4% had a history of transient ischemic attack or stroke, and 7.5% had a history of coronary artery disease (CAD). Renal and cerebrovascular arteries were affected in 70.4% and 74.7%, respectively. Anti-platelet agents were administered to 72.9% of patients. In multivariate analyses, factors associated with a greater likelihood of anti-platelet agent use were older age (OR=1.02 per year, p=0.005), CAD (OR=3.76, p=0.015), cerebrovascular artery FMD involvement in isolation (OR=2.31, p<0.0001) or a history of previous intervention for FMD (OR=1.52, p=0.036). A greater number of anti-HTN medications was evident in isolated renal versus isolated cerebrovascular FMD patients. Factors associated with a greater number of anti-HTN medications were older age (OR=1.03 per year, p<0.0001), history of HTN (OR=24.04, p<0.0001), history of CAD (OR=2.71, p=0.0008) and a history of a previous therapeutic procedure (OR=1.72, p=0.001). In conclusion, in FMD, medication use varies based on vascular bed involvement. Isolated renal FMD patients receive more anti-HTN agents and there is greater anti-platelet agent use among patients with cerebrovascular FMD. Further studies correlating medication use in FMD with clinically meaningful patient outcomes are necessary.

Acceptability of oral iodinated contrast media: a head-to-head comparison of four media.

OBJECTIVE: To assess the palatability of iodinated oral contrast media commonly used in abdominopelvic CT and CT colonography (CTC). METHODS: 80 volunteers assessed the palatability of a 20-ml sample of a standard 30 mg ml(-1) dilution of Omnipaque® (iohexol; GE Healthcare, Cork, Ireland), Telebrix® (meglumine ioxithalamate; Guerbet, Aulnay-sous-Bois, France), Gastromiro® (iopamidol; Bracco, High Wycombe, UK) and Gastrografin® (sodium diatrizoate and meglumine diatrizoate; Bayer, Newbury, UK) in a computer-generated random order. RESULTS: Gastrografin is rated significantly less palatable than the remaining media (p<0.005). Omnipaque and Telebrix are significantly more palatable than Gastromiro. No difference existed between Omnipaque and Telebrix. 39% of participants would refuse to consume the quantities of Gastrografin required for a CTC examination compared with Telebrix (7%) and Omnipaque (9%) (p<0.05). CONCLUSION: Omnipaque and Telebrix are significantly more palatable than both Gastromiro and Gastrografin, with participants more willing to ingest them in larger quantities as well as being less expensive. ADVANCES IN KNOWLEDGE: Omnipaque and Telebrix are significantly more palatable iodinated oral contrast media than both Gastromiro and Gastrografin, which has potential implications in compliance with both abdominopelvic CT and CTC.

Symmetrically medial bony gutters for open-door laminoplasty.

STUDY DESIGN: Observational cohort study. OBJECTIVE: The authors modified open-door laminoplasty in a manner that creates a bony gutter symmetrically and more medially away from the medial border of the lateral mass. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is becoming popular, but there was no definite position of bony gutter in performing open-door laminoplasty. METHODS: All of the patients underwent our modified open-door laminoplasty with medial bony gutters. The bony gutter on the open side was made 3 mm medially apart from the medial border of the lateral mass, and an opposite gutter on the hinge side was drilled symmetrically to that on the open side while preserving the ventral cortex. The lamina was kept elevated using titanium miniplates bridging the lamina and facet joint on the open side. On the computed tomography, distance of the bony gutters and the cross-sectional area were measured from C4 to C6. RESULTS: This study included consecutive 61 patients (46 men and 15 women; mean age, 61.6 y old). The average distance of the right bony gutter was 3.43 mm and that of left bony gutter was 3.35 mm. The average cross-sectional area of preoperative and postoperative computed tomography was 189.9 and 281.8 mm in all patients, respectively. In all patients, although bony gutter was placed medially, the spinal canal area was expanded significantly (P < 0.0001). Postoperative C5 palsy developed in one of the 61 patients (1.6%). Compared with patients without C5 palsy, the right bony gutter was placed much closer to the medial border of the lateral mass in a patient with C5 palsy in whom we opened the lamina on the right side. CONCLUSIONS: Our modified open-door laminoplasty with symmetrically and medially placed bony gutters produced low incidence of postoperative C5 palsy with effective expansion of the spinal canal area.

Chronic low dose Adderall XR down-regulates cfos expression in infantile and prepubertal rat striatum and cortex.

We previously reported that treatment of prepubertal male rats with low, injected or oral, doses of methylphenidate stimulated cfos, fosB and arc expression in many areas of the developing brain. In the present study our objective was to determine whether the widely prescribed psychostimulant Adderall XR (ADD) exerted similar effects in infantile and prepubertal rat brain. We report here, for the first time, that low threshold doses of oral ADD, an extended-release mixture of amphetamine salts, now routinely used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), also increased cfos expression in infantile (postnatal day 10; PD10) and prepubertal (PD24) rat brain. These threshold doses were correlated with blood levels of amphetamine determined by liquid chromatography-mass spectrometry. Moreover, we observed that chronic treatment with oral ADD (1.6 mg/kg; x 14 days) not only significantly down-regulated cfos expression following a final challenge dose of ADD in prepubertal (PD24) rat striatum and cortex, quantified in terms of FOS immunoreactivity (FOS-ir), but did so at a daily dose that was without effect with methylphenidate (MPH); that is a much higher oral dose of MPH (7.5 mg/kg; x 14 days) failed to induce down-regulation of cfos expression. Similar experiments in infantile rats (PD10), but using a threshold injected dose of ADD (1.25 mg/kg sc) also significantly reduced striatal and cingulate cortical FOS-ir. An additional finding in the prepubertal rats was that oral ADD-induced FOS-ir was observed in the cerebral cortex following doses lower than the threshold dose necessary to increase FOS-ir in the striatum. This was not the case in the PD10 rats. In conclusion, our efforts to calibrate biological responses, such as immediate early gene expression, to clinically relevant blood levels of stimulants confirmed that expression of cfos is very sensitive to repeated low doses of Adderall XR. It is now feasible to examine whether other genes are also affected in these young rats and if the changes we report are reversible. The implications of such studies should be relevant to the putative effects of psychostimulant treatment of very young children.

Methylphenidate regulates activity regulated cytoskeletal associated but not brain-derived neurotrophic factor gene expression in the developing rat striatum.

Methylphenidate (MPH) is a psychostimulant drug used to treat attention deficit hyperactivity disorder in children. To explore the central effects of chronic MPH, we investigated the expression of an effector immediate early gene, activity regulated cytoskeletal associated (arc), and the neurotrophin, brain-derived neurotrophic factor (bdnf) in the brain of immature and adult rats following repeated MPH. Prepubertal (postnatal day (PD) 25-38) and adult (PD 53-66) male rats were injected once daily for: a) 14 days with saline or MPH (2 or 10 mg/kg; s.c.) or b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg; s.c.). To determine possible long-term effects of MPH, prepubertal rats were allowed a drug-free period of 4 weeks following the 14 days of treatment, and then were given a challenge dose of MPH. We demonstrated, for the first time, that an acute injection of MPH increased levels of activity-regulated cytoskeletal protein (ARC) and arc mRNA in the prepubertal rat striatum and cingulate/frontal cortex. This response was significantly attenuated by chronic MPH. The desensitization in arc expression observed in prepubertal rats persisted in the adult striatum following a later MPH challenge. In contrast to these data we observed little effect of MPH on bdnf expression. We also developed an effective, non-stressful technique to treat freely moving immature rats with oral MPH. Consistent with the results described above, we observed that oral MPH (7.5 and 10 mg/kg) also increased arc expression in the prepubertal rat striatum. However, unlike the effects of injected MPH, repeated oral MPH (7.5 mg/kg) did not alter the normal arc response. This result raises the important possibility that oral doses of MPH that reproduce clinically relevant blood levels of MPH may not down-regulate gene expression, at least in the short term (14 days). We confirmed, using mass spectrometry, that the oral doses of MPH used in our experiments yielded blood levels within the clinical range observed in children. The novel oral administration paradigm that we describe thus provides a clinically relevant animal model to further explore the effects of chronic drug exposure on central gene expression in the developing rat brain.

Structural, genetic and functional characterization of the flagellin glycosylation process in Helicobacter pylori.

Mass spectrometry analyses of the complex polar flagella from Helicobacter pylori demonstrated that both FlaA and FlaB proteins are post-translationally modified with pseudaminic acid (Pse5Ac7Ac, 5,7-diacetamido-3,5,7,9-tetradeoxy-l-glycero-l-manno -n o n-ulosonic acid). Unlike Campylobacter, flagellar glycosylation in Helicobacter displays little heterogeneity in isoform or glycoform distribution, although all glycosylation sites are located in the central core region of the protein monomer in a manner similar to that found in Campylobacter. Bioinformatic analysis revealed five genes (HP0840, HP0178, HP0326A, HP0326B, HP0114) homologous to other prokaryote genes previously reported to be involved in motility, flagellar glycosylation or polysaccharide biosynthesis. Insertional mutagenesis of four of these homologues in Helicobacter (HP0178, HP0326A, HP0326B, HP0114) resulted in a non-motile phenotype, no structural flagella filament and only minor amounts of flagellin protein detectable by Western immunoblot. However, mRNA levels for the flagellin structural genes remained unaffected by each mutation. In view of the combined bioinformatic and structural evidence indicating a role for these gene products in glycan biosynthesis, subsequent investigations focused on the functional characterization of the respective gene products. A novel approach was devised to identify biosynthetic sugar nucleotide precursors from intracellular metabolic pools of parent and isogenic mutants using capillary electrophoresis-electrospray mass spectrometry (CE-ESMS) and precursor ion scanning. HP0326A, HP0326B and the HP0178 gene products are directly involved in the biosynthesis of the nucleotide-activated form of Pse, CMP-Pse. Mass spectral analyses of the cytosolic extract from the HP0326A and HP0326B isogenic mutants revealed the accumulation of a mono- and a diacetamido trideoxyhexose UDP sugar nucleotide precursor.

Typhoid fever in Kuala Lumpur and a comparative evaluation of two commercial diagnostic kits for the detection of antibodies to Salmonella typhi.

The aim of this study was to compare two commercial kits, theTyphidot and the PanBio ELISA with the present Widal test. Demographic data for all serodiagnosed cases for the years 1991-1998 were collected. From this data, 144 were selected as samples for comparative evaluation of the commercial kits. Fifty sera were culture positive for Salmonella typhi, 50 were culture negative but clinically diagnosed as typhoid fever and Widal positive and 44 were serodiagnosed as enteric of which 21 were culture positive for other Salmonella species, 20 were serodiagnosed for other febrile illnesses and three sera culture positive for other species of enterobacteriaceae. The specificity, sensitivity and efficiency of the tests were calculated with the positive culture for S. typhi as the gold standard. Sensitivity, specificity and efficiency of test for Typhidot and Typhidot M kits were 98%, 76.6% and 84.0% and PanBio ELISA were 78%, 80% and 79.9%. The two commercial kits evaluated were found to be less time consuming and easier to perform than Widal. The Typhidot M seems to be a practical alternative in the field and in small hospitals with lesser facilities.

The effect of chronic cocaine administration on hemodynamic stability and neurohumoral mediators during isoflurane anesthesia and shock in rats.

BACKGROUND: The aim of this investigation was to determine whether chronic cocaine administration altered endogenous vasoconstrictor secretion in response to hypotension from isoflurane anesthesia and blood loss in rats. METHODS: Rats received continuous intravenous infusions of saline (n=11), or cocaine 6 mg kg(-1) d(-1) (n=13) or 18 mg kg(-1) d(-1) (n=12) for 13 days. On day 14, rats were anesthetized with intraperitoneal ketamine and xylazine and a femoral artery catheter and a tracheotomy performed to allow lung ventilation (PaCO2, 30-40 mmHg). After baseline parameters were noted, isoflurane was introduced to end-tidal concentrations of 0.7% for 10 min (1/2 MAC), 1.4% for 10 min (MAC) and again 0.7% for 10 min (1/2 MAC-2) when 5 ml of blood was withdrawn (SHOCK). Blood samples were drawn to assess arterial blood gas indices at various time points as well as plasma epinephrine, angiotensin II and vasopressin at MAC, 1/2 MAC-2 and SHOCK. RESULTS: Rats administered cocaine had higher oxygen extraction, required higher minute ventilation and had lower PaO2 values than rats administered saline despite similar body temperatures and hematocrits. Isoflurane administration resulted in significant dose dependent but similar blood pressure decreases in all study groups. Plasma epinephrine, angiotensin II and vasopressin concentrations were not different in saline or cocaine treated animals at any time point. CONCLUSION: These data suggest that chronic cocaine treatment in rats does not impair endogenous vasoconstrictor secretion nor alter the heart rate and blood pressure response to isoflurane and blood loss.

Structural effects of Ti underlayer on CoCrPt magnetic films.

The effects of long-range and short-range orders of Ti underlayer thickness on the magnetic properties of sputtered Co72 Cr21 Pt7 films were investigated using synchrotron X-ray scattering and X-ray absorption near-edge structure spectroscopy. The results were consistent with that of magnetic measurements and X-ray photoelectron spectroscopy. For thin Ti underlayers (10 nm), the oxidation of Ti and significant mixing of other elements within this underlayer did not promote texture development, further resulting in poor texturing of magnetic films and undesirable magnetic properties. Increased crystallinity and texture of metallic Ti in thicker underlayers enhanced the magnetic peak alignment and its properties.

Chronic continuous cocaine infusion in rats: effect on urine cocaine, ecgonine methylester and benzoylecgonine concentrations and bolus-dose cocaine pharmacokinetics.

The aim of this study was to determine the effect of chronic cocaine infusion on urine cocaine, ecgonine methylester and benzoylecgonine concentrations to establish if they varied with dose and duration of cocaine administration. Male rats were continuously infused with cocaine at either 6 or 18 mg kg(-1) daily for 13 days. Three urine samples taken over the course of the infusion period showed that cocaine, ecgonine methylester and benzoylecgonine concentrations varied with the dose administered and the duration of administration. Cocaine, ecgonine methylester and benzoylecgonine concentrations were 2-3 times greater in the high-dose group than the low-dose group at each sampling time point. These decreased, respectively, from 7.0+/-1.1, 26.7+/-4.5 and 29.5+/-5.4 microg mL(-1) to 2.5+/-0.5, 10.5+/-1.8 and 11.8+/-1.5 microg mL(-1) in the high-dose group and from 1.0+/-0-2, 7.8+/-1.5 and 6.3+/-0.1 microg mL(-1) to 0.5+/-0.1, 4.0+/-0.6 and 3.1+/-0.4 microg mL(-1) in the low-dose group (P < 0.05) over the infusion period. We also studied the pharmacokinetic and metabolic profile of an intravenous bolus dose of 2.5 mg kg(-1) cocaine hydrochloride after a similar cocaine infusion in rats. Cocaine pharmacokinetics and the profile of ecgonine methylester, benzoylecgonine and norcocaine were no different from rats chronically infused with saline for the same period. Altered cocaine metabolism could not explain the effect of the duration of cocaine infusion on altered metabolite concentrations in urine. Ecgonine methylester/benzoylecgonine urine concentration ratios did not alter with duration of infusion (1.2+/-0.2 and 1.1+/-0.2 in the high-dose group at the first and last time point) and were not affected by the dose of cocaine (1.3+/-0.6 and 1.2+/-0.1 at corresponding times in the low-dose group (P > 0.05)). We conclude that chronic cocaine infusion does not alter cocaine metabolism. This was not reflected by absolute cocaine metabolite urine concentrations, which varied with time, but was represented by urine ecgonine methyl ester/benzoylecgonine concentration ratios.

Leptospirosis in Kuala Lumpur and the comparative evaluation of two rapid commercial diagnostic kits against the MAT test for the detection of antibodies to leptospira interrogans.

The aim of the study was to look into the epidemiology of serodiagnosed cases of leptospirosis at the University Hospital and compare two commercial ELISA Assays to the Microscopic Agglutination Test (MAT). Demographic data for all serodiagnosed cases for the years 1991-1997 were collected. From this data, 104 sera (n = 104) were selected as samples for comparative evaluation of the commercial ELISAs (INDX Dip-S-Ticks and PanBio ELISA) to the MAT test. Thirty two (n = 32) negative control sera were selected from serodiagnosed cases of other differential diagnosis of leptospira infection. The MAT test is a standard test that detects agglutination antibodies to leptospira biflexa, while the INDX Dip-S-Ticks is an ELISA dot test assaying for total anti-leptospira antibodies. The PanBio ELISA is a colorometric assay in test well strips to detect anti-leptospira IgM. The sensitivity, specificity, and efficiency of tests were calculated at a MAT cut-off value of 1:320. Demographic data showed that leptospirosis peaks during March-May and Aug-Nov coinciding with the inter-monsoon period with more men being infected than women and more adults than children. The sensitivity, specificity, and efficiency of test for the INDX Dip-S-Ticks were 83.3%, 93.8% and 87.5% while the values for the PanBio ELISA were 54.2%, 96.9% and 71.3%. The suboptimal PanBio result could be related to the blocking effect of high IgG titres or could be related to the diagnostic MAT cut-off values used in this study. The data hence reflects a pattern of transmission that is related to "wet" occupational risk factors. The commercial assays evaluated, are easier to perform but interpretation of results should be based on level of endemicity. The INDX Dip-S-Ticks allows this flexibility and is a practical alternative to the MAT test.

Cocaine, norcocaine, ecgonine methylester and benzoylecgonine pharmacokinetics in the rat.

We have compared the pharmacokinetics of bolus dose cocaine administration with that of its three most important metabolites; norcocaine, ecgonine methylester, and benzoylecgonine and assessed whether kinetics are dose dependent at two equimolar doses equivalent to cocaine hydrochloride 2.5 and 5 mg/kg respectively. Forty-nine male Sprague-Dawley rats were randomly divided into 8 groups to receive i.v. either high (14.7 umol/kg) (HI) or low (7.3 umol/kg) (LO) bolus doses of cocaine or one of its metabolites. Arterial blood samples for cocaine and metabolite analysis were taken repetitively over the next 3 h. Equimolar bolus doses of these congeners showed biexponential plasma concentration decay curves which were fitted to a two compartment model and subjected to noncompartmental analysis. The plasma concentration time profiles were significantly different for the HI and LO doses administered for each congener. The elimination half-lives of cocaine and norcocaine were similar (28-33 min), that for ecgonine methylester (60-71 min) was approximately twice this and for benzoylecgonine was 40-44 min. Cocaine clearance (155-158 ml/kg/min) was found to be in the range found in other rat studies. Ecgonine methylester clearance and benzoylecgonine clearance were found to be one quarter and one eighth of this value respectively. The pharmacokinetic profile of these congeners was not dose dependent when the two doses administered were compared.

Effect of glutathione deficiency on the adipocyte sn-glycerol-3-phosphate acyltransferase.

The present study investigates the effects of various glutathione (GSH) depleting agents on sn-glycerol-3-phosphate acyltransferase (GPAT) activity, the first committed step in adipose triacylglycerol formation. GPAT activity was measured in the presence of [14C]glycerol-3-phosphate and palmitoyl-CoA, using different subcellular fractions. Glutathione deficiency in animals was induced in the presence of diethylmaleate (DEM) or buthionine sulfoximine. In this respect, DEM (1.75 mmoles/kg) was more effective and caused over 75% decrease in GPAT activity within 4 h of DEM administration. Further studies indicated that this decrease in GPAT activity was mainly related to the microsomal form of GPAT, without any significant effect on mitochondrial GPAT activity. Adipocytes incubated with 2.5 mm DEM for 1 h at 37 degrees C also showed a reduction in the adipocyte glutathione content, which was accompanied by decreases in GPAT activity. The effect of DEM on adipocyte GPAT activity was partially reversible in the presence of cell permeable glutathione ethyl ester. Preincubation of adipose tissue homogenates with 2.5 mM DEM at 30 degrees C for 45 min also showed a significant loss of the GPAT activity. The presence of 5 mM dithiothreitol in the preincubation mixture offered a significant protection of the GPAT activity against DEM. However, glutathione was ineffective in this respect as it interfered with the utilization of palmitoyl-CoA in the GPAT assay. Therefore, on the basis of these three different approaches, the present studies suggest that the thiol environment offered by glutathione (in vivo and in vitro studies) or dithiothreitol (in a cell-free system) is critical for the maintenance of GPAT activity.

Determination of p-aminosalicylic acid and its N-acetylated metabolite in human urine by capillary zone electrophoresis as a measure of in vivo N-acetyltransferase 1 activity.

A capillary zone electrophoresis method has been developed for the determination of p-aminosalicylic acid (PAS) and its metabolite, N-acetyl-p-aminosalicylic acid (N-acetyl-PAS), in urine. A linear relationship was observed between time-normalized peak area and the concentration of the parent and metabolite with correlation coefficients greater than 0.9990. The method could be applied to the determination of PAS and N-acetyl-PAS in human urine without any sample pretreatment. A good separation of the analytes is achieved in a run time of 12 min (15 min total, including capillary wash). Using PAS as a probe for N-acetyltransferase 1 activity, 20 healthy volunteers were phenotyped after oral administration of a 1 g dose. The preliminary results seem to indicate a bimodal distribution of N-acetyl-PAS/PAS molar ratios.

Do synthetic adrenergic agents interfere with the measurement of endogenous plasma catecholamine concentrations?

PURPOSE: It is common to administer synthetic sympathomimetic and sympatholytic agents in the intensive care unit and operating room. The present study examines whether such agents, as well as the products of catecholamine metabolism, interfere with the quantitation of endogenous catecholamines by high-performance liquid chromatography. METHODS: Samples of drugs and metabolites were assayed before and after alumina extraction and their relative retention times were compared with dopamine, norepinephrine, and epinephrine relative retention times. Blood samples from patients receiving these drugs were also assayed for their interferences with catecholamine determination. RESULTS: Phenylephrine interfered with the quantitation of epinephrine. Isoproterenol's peak was so delayed it appeared in the following chromatogram. Dobutamine had two small peaks in vitro, whereas in the patient samples only one peak was identified; the other was probably masked by the dopamine peak. Labetalol had one peak when the pure drug was assayed but multiple peaks in patient samples, that were probably caused by metabolites of labetalol. CONCLUSION: Synthetic adrenergic agents and catecholamine metabolites can potentially interfere with the quantitation of the endogenous catecholamines. Thus, it is important to examine whether such interference occurs when conducting high-performance liquid chromatography assays.

Phase II trial of docetaxel (Taxotere) in metastatic colorectal carcinoma.

BACKGROUND: Docetaxel (Taxotere) is prepared from a noncytotoxic precursor extracted from the needles of the Taxus baccata. Preclinical investigations have demonstrated that docetaxel is very active in colon adenocarcinoma murine models. Phase I studies revealed granulocytopenia to be the dose-limiting toxicity. Initial clinical trials also demonstrated docetaxel's activity in ovarian, breast, and non-small cell lung cancer. Because of this encouraging preclinical and clinical activity, we initiated a phase II study of docetaxel in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Docetaxel, 100 mg/m2, was administered as a 1-hour intravenous infusion every 21 days. Nineteen patients were entered on the trial. All patients had measurable disease and had not received prior chemotherapy for metastatic disease. RESULTS: No complete or partial responses were observed. Granulocytopenia was the dose-limiting toxic effect. Seventeen patients had grade 4 granulocytopenia; 8 of these patients received antibiotics for neutropenic fevers. Twelve patients experienced hypersensitivity reactions, and 15 patients experienced cutaneous toxic reactions. One patient demonstrated evidence of fluid retention. CONCLUSIONS: Administered at the stated dose and schedule, docetaxel has little activity against metastatic colorectal carcinomas. The toxicity profile, consisting of granulocytopenia, hypersensitivity reactions, cutaneous reactions, and edema, has been previously described in patients receiving docetaxel.