bluuebunny/crossref_metadata_2025 huggingface dataset:
The Performance of Procedures on the Recently Deceased
Authors: Fourre Mark W.
Published: October 2002

Objective: To determine the prevalence of performing procedures on the recently deceased for training purposes in emergency departments (EDs) with emergency medicine (EM) training programs. Methods: Surveys were mailed to program directors of Accreditation Council for Graduate Medical Education (ACGME)‐approved residency programs in EM. A check‐off system was used to identify which procedures were performed and who performed the procedure. The survey also documented whether consent was obtained and whether written policies exist that address this issue. A Likert scale was used to evaluate respondents' attitudes toward this practice. Results: Ninety‐six (83%) of 116 surveys were returned. Forty‐seven percent of the respondents indicated procedures were performed on the recently deceased for teaching purposes in their EDs. Emergency medicine residents perform the procedures in all departments where this practice occurs, with off‐service residents and medical students using this technique in half of those departments. Paramedics, flight nurses, and attending physicians occasionally use this resource. Endotracheal intubation was the most commonly performed procedure. Seventy‐six percent stated they “almost never” obtain consent from family members. Only four of 96 respondents have written policies concerning this practice. The majority of program directors (69%) would favor a position statement from a national EM organization concerning this issue, while 11% were opposed. Conclusions: The performance of procedures on the recently deceased is a common and important practice in EM training programs. Consent is infrequently obtained and policies concerning this practice are rare and restrictive when present.
A Simple Plan—Faculty Compensation in an Academic Department of Emergency Medicine
Authors: Guss David A.
Published: October 2002

An equitable and effective compensation system is essential to the smooth and productive operation of any academic department. While academic departments of emergency medicine must meet clinical, teaching, research, and administrative missions, they are disproportionately reliant on funds derived from clinical activities. The Department of Emergency Medicine at UCSD is a freestanding academic hospital department with responsibility and accountability for its own finances. The compensation system addresses the reliance on clinical income yet recognizes the other, largely underfunded, missions. All salaries are comprised of a base amount tied to the core clinical workload, scaleable stipends for academic rank, years of service, and administrative role, as well as a provision for clinical bonus and additional clinical workload. Faculty have the option of adjusting clinical workload with resultant formulaic modification of departmental salary support. Salary adjustment fosters the core value of clinical service and provides incentive for senior faculty to remain clinically active. The system has been in place for more than six years and has been associated with an excellent record of patient care, teaching, academic productivity, administrative service, faculty stability, and fiscal integrity.
Heart Rate Variability in Emergency Department Patients with Sepsis
Authors: Barnaby Douglas , Ferrick Kevin , Kaplan Daniel T. , Shah Sachin , Bijur Polly , Gallagher E. John
Published: October 2002

Objective: To test the hypothesis that heart rate variability (HRV) can provide an early indication of illness severity among patients presenting to the emergency department (ED) with sepsis. Methods: The authors enrolled a convenience sample of 15 ED patients meeting the American College of Chest Physicians/Society of Critical Care Medicine criteria for sepsis. Each patient had continuous Holter monitoring performed in the ED. Acute Physiology and Chronic Health II (APACHE II) and Sequential Organ Failure (SOFA) scores were calculated for the day of presentation. Holter tapes obtained in the ED were analyzed off‐line to calculate HRV variables for the 5‐minute segment with the least artifact and non‐sinus beats. These variables were correlated with APACHE II and SOFA scores. Results: LFnu (normalized low‐frequency power), an assessment of the relative sympathetic contribution to overall HRV, was correlated with increased illness severity as calculated using APACHE II (r = ‐0.67, r2= 0.43) and SOFA (r = ‐0.80, r2= 0.64) scores. LF/HF ratio (low‐frequency/high‐frequency ratio), a measure of sympathovagal balance, was correlated with the SOFA score [r = ‐0.54 (95% CI = ‐0.83 to ‐0.01), r2= 0.29]. All five patients who required critical care monitoring or ventilatory support or who died during the first 5 days of their hospitalization had LFnu values below 0.5 and LF/HF ratios less than 1.0. None of the patients with measurements greater than these threshold values died or required these interventions during the five days following admission. Conclusions: A single variable, LFnu, which reflects sympathetic modulation of heart rate, accounted for 40‐60% of the variance in illness severity scores among patients presenting to the ED with sepsis. HRV, as reflected in LFnu and the LF/HF ratio and measured with a single brief (5‐minute) period of monitoring while in the ED, may provide the emergency physician with a readily available, noninvasive, early marker of illness severity. The threshold effect of LFnu and LF/HF in the prediction of early clinical deterioration was an unexpected finding and should be regarded as hypothesis‐generating, pending further study.
Gamma Hydroxybutyric Acid (GHB) Intoxication
Authors: Mason Phillip E. , Kerns William P.
Published: October 2002

Gamma hydroxybutyric acid (GHB) is a naturally occurring analog of gamma‐aminobutyric acid (GABA) that has been used in research and clinical medicine for many years. In the past decade it has become very popular as a dietary supplement and recreational drug. Acute overdose leads to profound alteration of mental status and variable amounts of respiratory depression. With proper management, most patients recover fully within six hours. However, respiratory arrest and death have been reported in severe GHB intoxication. In addition to acute overdose, there is a GHB withdrawal syndrome that is similar to sedative/hypnotic and ethanol withdrawal. Recently several congeners of GHB, gamma butyrolactone and 1,4‐butanediol, have emerged as drugs of abuse and show toxidromes similar to GHB. Emergency physicians should be familiar with the presentation and management of GHB‐related emergencies.
Hepatocellular Carcinoma in Children and Adolescents: Results From the Pediatric Oncology Group and the Children’s Cancer Group Intergroup Study
Authors: Katzenstein Howard M. , Krailo Mark D. , Malogolowkin Marcio H. , Ortega Jorge A. , Liu-Mares Wen , Douglass Edwin C. , Feusner James H. , Reynolds Marleta , Quinn John J. , Newman Kurt , Finegold Milton J. , Haas Joel E. , Sensel Martha G. , Castleberry Robert P. , Bowman Laura C.
Published: October 2002

PURPOSE: To determine surgical resectability, event-free survival (EFS), and toxicity in children with hepatocellular carcinoma (HCC) randomized to treatment with either cisplatin (CDDP), vincristine, and fluorouracil (regimen A) or CDDP and continuous-infusion doxorubicin (regimen B).

PATIENTS AND METHODS: Forty-six patients were enrolled onto Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group (POG) 8945/Children’s Cancer Group (CCG) 8881). After initial surgery or biopsy, children with stage I (n = 8), stage III (n = 25), and stage IV (n = 13) HCC were randomly assigned to receive regimen A (n = 20) or regimen B (n = 26).

RESULTS: For the entire cohort, the 5-year EFS estimate was 19% (SD = 6%). Patients with stage I, III, and IV had 5-year EFS estimates of 88% (SD = 12%), 8% (SD = 5%), and 0%, respectively. Five-year EFS estimates were 20% (SD = 9%) and 19% (SD = 8%) for patients on regimens A and B, respectively (P = .78), with a relative risk of 1.2 (95% confidence interval, 0.60 to 2.3) for regimen B when compared with regimen A. Outcome was similar for either regimen within disease stages. Events occurred before postinduction surgery I in 18 (47%) of 38 patients with stage III or IV disease, and tumor resection was possible in two (10%) of the remaining 20 children with advanced-stage disease after chemotherapy.

CONCLUSION: Children with initially resectable HCC have a good prognosis and may benefit from the use of adjuvant chemotherapy. Outcome was uniformly poor for children with advanced-stage disease treated with either regimen. New therapeutic strategies are needed for the treatment of advanced-stage pediatric HCC.
Decision-Analytic Model and Cost-Effectiveness Evaluation of Postmastectomy Radiation Therapy in High-Risk Premenopausal Breast Cancer Patients
Authors: Lee Jason H. , Glick Henry A. , Hayman James A. , Solin Lawrence J.
Published: October 2002

PURPOSE: To present a decision model that describes the clinical and economic outcomes of node-positive breast cancer with and without postmastectomy radiation therapy (PMRT).

METHODS: A Markov process was constructed to project the natural history of breast cancer following mastectomy in premenopausal node-positive women. Biannual hazards of local and distant recurrence without PMRT were derived from a large meta-analysis of adjuvant systemic therapy trials for breast cancer. The addition of PMRT reduced the risk of disease relapse by an odds ratio of 0.69. Costs of PMRT ($11,600) and recurrent breast cancer ($4,250 to 16,200/year) were estimated from available literature. The model projected number of recurrences, relapse-free and overall survival, and costs to 15 years, using a discount rate of 3%. Cost-effectiveness ratios were calculated per incremental year of life and quality-adjusted year of life gained. One- and two-way sensitivity analyses were performed to determine the sensitivity of results to clinical and economic assumptions.

RESULTS: The model projected 15-year relapse-free survival of 52% and 43% with and without PMRT, respectively. Overall survival was increased from 48% to 55% with PMRT, resulting in an incremental 0.29 years of life gained per subject. PMRT increased 15-year costs from $40,800 to $48,100. Cost per year of life gained was $24,900, or $22,600 when survival was adjusted for quality of life. Results of the model were relatively sensitive to radiation therapy cost and breast cancer relapse risk.

CONCLUSION: This analysis suggests that PMRT offers substantial clinical benefits achieved in a cost-effective manner, with an average cost per year of life gained of $24,900. Results of the model were robust under a wide range of clinical and economic parameters.
Impact of Addition of Maintenance Therapy to Intensive Induction and Consolidation Chemotherapy for Childhood Acute Myeloblastic Leukemia: Results of a Prospective Randomized Trial, LAME 89/91
Authors: Perel Yves , Auvrignon Anne , Leblanc Thierry , Vannier Jean-Pierre , Michel Gerard , Nelken Brigitte , Gandemer Virginie , Schmitt Claudine , Lamagnere Jean-Pierre , De Lumley Lionel , Bader-Meunier Brigitte , Couillaud Gerard , Schaison Gerard , Landman-Parker Judith , Thuret Isabelle , Dalle Jean-Hugues , Baruchel Andre , Leverger for the Guy ,   Group LAME of the French Society of Pediatric Hematology and Immunology
Published: October 2002

PURPOSE: To determine whether the use of maintenance therapy (MT) delivered after intensive induction and consolidation therapy confers any advantage in childhood acute myeloid leukemia (AML).

PATIENTS AND METHODS: A total of 268 children with AML were registered in the Leucámie Aiquë Myéloïde Enfant (LAME) 89/91 protocol. This regimen included an intensive induction phase (mitoxantrone plus cytarabine) and, for patients without allograft, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase, and amsacrine. In the LAME 89 pilot study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to receive or not receive MT.

RESULTS: A total of 241 (90%) of 268 patients achieved a complete remission. The overall survival and event-free survival at 6 years were 60% ± 6% and 48% ± 6%, respectively. For the complete responders after consolidation therapy, the 5-year disease-free survival was not significantly different in MT-negative and in MT-positive randomized patients (respectively, 60% ± 19% v 50% ± 15%; P = .25), whereas the 5-year overall survival was significantly better in MT-negative randomized patients (81% ± 13% v 58% ± 15%; P = .04) due to a higher salvage rate after relapse.

CONCLUSION: More than 50% of patients can be cured of AML in childhood. Either drug intensity or each of the induction and postremission phases may have contributed to the outstanding improvement in outcome. Low-dose MT is not recommended. Exposure to this low-dose MT may contribute to clinical drug resistance and treatment failure in patients who experience relapse.
Outcomes of Growth Hormone Replacement Therapy in Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Leung Wing , Rose Susan R. , Zhou Yinmei , Hancock Michael L. , Burstein Stephen , Schriock Elizabeth A. , Lustig Robert , Danish Robert K. , Evans William E. , Hudson Melissa M. , Pui Ching-Hon
Published: October 2002

PURPOSE: Little is known about the long-term efficacy or adverse effects of growth hormone (GH) replacement therapy in survivors of childhood acute lymphoblastic leukemia (ALL) who have GH deficiency. We investigated the adult height of patients who had received GH and estimated their risk of leukemia relapse or development of a second malignancy.

PATIENTS AND METHODS: Of 910 patients treated for ALL at a single institution, 47 had received GH replacement therapy. The linear growth of these 47 patients was retrospectively evaluated. Their risk of leukemia relapse or second malignancy was compared with that of survivors who did not undergo GH therapy.

RESULTS: The median height SD score at the start of GH therapy had decreased by 1.0 since the time of diagnosis of ALL. After a median duration of 4.5 years of GH therapy, adult height SD scores improved and approached height SD scores at the time of diagnosis of ALL. The median adult height for male patients was 173.2 cm (range, 157 to 191.9 cm), and for female patients, it was 158.1 cm (range, 141 to 168 cm). None of the patients developed adverse effects requiring discontinuation of GH treatment. At the 7-year and 11-year landmarks in continuous hematologic remission, there was no statistical evidence that GH therapy was associated with leukemia relapse or development of a second malignancy.

CONCLUSION: This study suggests that GH replacement therapy is safe and efficacious for the correction of GH deficiency in survivors of childhood ALL.
Molecular Biology of the Androgen Receptor
Authors: Gelmann Edward P.
Published: October 2002

ABSTRACT: Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.
Comparative Detection of Lymph Node Micrometastases of Stage II Colorectal Cancer by Reverse Transcriptase Polymerase Chain Reaction and Immunohistochemistry
Authors: Noura Shingo , Yamamoto Hirofumi , Ohnishi Tadashi , Masuda Norikazu , Matsumoto Takashi , Takayama Osamu , Fukunaga Hiroki , Miyake Yasuhiro , Ikenaga Masakazu , Ikeda Masataka , Sekimoto Mitsugu , Matsuura Nariaki , Monden Morito
Published: October 2002

PURPOSE: Inconsistent conclusions have been drawn about the clinical significance of micrometastases in lymph nodes (LNs) of node-negative colorectal cancer (CRC) patients. We performed a comparative study of detection of micrometastases using immunohistochemistry (IHC) by anti-cytokeratin antibody and carcinoembryonic antigen (CEA)-specific reverse-transcriptase polymerase chain reaction (RT-PCR) in the same patients, in an attempt to move closer to their clinical application.

PATIENTS AND METHODS: Sixty-four CRC patients, with RNA of good quality available from paraffin-embedded LN specimens, were selected from 84 stage II patients who underwent curative surgery between 1988 and 1996. We investigated associations between the presence of micrometastases by each method and prognosis.

RESULTS: Micrometastases were detected in 19 (29.6%) of 64 patients by RT-PCR and in 35 (54.7%) of 64 patients by IHC. By RT-PCR analysis, patients exhibiting a positive band for CEA mRNA had a significantly worse prognosis than those who were RT-PCR–negative, with respect to both disease-free and overall survival (P = .027 and .015, respectively). By IHC analysis, the presence of micrometastasis did not predict patient outcome in terms of either disease-free or overall survival. Infiltrating pattern of tumor growth characteristic was significantly associated with shorter disease-free survival among various clinical or pathologic factors. By multivariate Cox regression analysis, micrometastasis detected by RT-PCR and the Crohn’s-like lymphoid reaction were both independent prognostic factors.

CONCLUSION: Micrometastases detected by RT-PCR, but not IHC, may be of clinical value in identifying patients who may be at high risk for recurrence of CRC and who are therefore likely to benefit from systemic adjuvant therapy.
Prognostic Factors in Pancreatic Endocrine Neoplasms: An Analysis of 136 Cases With a Proposal for Low-Grade and Intermediate-Grade Groups
Authors: Hochwald Steven N. , Zee Sui , Conlon Kevin C. , Colleoni Roberto , Louie Otway , Brennan Murray F. , Klimstra David S.
Published: October 2002

PURPOSE: In some organs (eg, the lung), endocrine tumors are classified on the basis of mitotic rate and necrosis. The purpose of this study was to evaluate prognostic factors in pancreatic endocrine neoplasms recently treated at a single institution.

PATIENTS AND METHODS: In 136 patients undergoing surgery from 1979 to 1998, the influence on disease-free survival (DFS) and disease-specific survival (DSS) of tumor size, mitotic rate, vascular invasion, necrosis, metastases, and nuclear grade was determined. Cases were further grouped according to an existing proposed classification system and then regrouped on the basis of mitotic rate (< 2 mitoses per 50 high-power fields v higher) and necrosis (present or absent) into low- and intermediate-grade groups.

RESULTS: Correlations with DFS and DSS in univariate analysis included ≤ 2 mitoses per 50 high-power fields (P = .001, P = .002), vascular invasion (P = .02, P = .04), size ≤ 2 cm (P = .01, P = .05), metastases (P = .0002, P = .07), necrosis (P = .002, P = .16), and nuclear grade (P = .04, P = .33), respectively. By multivariate analysis, for DFS, tumor necrosis and presence of metastases retained significance (P = .01, P = .04, respectively). For DSS, only mitotic rate was a prognostic factor (P = .02). Among the 18 macroadenomas, eight borderline tumors, and 48 low-grade carcinomas, there was no significant difference in DSS between any groups (P = .3). However, in evaluating our newly proposed groups, the differences in DFS and DSS between low- and intermediate-grade groups were highly significant (P = .0007, P = .006, respectively).

CONCLUSION: Pancreatic endocrine neoplasms exhibit a spectrum of biologic behavior, and the proposed benign (macroadenoma) and borderline groups contain potentially aggressive tumors. An alternative system based on mitotic rate and necrosis correlates strongly with survival without specifically designating any group as benign.
Phase II Study of Anti–Gastrin-17 Antibodies, Raised to G17DT, in Advanced Pancreatic Cancer
Authors: Brett B. T. , Smith S. C. , Bouvier C. V. , Michaeli D. , Hochhauser D. , Davidson B. R. , Kurzawinski T. R. , Watkinson A. F. , Van Someren N. , Pounder R. E. , Caplin M. E.
Published: October 2002

PURPOSE: The prognosis for advanced pancreatic cancer remains poor. Gastrin acts as a growth factor for pancreatic cancer. We describe the first study of the antigastrin immunogen G17DT in pancreatic cancer. Our aims were to determine the antibody response, safety, tolerability, and preliminary evidence of efficacy of G17DT in advanced pancreatic cancer.

PATIENTS AND METHODS: Thirty patients with advanced pancreatic cancer were immunized with three doses of either 100 μg or 250 μg of G17DT.

RESULTS: In the whole group, 20 (67%) of 30 patients produced an antibody response. The 250-μg dose resulted in a significantly greater response rate of 82% compared with 46% for the 100-μg group (P = .018). The most significant side effects, seen in three patients, were local abscess and/or fever. The median survival for the whole group from the date of the first immunization was 187 days; median survival was 217 days for the antibody responders and 121 days for the antibody nonresponders. The difference in survival between the antibody responders and nonresponders was significant (P = .0023).

CONCLUSION: Patients with advanced pancreatic cancer are able to mount an adequate antibody response to G17DT. The 250-μg dose is superior to the 100-μg dose, and it appears to be generally well tolerated. Antibody responders demonstrate significantly greater survival than antibody nonresponders. Phase III studies are currently underway in order to determine efficacy.
Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918
Authors: Kruijtzer C. M.F. , Beijnen J. H. , Rosing H. , ten Bokkel Huinink W. W. , Schot M. , Jewell R. C. , Paul E. M. , Schellens J. H.M.
Published: October 2002

PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate–binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(−/−) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918.

PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m2 oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m2 intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan.

RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 ± 9.6 μg·h/L without GF120918 to 78.7 ± 20.6 μg·h/L when GF120918 was coadministered (P = .008). The mean maximum plasma concentration of total topotecan increased from 4.1 ± 1.5 μg/L without GF120918 to 11.5 ± 2.4 μg/L with GF120918 (P = .008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P = .008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan.

CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.
Pharmacobiologically Based Scheduling of Capecitabine and Docetaxel Results in Antitumor Activity in Resistant Human Malignancies
Authors: Nadella Padma , Shapiro Charles , Otterson Gregory A. , Hauger Marsha , Erdal Selnur , Kraut Eric , Clinton Steven , Shah Manisha , Stanek Mike , Monk Paul , Villalona-Calero Miguel A.
Published: October 2002

PURPOSE: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination.

PATIENTS AND METHODS: Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m2/wk, whereas capecitabine was escalated in successive patients cohorts.

RESULTS: Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m2/d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m2 capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m2 doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non–small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non–small-cell lung carcinoma, and bronchioloalveolar carcinoma.

CONCLUSION: Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m2/d (625 mg/m2 bid) with docetaxel 36 mg/m2/wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.
Spasmolytic effects of Baccharis conferta and some of its constituents
Authors: Weimann C , Göransson U , Pongprayoon-Claeson U , Claeson P , Bohlin L , Rimpler H , Heinrich M
Published: October 2002

The Nahua of the Mexican state of Veracruz use Baccharis conferta in the treatment of a variety of gastrointestinal illnesses, especially diarrhoea associated with gastrointestinal cramps. The aerial parts of B. conferta were investigated phytochemically and pharmacologically using the guinea pig ileum assay as a model (histamine, KCl and electric stimulation). The crude ethanolic extract showed a dose-dependent antispasmodic effect that was particularly strong in flavonoid-rich fractions (e.g. IC50 value for fraction E.3.1 from the ethyl acetate fraction, in histamine-induced contraction, 10 μg mL−1). Several flavonoids (apigenin-4′,7-dimethylether, naringenin-4,7-dimethylether, pectolinarigenin and cirsimaritin) were isolated, while others were identified in complex fractions by GC-MS. The flavonoids play an important role in the antispasmodic activity of this indigenous drug. Additionally, oleanolic acid and its methyl ester as well as erythrodiol were isolated. Oleanolic acid methyl ester shows weak antibacterial activity against M. luteus and E. coli (20 μg/spot in a TLC assay). The phytochemical as well as the pharmacological data provide some in-vitro evidence for the use of B. conferta in the treatment of gastrointestinal cramps.
Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro
Authors: Kang Hee-Chul , Nan Ji-Xing , Park Pil-Hoon , Kim Ji-Young , Lee Sung Hee , Woo Sun Wook , Zhao Yu-Zhe , Park Eun-Jeon , Sohn Dong Hwan
Published: October 2002

We previously demonstrated that curcumin, a well-known antioxidant, inhibits collagen deposition in carbon tetrachloride-induced liver injury in rats. The major effector cells responsible for collagen synthesis in the liver are activated hepatic stellate cells. In this study, we investigated the inhibitory effects of curcumin on the collagen synthesis and activation of rat hepatic stellate cells in-vitro, and on hepatic stellate cell activation in-vivo. The effects of curcumin on the production of collagen and smooth muscle α-actin proteins and of α1(I) collagen mRNA were studied in-vivo and in-vitro. The effect of curcumin on DNA synthesis was also determined in-vitro. In-vivo, treatment with curcumin reduced collagen deposition and smooth muscle α-actin-positive areas and lowered mRNA levels of type I collagen in the liver. In-vitro, curcumin at a concentration of 5 μg mL−1 reduced DNA synthesis, and downregulated smooth muscle α-actin and type I collagen expression, and α1(I) collagen mRNA expression. We concluded that curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro, and thus may prove a valuable anti-fibrogenic agent.
Synergistic effect of nicorandil and amlodipine on mitochondrial function during isoproterenol-induced myocardial infarction in rats
Authors: Sathish Venkatachalem , Vimal Veereshwarayya , Ebenezar Kesavarao Kumar , Devaki Thiruvengadam
Published: October 2002

The synergistic effects of nicorandil (KATP-channel opener) and amlodipine (calcium-channel blocker) on heart mitochondrial enzymes and the mitochondrial antioxidant defence system was examined on isoproterenol-induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg−1 daily, i.p.) for two days showed significant changes in marker enzymes, mitochondrial enzymes and the mitochondrial defence system. Pre-co-treatment with nicorandil (2.5 mg kg−1 daily, p.o.) and amlodipine (5.0 mg kg−1 daily, p.o.) for 3 days significantly prevented these alterations and restored enzyme activity to near normal. These f ndings demonstrate the protective and synergistic effect of nicorandil and amlodipine in combination against isoproterenol-induced cardiac damage.
α-Adrenergic responsiveness in rat isolated perfused heart after abdominal aortic coarctation
Authors: Silva Cristina O , Duarte Gloria P , Lahlou Saad
Published: October 2002

Chronic isoproterenol pre-treatment, a well-known model of compensatory hypertrophy associated with cardiac β-adrenoceptor desensitization, enhances the inotropic response to phenylephrine in rat isolated perfused hearts, supporting the hypothesis that myocardial α-adrenoceptor stimulation contributes to the maintenance of myocardial performance in situations in which cardiac β-adrenoceptor function is compromised. To further corroborate this hypothesis, the effects of abdominal aortic coarctation on cardiac α-adrenergic responsiveness were investigated in Langendorff heart preparations. Abdominal aortic coarctation causes cardiac hypertrophy (21 %) as shown by a significant increase in the ratio of ventricular dry weight to bodyweight. In preparations from hypertrophied rats, both maximum increases in left ventricular systolic pressure and heart rate elicited by isoproterenol (10−12 to 10−4 M) were significantly reduced (the isoproterenol concentration producing 50% of the maximum positive inotropic and chronotropic responses was enhanced almost 21- and 2-fold, respectively). However, the positive inotropic response to phenylephrine (10−12 to 10−4 M) remained unaffected following abdominal aortic coarctation, when compared with sham-operated rats. In preparations from both groups, phenylephrine infusion did not induce significant changes in heart rate. These results show that although abdominal aortic stenosis induced desensitization of cardiac β-adrenoceptors, it did not enhancecardiac α-adrenoceptor responsiveness. This suggests that such an enhancement depends on the experimental model used to induce cardiac hypertrophy associated with desensitization of cardiac β-adrenoceptors.
Design, synthesis and biological evaluation of novel β-substituted indol-3-yl ethylamido melatoninergic analogues
Authors: Iakovou K , Varvaresou A , Kourounakis A P , Stead K , Sugden D , Tsotinis A
Published: October 2002

A series of new melatonin analogues have been synthesized. Interestingly, two of the new compounds, 11c and 11e, which did not show any appreciable affinity for the melatonin receptor, were found to be potent inhibitors of lipid peroxidation in rat liver microsomes. Analogue 11c, in particular, is a better antioxidant than melatonin.
Vehicles for oligonucleotide delivery to tumours
Authors: Dass Crispin R
Published: October 2002

The vasculature of a tumour provides the most effective route by which neoplastic cells may be reached and eradicated by drugs. The fact that a tumour's vasculature is relatively more permeable than healthy host tissue should enable selective delivery of drugs to tumour tissue. Such delivery is relevant to carrier-mediated delivery of genetic medicine to tumours. This review discusses the potential of delivering therapeutic oligonucleotides (ONs) to tumours using cationic liposomes and cyclodextrins (CyDs), and the major hindrances posed by the tumour itself on such delivery. Cationic liposomes are generally 100–200 nm in diameter, whereas CyDs typically span 1.5 nm across. Cationic liposomes have been used for the introduction of nucleic acids into mammalian cells for more than a decade. CyD molecules are routinely used as agents that engender cholesterol efflux from lipid-laden cells, thus having an efficacious potential in the management of atherosclerosis. A recent trend is to employ these oligosaccharide molecules for delivering nucleic acids in cells both in-vitro and in-vivo. Comparisons are made with other ON delivery agents, such as porphyrin derivatives (< 1 nm), branched chain dendrimers (≈ 10 nm), polyethylenimine polymers (≈ 10 nm), nanoparticles (20–1000 nm) and microspheres (> 1 μm), in the context of delivery to solid tumours. A discourse on how the chemical and physical properties of these carriers may affect the uptake of ONs into cells, particularly in-vivo, forms a major basis of this review.
pH-sensitive, serum-stable and long-circulating liposomes as a new drug delivery system
Authors: Hong Myo-Sook , Lim Soo-Jeong , Oh Yu-Kyoung , Kim Chong-Kook
Published: October 2002

The lack of stability in blood and the short blood circulation time of pH-sensitive liposomes are major drawbacks for their application in-vivo. To develop pH-sensitive, serum-stable and long-circulating liposomes as drug delivery systems, the impact of polyethylene glycol-derived phosphatidylethanolamine (DSPE-PEG) on the properties of pH-sensitive liposomes was investigated. pH-sensitive liposomes were prepared with dioleoylphosphatidylethanolamine (DOPE) and oleic acid (DOPE/oleic acid liposome) or DOPE and 1,2-dipalmitoylsuccinylglycerol (DOPE/DPSG liposome). The inclusion of DSPE-PEG enhanced the serum stability of both DOPE/oleic acid and DOPE/DPSG liposomes, but also shifted the pH-response curve of pH-sensitive liposomesto more acidic regions and reduced the maximum leakage percentage. The impact of DSPE-PEG, however, was much lower in the DOPE/DPSG liposomes than in the DOPE/oleic acid liposomes. In tumourtissue homogenates, where the pH is lower than normal healthytissues, the pH-sensitive DOPE/DPSG liposomes released the entrapped markers rapidly, in comparison with pH-insensitive dipalmitoylphosphatidylcholine/cholesterol/DSPE-PEG liposomes. Moreover, the release rate was not affected by the content of DSPE-PEG. The blood circulation time of methotrexate incorporated in DOPE/DPSG liposomes was significantly prolonged with increasing content of DSPE-PEG. Taken together, the liposomes composed of DOPE, DPSG and DSPE-PEG (up to 5%) were pH sensitive, plasma stable and had a long circulation time in the blood. The complete destabilization of the liposomes at tumour tissues suggests that the liposomes might be useful for the targeted delivery of drugs such as anticancer agents.
Bronchodilator activity of Mikania glomerata Sprengel on human bronchi and guinea-pig trachea
Authors: de Moura R Soares , Costa S S , Jansen J M , Silva C A , Lopes C S , Bernardo-Filho M , da Silva V Nascimento , Criddle D N , Portela B Nunes , Rubenich L M S , Araújo R Gagliardi , Carvalho L C R M
Published: October 2002

The effects of aqueous extracts and hydro-alcoholic extract (HAE), and of a dichloromethane fraction (MG1) obtained from the HAE of Mikania glomerata leaves on isolated respiratory and vascularsmooth muscle have been investigated. Aqueousextracts and HAE induced a significant inhibition on the histamine contractions on the isolated guinea-pig trachea. HAE extract induced a concentration-dependent relaxation on guinea-pig trachea pre-contracted with histamine (IC50 0.34 (0.29-0.39) mg mL−1), acetylcholine (IC50 0.72 (0.67-0.77) mg ml−1) or K+ (IC50 1.41 (1.18-1.64) mg mL−1) and on isolated human bronchi precontracted with K+ (IC50 0.34 (0.26-0.42) mg mL−1). The dichloromethane fraction induced a concentration dependent relaxation in guinea-pig trachea precontracted with K+ (IC50 0.017 (0.012-0.022) mg mL−1). The dichloromethane fraction had also a small vasodilator effect on the isolated mesenteric vascular bed and on the isolated rat aorta, and a significant reduction of the oedema induced by subplantar injections of Bothrops jararaca venom in mice. When tested on plasmid DNA, MG1 did not damage the DNA. Chromatographic analysis showed the presence of 11.4% w/w coumarin in MG1. The results supported the indication of M. glomerata products for the treatment of respiratory diseases where bronchoconstriction is present.
Inhibition of CYP3A-mediated oxidation in human hepatic microsomes by the dietary derived complex phenol, gallic acid
Authors: Stupans Ieva , Tan Hai-Wei , Kirlich Amra , Tuck Kellie , Hayball Peter , Murray Michael
Published: October 2002

Plant polyphenols, such as gallic acid, have been reported to have a range of biological activities including antimutagenic effects. Previously, we reported that gallic acid (3,4,5-trihydroxy-benzoic acid), an agent found in wine and tea, inhibits androstenedione 6β-hydroxylase activity (Ki 70 μM), a cytochrome P450 (CYP3A) marker in human liver microsomes. The preincubation of gallic acid (100 μM) with human liver microsomes in the absence of NADPH, as compared with the presence of NADPH, before assay of androstenedione 6β-hydroxylase activity significantly increased the inhibitory effects of the gallic acid (0.03 ± 0.03 nmol (mg microsomal protein)−1 min−1 compared with 0.20 ± 0.06 nmol (mg microsomal protein)−1 min−1 (P< 0.05)). The antioxidant ascorbic acid and the radical scavenger glutathione prevented this observed increase in inhibition. Removal of gallic acid-derived products from the incubation completely restored CYP3A activity. In contrast, the activities of CYP1A and CYP2E, and non-CYP mediated reductive microsomal 17β-hydroxysteroid dehydrogenase activity were refractory to inhibition by gallic acid.
Identification of indolyl-3-acryloylglycine in the urine of people with autism
Authors: Anderson Rosaleen J , Bendell David J , Garnett Ian , Groundwater Paul W , Lough W John , Mills Malcolm J , Savery Dawn , Shattock Paul E G
Published: October 2002

HPLC analysis of the urine of autistic subjects indicated the presence of an unidentified component in greatly increased concentrations. We have reported the isolation of this component by HPLC and its identification. Mass spectrometry, NMR and UV spectroscopy identified the peak as corresponding to indolyl-3-acryloylglycine (IAG, 3), and this has been confirmed by an independent synthesis.
Gastroprotective activity of solidagenone on experimentally-induced gastric lesions in rats
Authors: Rodríguez Jaime A , Bustamante Carlos , Astudillo Luis , Schmeda-Hirschmann Guillermo
Published: October 2002

The gastroprotective effect of the labdane diterpene solidagenone was assessed on gastric ulcer in rats. The effect of a single oral dose of the compound was evaluated at 50, 100 and 200 mg kg−1 in the following test systems: pylorus ligature (Shay), aspirin- and ethanol-induced gastric ulcers. In pylorus-ligated rats (Shay model), the ulcerative index decreased by 37% with solidagenone pre-treatment at the three assayed doses. The effect of a single oral dose of 50 mg kg−1 solidagenone was comparable with ranitidine at the same concentration and similar to higher doses of the compound. A significant effect (P< 0.001) at 100 and 200 mg kg−1 was observed in the aspirin-induced ulcer model. At both doses, reduction in the number of lesions was approximately 50% compared with controls. The effect was comparable with the reference compound ranitidine (50 mg kg−1). With the ethanol-induced gastric ulcers, the effect of solidagen one at 100 and 200 mg kg−1 was similar to a single oral dose of 20 mg kg−1 omeprazole with a 50% reduction of the mean number of lesions compared with controls. In acute toxicity tests on mice, intraperitoneal administration of solidagenone showed no toxicity at doses up to 600 mg kg−1. This is the first report on the gastroprotective activity of a labdane diterpene.
Simvastatin and lovastatin, but not pravastatin, interact with MDR1
Authors: Sakaeda Toshiyuki , Takara Kohji , Kakumoto Mikio , Ohmoto Nobuko , Nakamura Tsutomu , Iwaki Koichi , Tanigawara Yusuke , Okumura Katsuhiko
Published: October 2002

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, was compared with simvastatin and lovastatin from the viewpoint of susceptibility to interaction with or via the multidrug transporter, MDR1 (P-glycoprotein). This was carried out using the MDR1-overexpressing cell line LLC-GA5-COL150, established by transfection of MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells, and [3H]digoxin, which is a well-documented substrate for MDR1. Pravastatin, at 25–100 μM, had no effect on the transcellular transport of [3H]digoxin whereas simvastatin and lovastatin suppressed the basal-to-apical transport of [3H]digoxin and increased the apical-to-basal transport. It was suggested that recognition by MDR1 was due to the hydrophobicity. In conclusion, simvastatin and lovastatin are susceptible to interaction with or via MDR1, but pravastatin is not. This is important information when selecting the HMG-CoA reductase inhibitors for patients taking drugs that are MDR1 substrates.
Poly(L-lysine) as a model drug macromolecule with which to investigate secondary structure and membrane transport, part I: physicochemical and stability studies
Authors: Chittchang Montakarn , Alur Hemant H , Mitra Ashim K , Johnston Thomas P
Published: October 2002

Low oral bioavailability of therapeutic peptides and proteins generally results from their poor permeability through biological membranes and enzymatic degradation in the gastrointestinal tract. Since different secondary structures exhibit different physicochemical properties such as hydrophobicity, size and shape, changing the secondary structure of a therapeutic polypeptide may be another approach to increasing its membrane permeation. Poly(L-lysine) was used as a model polypeptide. The objectives of this study were to induce secondary structural changes in poly(L-lysine) and to determine the time course over which a given conformer was retained. In addition, the hydrophobicity of each secondary structure of poly(L-lysine) was assessed. The circular dichroism (CD) studies demonstrated that the conditions employed could successfully induce the desired secondary structural changes in poly(L-lysine). The α-helix conformer appeared to be more stable at 25° C whereas the β-sheet conformer could be preserved at 37° C. On the other hand, the random coil conformer was retained at both temperatures. Significant losses of the α-helix and the β-sheet conformers were observed when the pH was reduced. The change in ionic strength did not affect any of the conformers. The octanol/buffer partitioning studies indicated that the α-helix and the β-sheet conformers exhibited significantly different (P< 0.05) hydrophobicities. In conclusion, variation of pH and temperature conditions can be used to induce secondary structural changes in poly(L-lysine). These changes are reversible when the stimuli are removed. The α-helix and the β-sheet conformers of poly(L-lysine) are more lipophilic than the native random coil conformer. Thus, poly(L-lysine) may represent an ideal model polypeptide with which to further investigate the effects of secondary structure on membrane diffusion or permeation.
Stereoselective distribution and stereoconversion of zopiclone enantiomers in plasma and brain tissues in rats
Authors: Fernandez Christine , Alet Patrice , Davrinche Catherine , Adrien Joelle , Thuillier Alain , Farinotti Robert , Gimenez François
Published: October 2002

Concentrations of (-)-zopiclone and (+)-zopiclone were determined in plasma and brain after oral administration, to investigate the stereoselectivity of distribution in rats. Zopiclone enantiomers were administered separately to rats and concentrations were determined by chiral HPLC in plasma and brain. In initial experiments, rats were treated with urethane before cannulation for blood sampling but as this drug modified zopiclone pharmacokinetics, it was not used in subsequent studies. This study showed that zopiclone pharmacokinetics after oral gavage in rats are stereoselective. After oral administration of (+)-zopiclone, no stereoconversion was observed in plasma. Conversely, after administration of (-)-zopiclone, both enantiomers were found in plasma and brain with (+)-zopiclone/(-)-zopiclone ratios of 1 and 8.4 in plasma and brain, respectively. Our findings suggest that zopiclone undergoes stereoconversion and that it is stereospecifically distributed to the brain.
A study of the substrate specificity of Na+-dependent and Na+-independent neutral amino acid transport systems in dog intestinal brush-border membrane vesicles using L-alanine analogues
Authors: Hatanaka Takahiro , Nabuchi Yoshiaki , Ushio Hidetoshi
Published: October 2002

Neutral amino acids are mainly transported across the intestinal brush-border membrane by two Na+-dependent systems (system B0 and system B0,+) and one Na+-independent system (system b0,+). To investigate potential differences in substrate specificity between these systems, we screened ten different alanine analogues for their ability to inhibit the transport of L-alanine in dog intestinal brush-border membrane vesicles. The results suggested that a phenyl group directly attached to the α-carbon has different effects on the Na+-dependent and Na+-independent transport systems, with an increased affinity for the former and a decreased affinity for the latter. Based on these inhibition studies, we investigated [14C] L-phenylglycine transport kinetics in comparison with L-alanine. Similarto L-alanine, L-phenylglycine transport followed at least three routes, however, the km of the Na+-dependent transport system was lower and the k'm of the Na+-independent system was higher than the corresponding values for L-alanine. These results corroborated the conclusions drawn from the inhibition studies. Based on these data, we conclude that different sizes of immediate parts to the α-carbon in functional groups of amino acid analogues have differential effects on the interaction of these amino acid analogues with the Na+-dependent and Na+-independent transport systems for neutral amino acids.