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Biomedical subjects

K Rowland

Publications and source records attributed to K Rowland.

At least 19 recordsLinked to original sources
PubMed1999

Laparoscopic gastrostomy and jejunostomy: safety and cost with local vs general anesthesia.

BACKGROUND AND HYPOTHESIS: General anesthesia is used for laparoscopic enteral access because pneumoperitoneum requires relaxation of the abdominal muscles. We wanted to determine whether these procedures could be performed with similar results and cost under local anesthesia. DESIGN: Randomized controlled study with 30-day follow-up including a cost-benefit analysis. SETTING: University-affiliated hospitals. PATIENTS: Forty-eight patients (32 men, 16 women; mean age, 67 years) undergoing laparoscopic gastrostomies (n = 32) and jejunostomies (n = 16). INTERVENTION: Twenty-four patients underwent laparoscopic gastrostomy (n = 15) and jejunostomy (n = 9) under local anesthesia with intravenous conscious sedation and monitored anesthesia care. Twenty-four patients had general anesthesia. MAIN OUTCOME MEASURES: Conversion to general anesthesia, complications, and cost. RESULTS: Ten patients under local anesthesia had periods of deep sedation and 1 required conversion to general anesthesia. One patient under general anesthesia required conversion to open gastrostomy. No patients had intraoperative aspiration; however, 4 aspirated after the procedure. One patient died of myocardial infarction during the 30-day follow-up. We found no significant difference in the total mean cost and actual procedure time. The surgeon's fee accounted for 31% of the total cost. CONCLUSIONS: Some patients undergoing laparoscopic enteral access may require deep sedation and a rare patient may require general anesthesia. Clinical conditions and surgeon preference, therefore, should determine whether local anesthesia is suitable for laparoscopic gastrostomies and jejunostomies, and in what setting, since there is no difference in success rate or complications when compared with general anesthesia. Potential savings are possible from the operating room (26% of total cost) or anesthesiologist (12% of total cost) if these procedures are performed in an endoscopy suite without monitored anesthesia care.

Aged↗
PubMed1999

Insertion, efficacy, and removal of a nonendoscopically removable percutaneous endoscopic gastrostomy (PEG) tube.

BACKGROUND: Externally removable PEG tubes require an internal bumper that can collapse to a size that is small enough to allow for its removal through the abdominal wall by external traction. Adequate force must be maintained to avoid accidental dislodgement of the tube prior to its desired removal. METHODS: A nonendoscopically removable PEG (Inverta-PEG, Ross Products Division, Abbott Laboratories, Columbus, OH, USA) was evaluated in a nonmasked, prospective clinical study involving 131 patients enrolled by 25 physicians. The over-the-wire (Sacks-Vine) technique was used for all placements. After insertion, patients were followed weekly for 8 weeks. During week 9, the PEGs were removed percutaneously (nonendoscopically). Insertion, efficacy, and removal performance were evaluated. RESULTS: Complication rate during insertion was 1.5% and removal was 1.2%. Qualitatively, investigators rated ease of insertion and removal as very easy, easy, average, difficult, or very difficult. Investigators rated 98.5% of insertions as very easy, easy, or average; 95.4% of removals were rated as very easy, easy, or average. Some patients exited the study prematurely due to leakage around the stoma (2.3%) and inadvertent tube removal (5.3%). These complication rates were consistent with earlier reports of other PEG studies. CONCLUSIONS: These results demonstrate that Inverta-PEG is a safe and effective tube that can be removed nonendoscopically with ease in 95% of the cases.

Adult↗
PubMed1999

In vitro metabolism of 6-mercaptopurine by human liver cytosol.

1. The aim of this study was to investigate 6-mercaptopurine (6MP) metabolism by human liver cytosol in vitro. 2. Cytosol was prepared from seven human livers (A-G). A single cytosol (C) was used to optimize incubation conditions. 3. Cytosols A-G were incubated with 6MP at 2, 10 and 500 microM for two fixed times (5 and 48 h). Parent drug, thiopurine and thionucleotide metabolites were quantitated by high performance liquid chromatography at all time points. 4. At 5 and 48 h the 2 microM and 10 microM 6MP incubations contained both 6MP and its initial nucleotide metabolite, thioinosine 5'-monophosphate (TIMP). In addition, the 10 microM 6MP 48 h incubates contained small amounts of 6-thioguanine (6TG, median 0.12 microM). At 500 microM 6MP all seven liver incubates produced a range of metabolites. At 48 h these included thiouric acid, 8-hydroxy-6-mercaptopurine and 6-methylmercaptopurine (median 31, 19.5 and 8.8 microM respectively), with TIMP, 6TG, thioxanthine and thioxanthine nucleotide at median concentrations of 61, 0.79, 2.11 and 0.80 microM respectively. Thioguanine nucleotides, major metabolites measured in vivo, were not detected. 5. These results indicate that the human liver 6MP metabolic profile is dependent upon drug concentration.

Antimetabolites, Antineoplastic↗
PubMed1998

High-performance liquid chromatographic assay of methylthioguanine nucleotide.

This paper describes a specific and sensitive reversed-phase HPLC assay for the measurement of 6-methylthioguanine (methyl-TG) and methyl-TG nucleotides (methyl-TGNs) in red blood cells (RBCs), which is suitable for routine clinical use. Briefly, an ethyl acetate extract of RBCs is evaporated and reconstituted in 0.1 M HCl. The methyl-TG is separated from other thiopurines by reversed-phase HPLC and quantitated using UV detection. For the measurement of methyl-TGNs the free base (methyl-TG) is obtained by acid hydrolysis of the nucleotide back to the parent thiopurine. The intra-assay C.V. over the concentration range of 0.055-1.10 nmol methyl-TG per 4x10(8) (100 microl) RBCs ranged from 2.8 to 8.5%, and the mean recovery of methyl-TG over the calibration range was 61.6% (coefficient of variation, C.V., 3.8%). The lower limit of reproducibility was 0.055 nmol extracted from 100 microl RBCs. Analysis of blood samples from children with leukaemia receiving 6TG chemotherapy, revealed RBC methyl-TGNs at concentrations ranging from 323 to 1365 pmol per 8x10(8) RBCs. No methyl-TG was detected in any of the patient samples.

Antimetabolites, Antineoplastic↗
PubMed1998

Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia: a comparison of haematological toxicity and drug metabolite concentrations.

As a prelude to a nationwide randomized trial of thioguanine (TG) versus mercaptopurine (MP) for childhood lymphoblastic leukaemia we compared a pilot group of 23 children taking TG with a matched group taking MP. We assessed drug tolerance based on haematological toxicity and measured erythrocyte (RBC) concentrations of thioguanine nucleotides (TGN). The median tolerated dose of TG was 30 mg/m2 compared to 55 mg/m2 for MP. There was no difference in the pattern of anaemia or neutropenia between the two groups, but dose-limiting thrombocytopenia was more evident in the TG children (P< 0.001), four of whom had a decrease in platelet count to <20 x 10(9)/l compared to only one on MP. The median RBC TGN concentration for those on 40 mg/m2 TG was 1726 pmol/8 x 10(8) RBCs compared with 308 pmol/8 x 10(8) RBCs for those on 75 mg/m2 MP (P< 0.0001). There was an inverse correlation between RBC TGNs and neutrophil count in the MP group but not in those on TG. No correlation between metabolite concentration and thrombocytopenia was found in either group. These results provide further evidence that TG has a selective effect on platelets. They also showed that RBC TGN were, on average, 5-fold higher in those taking TG but did not obviously relate to myelotoxicity as found in children on MP. The higher concentrations seen may partly reflect the erythrocyte's ability to metabolize TG directly to TGN by pathways not open to MP.

Adolescent↗
PubMed1996

Influence of amino acid residue 374 of cytochrome P-450 2D6 (CYP2D6) on the regio- and enantio-selective metabolism of metoprolol.

Cytochrome P-450 2D6 (CYP2D6) is an important human drug-metabolizing enzyme responsible for the oxidation of more than 30 widely used therapeutic agents. The enzymes encoded by the published genomic [Kimura, Umeno, Skoda, Meyer and Gonzalez (1989) Am. J. Hum. Genet. 45, 889-904] and cDNA [Gonzalez, Skoda, Kimura, Umeno, Zanger, Nebert, Gelboin, Hardwick and Meyer (1988) Nature 331, 442-446] sequences of CYP2D6, and presumed to represent wild-type sequences, differ at residue 374 and encode valine (CYP2D6-Val) and methionine (CYP2D6-Met) respectively. The influence of this amino acid difference on cytochrome P-450 expression, ligand binding, catalysis and stereoselective oxidation of metoprolol was investigated by the heterologous expression of the corresponding cDNAs in the yeast Saccharomyces cerevisiae. The level of expression of apo- and holo-protein was similar with each form of CYP2D6 cDNA, and the binding affinities of a series of ligands to CYP2D6-Val and CYP2D6-Met were identical. The enantioselective O-demethylation and alpha-hydroxylation of metoprolol were also similar with each form of CYP2D6, O-demethylation being R-(+)- enantioselective (CYP2D6-Val: R/S, 1.6; CYP2D6-Met: R/S, 1.4), whereas alpha-hydroxylation showed a preference for S-(-)-metoprolol (CYP2D6-Val: R/S, 0.7; CYP2D6-Met: R/S, 0.8). However, although the favoured regiomer overall was O-demethylmetoprolol (ODM), the regioselectivity for O-demethylation of each metoprolol enantiomer was significantly greater for CYP2D6-Val [R-(+)-: ODM/alpha-hydroxymetoprolol (alpha OH), 5.9; S-(-)-: ODM/alpha OH, 2.5) than that observed for CYP2D6-Met [R-(+)-: ODM/alpha OH, 2.2; S-(-)-: ODM/alpha OH, 1.4]. The stereoselective properties of CYP2D6-Val were consistent with those observed for CYP2D6 in human liver microsomes. The difference in the stereoselective properties of CYP2D6-Val and CYP2D6-Met were rationalized with respect to a homology model of the active site of CYP2D6 based on an alignment with the crystal structure of the bacterial cytochrome P-450BM-3' CYP102.

Amino Acid Sequence↗
PubMed1996

Variable contribution of CYP2D6 to the N-dealkylation of S-(-)-propranolol by human liver microsomes.

Recombinant cDNA expression systems for CYP2D6 have been shown to have significant catalytic activity with respect to the N-dealkylation of propranolol. However, the involvement of CYP2D6 in this reaction in human liver is inconclusive. We have re-evaluated the role of CYP2D6 in the dealkylation of S-(-)-propranolol using a bank of 10 human livers characterized for their specific CYP2D6 and CYP1A2 activities, the latter enzyme being known to be involved substantially in the formation of N-desisopropylpropranolol. Using quinidine (1 microM) or LKM-1 antibodies as selective inhibitors of CYP2D6, the contribution of this enzyme to net N-desisopropylation of S-(-)-propranolol (10 microM) by microsomes from the range of livers was found to vary from nil (poor metabolizer genotype) to 60%. N-desisopropylpropranolol formation inhibitable by quinidine was highly correlated with specific CYP2D6 activity, as measured by the alpha-hydroxylation of metoprolol (rs = 0.90; P < 0.001). The two livers with the highest proportion of CYP2D6-mediated N-dealkylation had relatively high ratios of specific CYP2D6 to CYP1A2 activity. These findings emphasize that data obtained using microsomes from single human livers or pooled microsomes from several livers may be misleading inasmuch as the relative contribution of different isoenzymes to the same metabolic reaction may show considerable between-subject variation.

Adrenergic beta-Antagonists↗
PubMed1994

Inhibition of CYP2D6 activity by treatment with propranolol and the role of 4-hydroxy propranolol.

1. The 4-hydroxylation of propranolol by rat and human liver microsomes is associated with formation of a chemically reactive species which binds irreversibly to cytochrome P4502D6 (CYP2D6) destroying its catalytic function. Therefore, the effect of propranolol treatment (80 mg twice daily) on debrisoquine phenotype was examined, to see if it resulted in phenocopying in vivo. The role of 4-hydroxypropranolol (4OHP) in the inhibition of CYP2D6 activity was also studied using microsomes from yeast expressing CYP2D6 and from human livers; metoprolol was used as the CYP2D6 substrate. 2. Although a significant effect on apparent oxidation phenotype was demonstrated, the absolute change in the urinary debrisoquine/4-hydroxydebrisoquine ratio (D/4HD) was small, such that no extensive metaboliser who received propranolol treatment was reclassified as a poor metaboliser. The in vitro studies indicated that 4OHP is a potent inhibitor of metoprolol metabolism (Ki approximately 1 microM). This inhibitory effect was enhanced when 4OHP was pre-incubated in the presence of a NADPH generating system and human liver microsomes. The effect was decreased significantly when reduced glutathione was added to the pre-incubation mixture. Metabolism of 4OHP occurred when incubated with human liver microsomes in the presence of a NADPH generating system and irrespective of CYP2D6 phenotype; yeast expressing CYP2D6 did not metabolise 4OHP. 3. We conclude that, although treatment with propranolol 80 mg twice daily significantly decreases the catalytic function of CYP2D6, the inhibition is insufficient to result in phenocopying. The reactive intermediate produced by further metabolism of 4OHP is probably scavenged effectively in vivo by glutathione and other nucleophiles.

Adult↗
PubMed1991

Pre-treatment prognostic factors in stage III non-small cell lung cancer patients receiving combined modality treatment.

Approximately one-third of non-small cell lung cancer (NSCLC) patients present with locally advanced disease. Increasing numbers of clinical trials are being conducted in this group of patients and recently a new international staging system has been introduced, resulting in the sub-division of Stage III into IIIa (potentially operable disease) and IIIb (inoperable disease). Kaplan-Meier survival analyses and Cox regression analyses were used to analyze data from 129 Stage III NSCLC patients who had been treated on two consecutive Phase II trials testing combined modality treatment. The pretreatment characteristics of these patients were: median age--59 years, males/females--87/42, caucasian/non-caucasian--111/18, squamous cell or adenocarcinoma/large cell carcinoma--57/72, previous weight loss less than or equal to 5%/greater than 5%-76/46, previous history of cardiorespiratory disease--no/yes--91/36, performance status (PS) 0-1/2-3--102/27, Stage III, 2 groups--IIIa/IIIb--83/46, Stage III, 3 groups--IIIa T3 N0/IIIa N2/IIIb--41/41/47, surgical eligibility--eligible/ineligible--83/46. Kaplan-Meier statistics revealed significantly longer survival for PS 0-1 versus 2-3 (p = .001), for eligible versus ineligible for surgery (p = .003), for Stage-IIIa versus IIIb (p = .004), and for Stage-IIIa T3N0 versus IIIa N2 versus IIIb (p = .004). The best model developed from Cox regression analyses included stage (IIIa T3 N0 vs IIIa N2 vs IIIb), PS, and sex. These observations appear to have implications for clinical research in Stage III NSCLC.

Adenocarcinoma↗
PubMed1990

Combined modality therapy for locally advanced non-small cell lung carcinoma.

Multi-modality treatment consisting of cisplatin, VP-16, and 5-fluorouracil chemotherapy given concomitantly with external beam radiation was used to treat 64 patients with locally advanced Stage III non-small cell lung carcinoma. This regimen was used in a preoperative fashion for four cycles in patients considered surgically resectable and with curative intent for six cycles in the remainder of patients. The clinical response rate for the entire group was 84% and the overall local control rate was 74%. The median survival was 13 months with a median follow-up for live patients of 19 months. The actuarial 3-year survival and disease-free survival rates were 30% and 23%, respectively. Histologic complete response was 39% and appeared to predict for survival. The 3-year actuarial survival and disease-free survival rates for 23 resected patients were 69% and 45%, respectively, with the complete histologic responders having a disease-free survival of 78%. The pattern of first recurrence did not appear to differ by histology or presence of lymph nodes in this subset of patients. The actuarial 3-year survival and disease-free survival rates for inoperable patients receiving six cycles of treatment were 18% and 23%, respectively. The local control was 67% with the majority of these patients having Stage IIIB disease. The Mountain International staging system appeared to predict for operability, local recurrence, and survival. This concomitant treatment regimen is feasible, with the major toxicities being leukopenia, nausea, and vomiting.

Adult↗
PubMed1990

The discharge of elderly patients from an accident and emergency department: functional changes and risk of readmission.

Four hundred and fifty patients aged 75 years or older were followed up after discharge from an accident and emergency department. Forty-three per cent of all patients experienced some loss of functional independence. A small number, 5.6%, were readmitted to hospital within 14 days. This group were significantly less able to perform certain activities of daily living than those not readmitted. Attention to functional assessment by casualty staff may help to prevent readmission to hospital of this frail elderly group of patients.

Activities of Daily Living↗
PubMed1989

Evaluation of homoharringtonine efficacy in the treatment of squamous cell carcinoma of the head and neck: a phase II Illinois Cancer Council Study.

Eighteen patients entered this study of the efficacy of homoharringtonine (HHT) treatment in advanced squamous cell carcinoma of the head and neck (SCCHN). Seventeen eligible patients received at least one day of the first 5-day cycle of HHT (4.0 mg/m2/day) by continuous IV infusion. Cycles were scheduled to repeat every 28 days. The major severe toxicities encountered were hypotension and myelosuppression. There was one drug-related death. Fourteen patients were evaluable for response, and no patient exhibited an objective response to treatment with HHT.

Adult↗
PubMed1988

Preoperative combined modality therapy for stage III M0 non-small cell lung carcinoma.

More than 1/3 of all non-small cell lung carcinoma (NSCLC) patients present with locally advanced non-metastatic disease. Despite radiation therapy and surgery the survival of these patients remains poor. In an effort to improve upon these results 33 clinical Stage III M0 patients from April 1985 through September 1986 were entered into a Phase II study at Rush-Presbyterian-St. Luke's Medical Center. Treatment included 5-FU by continuous infusion, VP-16, cisplatin and concurrent split course radiation therapy followed by surgical resection when possible. The overall clinical response rate is 74%. Fifty-seven percent of the preoperative group of patients went to surgery with a 100% resectability rate. These patients had a 50% pathologic complete response with no tumor found in the resected specimen. All surgical margins were free of disease and there were no operative deaths. This concurrent combined modality therapy is feasible with the major toxicities being leukopenia, nausea, and vomiting. With an overall median follow-up of 15 months, 36% of the patients remain alive. Overall local control is 71%. Actuarial observed 2 yr. survival is 33% and the median survival is 15 months. Histologic complete response appears to be an early indicator of the efficacy of this treatment regime. With 83% of the resected pathologic complete responders alive without evidence of disease, this preoperative combined modality therapy offers an appealing approach.

Adenocarcinoma↗
PubMed1986

Phase II trial of etoposide, cisplatin, continuous infusion 5-fluorouracil, and simultaneous split-course radiation therapy in stage III non-small-cell bronchogenic carcinoma.

Survival in patients with locally advanced, non-small-cell lung cancer (NSCLC) is relatively short, despite treatment with surgery or radiation. A phase II study of simultaneous continuous infusion 5-fluorouracil and split-course radiation with or without surgery has shown possible improvement in median survival compared with that observed in trials of radiation alone. Past success with etoposide plus cisplatin in NSCLC has led to the addition of etoposide to the 5-fluorouracil plus cisplatin plus radiation combination. Twenty-four stage III NSCLC patients were treated with this three-drug regimen, and a 74% clinical partial remission rate was observed. Thoracotomy was done in eight of these patients; subsequent histologic examination of the resected specimen revealed no residual tumor in four patients (50%) and only microscopic foci of tumor in two patients (25%). Major toxicities were leukopenia, nausea, and vomiting. Median leukocyte nadir was 2,900/mm3. A leukocyte count less than 1,000/mm3 was observed in two of 24 patients (8%), one of whom expired from progressive pneumonia. All patients experienced nausea and vomiting, which were classified as moderate in three patients (12%) and severe in four (16%). Moderate to severe esophagitis, dermatitis, and pneumonitis were not observed. Median progression-free interval and median survival were not reached after a median follow-up of 163 days.

Antineoplastic Combined Chemotherapy Protocols↗