Biomedical subjects

D C Young

Publications and source records attributed to D C Young.

At least 37 records · Page 2Linked to original sources

PubMed2000

Quantification of the learning curve for percutaneous dilatational tracheotomy.

OBJECTIVES/HYPOTHESIS: Although numerous investigators have reported a bedside percutaneous dilatational tracheotomy (PDT) complication incidence similar to that of standard operative tracheostomy, others have proposed a "learning curve" for PDT resulting in increased complications early in individual or institutional experience with this procedure. The objective of this investigation is to characterize and quantify the proposed learning curve for PDT. STUDY DESIGN: Prospective analysis of complication incidence for the first 100 PDT procedures performed in a local community hospital Department of General Surgery. METHODS: Demographic data, patient disease variables, and patient anatomic features, as well as perioperative, postoperative, and late complications, were recorded prospectively. Patients were divided into sequential cohorts of 20 and were evaluated for complications at regular intervals. RESULTS: Perioperative and late complication incidence was significantly higher in the first 20 patients who underwent PDT. However, postoperative complication incidence did not significantly vary with operator or institutional experience. In addition, patients with suboptimal anatomy were found to have a significantly increased complication incidence, independent of operator and institutional experience. CONCLUSIONS: Percutaneous dilational tracheotomy has an identifiable learning curve that is most prominent in the first 20 patients treated. Early experience with PDT should be obtained under controlled circumstances, ideally the operating suite. Although most complications occur during acquisition of early experience with PDT, certain life-threatening complications such as tube dislodgment or inability to complete procedure may occur even after extensive experience is obtained. Bedside PDT has an acceptable complication incidence, but any surgeon employing this technique must be prepared to perform immediate standard open tracheotomy to minimize potentially lethal complications of this elective procedure.

Adolescent↗

PubMed2000

Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyltransferase gene.

Peptide deformylase, a bacterial enzyme, represents a novel target for antibiotic discovery. Two deformylase homologs, defA and defB, were identified in Staphylococcus aureus. The defA homolog, located upstream of the transformylase gene, was identified by genomic analysis and was cloned from chromosomal DNA by PCR. A distinct homolog, defB, was cloned from an S. aureus genomic library by complementation of the arabinose-dependent phenotype of a P(BAD)-def Escherichia coli strain grown under arabinose-limiting conditions. Overexpression in E. coli of defB, but not defA, correlated to increased deformylase activity and decreased susceptibility to actinonin, a deformylase-specific inhibitor. The defB gene could not be disrupted in wild-type S. aureus, suggesting that this gene, which encodes a functional deformylase, is essential. In contrast, the defA gene could be inactivated; the function of this gene is unknown. Actinonin-resistant mutants grew slowly in vitro and did not show cross-resistance to other classes of antibiotics. When compared to the parent, an actinonin-resistant strain produced an attenuated infection in a murine abscess model, indicating that this strain also has a growth disadvantage in vivo. Sequence analysis of the actinonin-resistant mutants revealed that each harbors a loss-of-function mutation in the fmt gene. Susceptibility to actinonin was restored when the wild-type fmt gene was introduced into these mutant strains. An S. aureus Deltafmt strain was also resistant to actinonin, suggesting that a functional deformylase activity is not required in a strain that lacks formyltransferase activity. Accordingly, the defB gene could be disrupted in an fmt mutant.

Amidohydrolases↗

PubMed2000

Adhesive capsulitis of the shoulder in male cardiac surgery patients.

Two hundred fourteen consecutive male cardiac surgery patients were retrospectively evaluated for the incidence of adhesive capsulitis of the shoulder and were assessed for risk factors. Only male patients were included, as the study took place at a Veteran's hospital. Patients who had no shoulder problems prior to cardiac surgery and were experiencing shoulder pain or stiffness postoperatively underwent history, physical examination, and radiographic studies. Thirty-five patients who had shoulder complaints were identified and evaluated. A 3.3% incidence (seven patients) of adhesive capsulitis of the shoulder in a male post-cardiac surgery population was established.

Age Distribution↗

PubMed1999

Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene.

There is substantial evidence to suggest that aberrant DNA methylation in the regulatory regions of expressed genes may play a role in hematologic malignancy. In the current report, the Restriction Landmark Genomic Scanning (RLGS) method was used to detect aberrant DNA methylation (M) in acute myeloid leukemia (AML). RLGS-M profiles were initially performed using DNA from diagnostic, remission, and relapse samples from a patient with AML. Rp18, one of the eight spots found that was absent in the relapse sample, was cloned. Sequence analysis showed that the spot represented a portion of the WIT-1 gene on human chromosome 11p13. Rp18 was missing in the relapse sample due to a distinct DNA methylation pattern of the WIT-1 gene. Twenty-seven AML patients that entered CR after therapy (i.e., chemosensitive) were studied and only 10 (37%) of the diagnostic bone marrow (BM) samples showed methylation of WIT-1. However, seven of eight (87.5%) diagnostic BM samples from primary refractory AML (chemosensitive) showed methylation of WIT-1. The incidence of WIT-1 methylation in primary refractory AML was significantly higher than that noted in chemosensitive AML (P=0.018). Together, these results indicate that RLGS-M can be used to find novel epigenetic alterations in human cancer that are undetectable by standard methods. In addition, these results underline the potential importance of WIT-1 methylation in chemoresistant AML.

Acute Disease↗

PubMed1999

Limitations with light microscopy in the detection of colorectal cancer cells.

PURPOSE: The failure of light microscopy to predict individual patient survival accurately in pStage I and II colorectal carcinoma can hinder planning postoperative therapy and follow-up. This study was designed and conducted in two parts to assess the influence of relative sensitivity of the light microscope on the pathologist's ability to detect malignant cells in lymph nodes. METHODS: The first part of the study examined the issue of sampling error as a fraction of the number of lymph node sections examined by asking the question, "Does increasing the number of sections (sampling) taken from the block increase tumor cell detection in a lymph node?" Three levels of five sections 4 to 5 microm thick separated by 15 to 20 microm were obtained from each of 494 blocks from 173 cases of pStage I and II colorectal carcinoma. A total of 1,721 lymph nodes were examined. Sections from each level were stained with hematoxylin and eosin and for the expression of cytokeratin. The second part of the study examined the relative sensitivity of the light microscope to detect tumor cells in a lymph node. To simulate lymph nodes, cell blocks were made that contained 10(6) or 10(7) mononuclear cells admixed with increasing numbers of SW480 tumor cells (0, 50, 10(2), 5 x 10(2), 10(3), and 5 x 10(3)). Three pathologists independently examined sections from ten control and ten experimental blocks. RESULTS: Results from the first part of the study demonstrated cytokeratin-positive cells in 278 lymph nodes from 102 of 172 (59 percent) cases. These cells were identified in the first level in 177 (64 percent) as compared with the second or third level or both in 101 (36 percent) of the lymph nodes. Results from the second part of the study demonstrated an overall sensitivity of light microscopic examination of hematoxylin and eosin-stained sections to be approximately 23 percent, representing tumor cells correctly detected in 7 sections of the 30 sections containing tumor cells. The overall specificity was 87 percent or 26 sections correctly classified as lacking tumor cells of a possible 30. Immunohistochemical staining for cytokeratin expression improved sensitivity of the light microscope to detect tumor cells to 18 of 30 (60 percent) and the specificity to 30 of 30 (100 percent). CONCLUSION: This study demonstrates several sources of variability that can induce errors in pathologic staging. These include 1) inadequate section, i.e., sampling, of lymph nodes, 2) use of only hematoxylin and eosin-stained sections, 3) samples with tumor cells below the level of detection sensitivity of the light microscope, and 4) observer variability.

Colorectal Neoplasms↗

PubMed1999

Is carcino-embryonic antigen useful in the follow-up management of patients with colorectal liver metastases?

BACKGROUND: The role of carcino-embryonic antigen (CEA) in monitoring early detection of recurrent or metastatic colorectal cancer, and its impact on resectability rate and patient survival remains controversial. Our objective was to determine any association between the preoperative level of CEA and prognosis, and the resectability and survival by method of diagnosis of colorectal hepatic metastases. METHODS: We analyzed patients who underwent exploration for hepatic resection for metastatic colorectal cancer over a 15-year period. The patient population consisted of those patients who had undergone primary colon or rectal resection and were followed up with serial CEA levels and of patients who were followed up with physical examination, liver function tests (LFTs) or computed tomography (CT) of the abdomen and pelvis that led to the diagnosis of liver metastases. Also included in the study were patients who were diagnosed with liver metastases at the time of the primary colon or rectal resection and underwent planned hepatic resection at a later time. RESULTS: Three hundred and one (301) patients who underwent a total of 345 planned hepatic resections for metastatic colorectal cancer between January 1978 and December 1993 were included in this analysis. The median preoperative CEA level was 24.8 ng/mL in the resected group, 53.0 ng/mL in the incomplete resection group, and 49.1 ng/mL in the nonresected group (P = 0.02). More of the patients who had a preoperative CEA < or =30 ng/mL were in the resected group, while those who had a preoperative CEA >30 ng/mL were likely to be in the nonresected group (P = 0.002). The median survival was 25 months for patients with a preoperative CEA level < or =30 ng/mL and 17 months for patients with a preoperative CEA >30 ng/mL (P = 0.0005). The resectability rate and the survival of patients by method of diagnosing liver metastases-rising CEA versus history and physical, elevated LFTs, CT scan versus diagnosis at the time of primary resection-was not significant (P = 0.06 and P = 0.19, respectively). Given the nonstandardized retrospective nature of the study cohort and relative small groups of patients, the power to detect small differences in survival by method of diagnosis is limited. In the complete resection group of patients with unilobar liver disease (5-year survival of 28.8%) there was no difference in survival between those patients who had normal preoperative CEA and those who had elevated preoperative CEA, and approximately 90% of them had an abnormal preoperative serum CEA level. CONCLUSIONS: CEA is useful in the preoperative evaluation of patients with hepatic colorectal metastases for assessing prognosis and is complimentary to history and physical examination in the diagnosis of liver metastases. Patients with colorectal liver metastases and preoperative CEA < or =30 ng/mL are more likely to be resectable, and they have the longest survival.

Biomarkers, Tumor↗

PubMed1999

Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture.

OBJECTIVES: To compare labor induction intervals between oral misoprostol and intravenous oxytocin in women who present at term with premature rupture of membranes. METHODS: One hundred eight women were randomly assigned to misoprostol 50 microg orally every 4 hours as needed or intravenous oxytocin. The primary outcome measure was time from induction to vaginal delivery. Sample size was calculated using a two-tailed alpha of 0.05 and power of 80%. RESULTS: Baseline demographic data, including maternal age, gestation, parity, Bishop score, birth weight, and group B streptococcal status, were similar. The mean time +/-standard deviation to vaginal birth with oral misoprostol was 720+/-382 minutes compared with 501+/-389 minutes with oxytocin (P = .007). The durations of the first, second, and third stages of labor were similar. There were no differences in maternal secondary outcomes, including cesarean birth (eight and seven, respectively), infection, maternal satisfaction with labor, epidural use, perineal trauma, manual placental removal, or gastrointestinal side effects. Neonatal outcomes including cord pH, Apgar scores, infection, and admission to neonatal intensive care unit were not different. CONCLUSION: Although labor induction with oral misoprostol was effective, oxytocin resulted in a shorter induction-to-delivery interval. Active labor intervals and other maternal and neonatal outcomes were similar.

Female↗

PubMed1998

Maxillary removal and reinsertion for anterior cranial base tumors: long-term results.

OBJECTIVE: To evaluate complications and sequelae of maxillary removal and reinsertion for anterior cranial base tumors. DESIGN: A retrospective review of patients who underwent maxillary removal and reinsertion from 1990 to 1996. SETTING: The Arthur G. James Cancer Hospital and Research Institute at The Ohio State University, Columbus. PATIENTS: A consecutive sample of 46 patients who underwent maxillary removal and reinsertion. The patients ranged in age from 11 to 77 years and were followed up for as long as 6 years after surgery. There were 16 benign and 30 malignant lesions. MAIN OUTCOME MEASURES: Intraoperative, postoperative (1-10 days), short-term (11 days through 3 months), and long-term (>3 months) complications; survival status of patients; and adjuvant therapy. RESULTS: Four patients (9%) had undergone previous radiotherapy; 9 (20%) received intraoperative radiation therapy; and 23 (50%) received planned postoperative radiotherapy. No intraoperative complications were noted. The most common short-term complication found was transient diplopia, affecting 9 patients (20%). Diplopia resolved within 3 months in all but 2 patients, in whom the condition was permanent. There were 4 patients (9%) who required removal of the nasal dorsum plate, and 4 (9%) who required removal of maxillary plates that were exposed intranasally. Midface asymmetry as reported by the patient or noted on the physical examination was documented in only 2 patients. The most common long-term complication was nasal asymmetry, affecting 13 patients (28%). CONCLUSIONS: Maxillary removal allows improved visualization and access to anterior skull base lesions, while reinsertion of the maxillary fragment provides functional preservation and excellent cosmesis with few short- or long-term complications, even when adjuvant radiotherapy is used.

Adolescent↗

PubMed1998

Myosin-reactive autoantibodies in rheumatic carditis and normal fetus.

EBV-transformed B cells from a 20-week human fetal spleen and from blood of patients with poststreptococcal rheumatic carditis were studied. Most antibodies from nine fetal and six patient myosin-reactive B cell clones were multireactive (reacting with cardiac myosin, Streptococcus pyogenes, and rat cardiac myocytes) which supports a role for molecular mimicry in stimulation of these autoantibodies. Sequence analysis revealed that fetal and patient anti-myosin repertoires were composed of unrelated clones with diverse V gene usages. Fetal and patient antibodies had reduced VH CDR3 length on average and reduced light chain N region addition with a low rate of somatic mutation in the variable region genes, characteristics generally associated with fetal B cells but also with some adult B cells. Five of six myosin-reactive patient clones used VH3, whereas only two of nine fetal clones used VH3, suggesting skewing from the average 50-60% VH3 gene usage found in randomly selected adult and fetal antibodies.

Adult↗

PubMed1998

Determinants of survival following hepatic resection for metastatic colorectal cancer.

Hepatic resection remains the only potentially curative treatment for metastatic colorectal cancer. This retrospective review study was undertaken in an attempt to identify factors that influence patient survival following hepatic resection for metastatic colorectal cancer. From January 1978 to December 1993, a total of 301 patients underwent a total of 345 planned hepatic resections for metastatic colorectal cancer. Of those, 245 patients had one resection, 44 had two resections, and 12 had three resections. For all patients the overall median survival was 20.6 months, operative mortality was 1.1%, and overall morbidity was 17.2%. Average hospital stay was 9 days. Statistical analysis included univariate analysis using log rank comparisons, Kaplan-Meier survival curves, and multivariate analysis using Cox proportional hazards regression. The statistically significant factors that influenced survival were distribution of liver metastases, unilobar versus bilobar (p = 0.0001), resected versus nonresected (p < 0.0001), and tumor-free surgical margins versus positive margins (p = 0.001). Surprisingly, the disease-free interval and the original stage of the primary tumor did not predict survival (p = not significant). Other factors that had no influence on survival were type of resection, size and number of liver metastases, ABO blood group, and the number of perioperative blood transfusions. For those patients who underwent resection of unilobar metastases with tumor-free margins, the 5-year survival rate was 29% with a median survival of 35 months and eight survivors > 7 years. In addition, one patient with bilobar disease had survival > 7 years and five patients who had resection of hepatic metastases and extrahepatic cancer simultaneously had survival > 3 years. Our data support the concept that patients with unilobar metastatic disease who undergo surgical resection with tumor-free surgical margins can be afforded a significant opportunity at long-term survival with acceptable morbidity, mortality, and hospital stay. Also, certain patients with bilobar or extrahepatic disease (or both) who undergo complete resection can enjoy a long-term survival. In these subgroups of patients resection should be considered on an individual basis.

Adenocarcinoma↗

PubMed1998

A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction.

OBJECTIVE: To test the null hypothesis that administering misoprostol orally or vaginally will result in no difference in time to vaginal birth, and to determine whether different frequencies of tachysystole and hyperstimulation are associated with route of administration. METHODS: Two hundred six women after 37 completed weeks' gestation who presented with an indication for induction were randomly assigned to receive misoprostol (50 microg) either orally or vaginally every 4 hours as needed to induce labor. Placebo use and allocation concealment accomplished blinding until data analysis was completed. Sample size was calculated to allow a two-tailed alpha of .05 and power (1-beta) of 80%. All fetal heart rate and uterine activity graphs were classified according to Curtis' criteria before induction groups were unmasked. RESULTS: Analysis involved 104 women in the oral group and 102 in the vaginal group. The mean time (+/-standard deviation) to vaginal birth with oral misoprostol was 1072 (+/-593) minutes compared with 846 (+/-385) minutes with the vaginal protocol (P=.004). There were no significant differences in cesarean rate, epidural use, or neonatal outcomes. More frequent tachysystole for 20 minutes (P < .01) and hyperstimulation (P < .04) were observed with vaginal misoprostol. No neonatal asphyxia occurred in either group. CONCLUSION: Misoprostol effectively induces labor, given orally or vaginally. There is a shorter interval to vaginal birth with vaginal application; however, the more frequent occurrence of fetal heart rate graph abnormalities in this group suggests that, until the optimal dosing interval for vaginal use is determined, the preferred route of misoprostol administration might be oral.

Abortifacient Agents, Nonsteroidal↗

PubMed1998

Tissue-conserving surgery for prognosis, treatment, and function preservation.

OBJECTIVES: To describe an approach based on initial tissue-conserving surgery used to obtain histologically determined prognostic information that has therapeutic implications and the potential to enhance preservation of function. STUDY DESIGN: Analysis of a group of patients with head and neck cancer treated initially with tissue-conserving surgery based on Mohs' histographic sectioning and selected neck dissection to derive histologically determined prognostic information with therapeutic implications and preservation in function. METHODS: This study is primarily based on an analysis of patients from January 1, 1989, through June 4, 1996 assigned to a protocol evaluating resection of oral cavity squamous cell cancer with margin control using Mohs' histographic technique and/or a group of patients with neck assessment of NO on clinical examination who are undergoing supraomohyoid neck dissections. RESULTS: Thirty-three primary tumor resections were performed using the Mohs' technique, and 54% required two or more Mohs' sections before clear histologic margins were obtained following resection based on clinically determined negative margins. There were 44 patients who underwent unilateral or bilateral supraomohyoid neck dissections, and 33% had occult, histologically positive nodes. When compared with the disease of the neck specimens, a preoperative computed tomography scan had a sensitivity of 25%, a specificity of 77%, and an accuracy of 63%. CONCLUSIONS: This report describes the effectiveness of Mohs' histographic sectioning and selective neck dissection as a means of determining prognostic information that can be used to develop a focused and cost-effective treatment program that, along with contemporary reconstructive techniques, provides a potential enhancement of function preservation.

Adult↗

PubMed1997

Intensified regimen for advanced head and neck squamous cell carcinomas.

OBJECTIVE: To devise an intensified treatment regimen for patients with advanced, resectable head and neck squamous cell carcinomas. DESIGN: Phase I/II clinical trial consisting of perioperative cisplatin chemoradiotherapy, surgical resection, intraoperative radiotherapy, and postoperative cisplatin chemoradiotherapy. SETTING: The Ohio State University Comprehensive Cancer Center, Columbus. PATIENTS: Thirty-seven patients (median age, 63 years) with advanced oral cavity, oropharyngeal, or hypopharyngeal carcinomas. RESULTS: The range of time at risk was 1 to 30 months (median, 21 months). Thirty of the 37 registered patients were analyzable; 11 have died (5 with distant metastases; 1 of lung carcinoma; and 5 were cancer-free); 2 experienced second primary tumors in the oral cavity (out of or adjacent to the previous radiotherapy portals). Treatment compliance was excellent (92%), morbidity was low, and excellent locoregional control was achieved. CONCLUSIONS: The initial results are encouraging; the future strategy will intensify the systemic component of therapy based on results from concurrent laboratory studies.

Antineoplastic Agents↗

PubMed1997

Seroma formation following axillary dissection for breast cancer: risk factors and lack of influence of bovine thrombin.

BACKGROUND: Seromas of the axillary space following breast surgery can lead to significant morbidity and delay in the initiation of adjuvant therapy. A prospective, randomized study was undertaken to evaluate the effect of bovine spray thrombin on seroma formation following either modified radical mastectomy (MRM) or lumpectomy with axillary dissection (LAD). In addition, risk factors for seroma formation were analyzed and identified. METHODS: A total of 101 patients were randomized to receive either bovine thrombin (20,000 units) (treatment group) or no thrombin (control group) applied to their axilla following either MRM or LAD. Drains were left in place until the preceding 24-hour drainage was < 40 milliliters. The number of days the drains were in place and wound complications (including seroma formation) were recorded. RESULTS: Forty-nine (n = 49) patients were assigned to the treatment gorup and 52 (n = 52) to the control group. MRM was performed on 60 patients (59%) and LAD oN 41 (41%). Eighteen of the 49 patients (37%) in the thrombin group developed a seroma in comparison to 21 of the 52 control patients (40%) (P = 0.71). Significant risk factors for seroma formation included increased age, patient weight, initial 72-hour wound drainage, and LAD. No statistically significant differences were observed between treatment and control groups with respect to time to drain removal, or the incidence of other wound complications. CONCLUSION: Although thrombin by itself appears to have no effect on subsequent seroma development following axillary dissection, the identification of predictive variables will be helpful in designing future trials aimed at reducing the incidence of this common complication of breast surgery.

Animals↗

PubMed1997

Characterization of the receptor binding determinants of granulocyte colony stimulating factor.

We performed a series of experiments using alanine-scanning mutagenesis to locate side chains within human granulocyte colony-stimulating factor (G-CSF) that are involved in human G-CSF receptor binding. We constructed a panel of 28 alanine mutants that examined all surface exposed residues on helices A and D, as well as all charged residues on the surface of G-CSF. The G-CSF mutants were expressed in a transiently transfected mammalian cell line and quantitated by a sensitive biosensor method. We measured the activity of mutant proteins using an in vitro proliferation assay and an ELISA binding competition assay. These studies show that there is a region of five charged residues on helices A and C employed by G-CSF in binding its receptor, with the most important residue in this binding patch being Glu 19. Both wild-type G-CSF and the E19A mutant were expressed in E. coli. The re-folded proteins were found to have proliferative activities similar to the analogous proteins from mammalian cells: furthermore, biophysical analysis indicated that the E19A mutation does not cause gross structural perturbations in G-CSF. Although G-CSF is likely to signal through receptor homo-dimerization, we found no compelling evidence for a second receptor binding region. We also found no evidence of self-antagonism at high G-CSF concentrations, suggesting that, in contrast to human growth hormone (hGH) and erythropoietin (EPO), G-CSF probably does not signal via a pure 2:1 receptor ligand complex. Thus, G-CSF, while having a similar tertiary structure to hGH and EPO, uses different areas of the four helix bundle for high-affinity interaction with its receptor.

Alanine↗

PubMed1997

Oral administration of misoprostol for labor induction: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness, safety, and gastrointestinal tolerance of misoprostol taken orally for induction of labor, against our established protocol, with the interval from induction to vaginal birth as the primary outcome measure. METHODS: Two hundred seventy-five women who presented with indication for induction of labor were assigned randomly to receive either 50 micrograms of misoprostol orally every 4 hours as needed or treatment according to our established protocol (physician-chosen combinations of intracervical or vaginal prostaglandins every 4-6 hours, artificial rupture of membranes, and oxytocin infusion). Sample size was calculated with a two-tailed alpha = .05 and power of 95%. RESULTS: The mean time (+/-standard deviation) to vaginal birth with oral misoprostol was 926 +/- 521 minutes versus 909 +/- 585 minutes with the established protocol, a nonsignificant difference. There were no clinically or statistically significant differences in maternal secondary outcome measures (cesarean rate, frequency of epidural use, perineal trauma, or manual removal of the placenta). There was no difference in frequency of maternal gastrointestinal side effects. Neonatal outcomes, including cord blood acid-base analysis, were not different. CONCLUSIONS: Oral misoprostol may be a new option for labor induction. It appears to be no less effective or safe than our usual regimen for induction of labor at term and is well tolerated. Further studies are warranted to confirm the safety of this approach and to determine optimal dose and frequency of administration.

Administration, Oral↗

PubMed1997

Antiviral properties of 3-quinolinecarboxamides: a series of novel non-nucleoside antiherpetic agents.

Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.

Acyclovir↗

PubMed1996

A phase II evaluation of high dose cisplatin and etoposide in patients with advanced esophageal adenocarcinoma.

BACKGROUND: In patients with advanced esophageal adenocarcinoma, the efficacy and palliative role of systemic chemotherapy are not well defined. The primary objective of this Phase II trial was to evaluate the antitumor activity and toxicity of a multiday chemotherapy schedule of high dose cisplatin and etoposide in patients with unresectable or metastatic esophageal adenocarcinoma. A secondary objective was to assess the efficacy of this regimen in palliating dysphagia. METHODS: Twenty-seven eligible patients with unresectable locoregional or metastatic esophageal adenocarcinoma were treated with cisplatin, 30 mg/m2/day, and etoposide, 60 mg/m2/day, intravenously daily for 5 days, every 3 weeks. After three cycles of chemotherapy, all patients were assessed for response. Patients with responding metastatic disease were given one additional cycle of chemotherapy, and patients with locoregional disease received radiation and concurrent continuous infusion of 5-fluorouracil at 300 mg/m2/day for the duration of radiation therapy. Patients were questioned about dysphagia symptoms initially and then weekly during chemotherapy. RESULTS: The major toxicities included myelosuppression, nausea and vomiting, and peripheral sensory neuropathy, with one treatment-related death. Major responses were observed in 13 patients (48%; 95% confidence intervals, 36-74%), including 5 complete and 8 partial responses. Dysphagia relief occurred in 89% of 18 symptomatic patients within a median time of 16 days. The median survival duration for all patients was 9.8 months, and the actuarial 3-year survival rate was 22%. CONCLUSIONS: Multiday chemotherapy with high dose cisplatin and etoposide is active in patients with advanced esophageal adenocarcinoma. Toxicities associated with this regimen are substantial but manageable.

Adenocarcinoma↗