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Biomedical subjects

G Weiss

Publications and source records attributed to G Weiss.

At least 37 records · Page 2Linked to original sources
PubMed2001

Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties.

PURPOSE: To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649. RESULTS: Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin. CONCLUSION: Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.

Adult↗
PubMed2001

Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

Adult↗
PubMed2001

Regulatory interactions between iron and nitric oxide metabolism for immune defense against Plasmodium falciparum infection.

Iron chelation therapy of Plasmodium falciparum infection alleviates the clinical course of cerebral malaria in children. This study assessed the underlying mechanisms of this therapy. Cytokine stimulation of human (intestinal cell line DLD-1) or murine cells (murine macrophage cell line RAW 264.7) resulted in increased nitric oxide (NO) formation and decreased survival of plasmodia within cocultured human erythrocytes. The addition of desferrioxamine (DFO) before cytokine treatment increased both NO formation and parasite killing but had no effect in the presence of the inhibitor of NO formation, L-N6-(1-iminoethyl)-lysine. Moreover, peroxynitrite, which is formed after chemical reaction of NO with superoxide, appears to be the principal effector molecule for macrophage-mediated cytotoxicity toward P. falciparum, and interferon-gamma is a major regulatory cytokine for this process. The effect of DFO on the clearance of plasmodia appears to be due to enhanced generation of NO, rather than to limitation of iron availability to the parasite.

Animals↗
PubMed2001

Modulation of cellular iron metabolism by hydrogen peroxide. Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts.

Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs. The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H(2)O(2) that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 microm H(2)O(2) for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H(2)O(2) induces a approximately 4-fold increase in TfR mRNA levels within 2-6 h, and subsequent accumulation of newly synthesized protein after 4 h. This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells. Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the Divalent Metal Transporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs. Finally, H(2)O(2)-treated cells display an increased capacity to sequester (59)Fe in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of (59)Fe intracellular distribution. Our data suggest that H(2)O(2) regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.

Amino Acid Sequence↗
PubMed2001

Pronounced postprandial lipemia impairs endothelium-dependent dilation of the brachial artery in men.

OBJECTIVE: Pronounced postprandial lipemia has been established as a risk factor for cardiovascular disease, but reports regarding its effect on endothelial function have been controversial. In the present study the influence of a standardized fatty meal with its ensuing postprandial lipemia of highly varying magnitude on endothelium-dependent dilation (EDD) was investigated. METHODS: In 17 healthy, normolipidemic men EDD of the brachial artery was quantified in two series of three measurements each. In both series initial measurements were performed at 08:00 h after an overnight fast followed by measurements at 12:00 and 16:00 h, in the first series with continued fasting and in the second following the ingestion of a standardized fatty test meal 4 and 8 h postprandially. RESULTS: Measurements of EDD in the fasting state revealed the recently appreciated diurnal variation with higher values in noon and afternoon hours compared with morning values (2.5+/-1.6% at 08:00, 7.5+/-2.7% at 12:00, and 7.0+/-2.1% at 16:00 h, P<0.001 by analysis of variance). Postprandial EDD values measured at 12:00 h were, at the average, lower than fasting EDD values measured at 12:00 h and correlated inversely with the magnitude of postprandial triglyceridemia (r=-0.81, P<0.001). In multivariate analysis, higher postprandial lipemia was associated with impaired postprandial EDD (P<0.001) independent of fasting triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, insulin, age and body mass index. CONCLUSION: We conclude that pronounced postprandial lipemia is associated with transient impairment of endothelial function. Our findings support the notion that impaired triglyceride metabolic capacity plays an important role in atherogenesis.

Adult↗
PubMed2001

Utilisation of locally delivered doxycycline in non-surgical treatment of chronic periodontitis. A comparative multi-centre trial of 2 treatment approaches.

AIM: In the present 6-month multicentre trial, the outcome of 2 different approaches to non-surgical treatment of chronic periodontitis, both involving the use of a locally delivered controlled-release doxycycline, was evaluated. MATERIAL AND METHODS: 105 adult patients with moderately advanced chronic periodontitis from 3 centres participated in the trial. Each patient had to present with at least 8 periodontal sites in 2 jaw quadrants with a probing pocket depth (PPD) of > or =5 mm and bleeding following pocket probing (BoP), out of which at least 2 sites had to be > or =7 mm and a further 2 sites > or =6 mm. Following a baseline examination, including assessments of plaque, PPD, clinical attachment level (CAL) and BoP, careful instruction in oral hygiene was given. The patients were then randomly assigned to one of two treatment groups: scaling/root planing (SRP) with local analgesia or debridement (supra- and subgingival ultrasonic instrumentation without analgesia). The "SRP" group received a single episode of full-mouth supra-/subgingival scaling and root planing under local analgesia. In addition, at a 3-month recall visit, a full-mouth supra-/subgingival debridement using ultrasonic instrumentation was provided. This was followed by subgingival application of an 8.5% w/w doxycycline polymer at sites with a remaining PPD of > or =5 mm. The patients of the "debridement" group were initially subjected to a 45-minute full-mouth debridement with the use of an ultrasonic instrument and without administration of local analgesia, and followed by application of doxycycline in sites with a PPD of > or =5 mm. At month 3, sites with a remaining PPD of > or =5 mm were subjected to scaling and root planing. Clinical re-examinations were performed at 3 and 6 months. RESULTS: At 3 months, the proportion of sites showing PPD of < or =4 mm was significantly higher in the "debridement" group than in the "SRP" group (58% versus 50%; p<0.05). The CAL gain at 3 months amounted to 0.8 mm in the "debridement" group and 0.5 mm in the "SRP" group (p=0.064). The proportion of sites demonstrating a clinically significant CAL gain (> or =2 mm) was higher in the "debridement" group than in the "SRP" group (38% versus 30%; p<0.05). At the 6-month examination, no statistically significant differences in PPD or CAL were found between the two treatment groups. BoP was significantly lower for the "debridement" group than for the "SRP" group (p<0.001) both at 3- and 6 months. The mean total treatment time (baseline and 3-month) for the "SRP" patients was 3:11 h, compared to 2:00 h for the patients in the "debridement" group (p<0.001). CONCLUSION: The results indicate that simplified subgingival instrumentation combined with local application of doxycycline in deep periodontal sites can be considered as a justified approach for non-surgical treatment of chronic periodontitis.

Adult↗
PubMed2001

Great ape DNA sequences reveal a reduced diversity and an expansion in humans.

The extent of DNA sequence variation of chimpanzees is several-fold greater than that of humans. It is unclear, however, if humans or chimpanzees are exceptional among primates in having low and high amounts of DNA sequence diversity, respectively. To address this, we have determined approximately 10,000 bp of noncoding DNA sequences at Xq13.3 (which has been extensively studied in both humans and chimpanzees) from 10 western lowland gorillas (Gorilla gorilla gorilla) and 1 mountain gorilla (Gorilla gorilla beringei; that is, from 2 of the 3 currently recognized gorilla subspecies), as well as 8 Bornean (Pongo pygmaeus pygmaeus) and 6 Sumatran (Pongo pygmaeus abelii) orang-utans, representing both currently recognized orang-utan subspecies. We show that humans differ from the great apes in having a low level of genetic variation and a signal of population expansion.

Animals↗
PubMed2001

Wolf's isotopic response: a case of zosteriform lichen planus on the site of healed herpes zoster.

Based on histological findings, the patient had lichen planus. The clinical picture suggests Wolf's isotopic response on the site of healed herpes zoster. These conditions taken into account lead to the diagnosis of zosteriform lichen planus. Lichenoid papules in a dermatomal arrangement are extremely rare. The clinical, dermoscopic and histological features of this case are described.

Adult↗
PubMed2001

Total lower lip reconstruction with innervated muscle-bearing flaps: a modification of the Webster flap.

BACKGROUND: Mohs surgery and other surgical techniques are used for the removal of squamous cell carcinoma of the lower lip and may leave a large defect in the vermilion and underlying tissue. When nearly the entire lower lip is excised, reconstruction of this defect is a challenge. Repair requires the matching of vermilion color, maintenance of oral sphincter function and mouth opening size, and retention of sensation. Several techniques have been suggested. We present a modification of the Webster flap for total lower lip reconstruction using innervated muscle-bearing flaps. OBJECTIVE: To present a surgical technique for the reconstruction of total lower lip defects after excision of squamous cell carcinoma. METHODS: Innervated muscle-bearing flaps are used and demonstrated in one case. The surgical technique is discussed in detail. RESULTS: The reconstructive results were excellent. There were no postoperative complications. CONCLUSION: The use of innervated muscle-bearing flaps is a useful and effective option for the reconstruction of total lower lip defects.

Carcinoma, Squamous Cell↗
PubMed2001

Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload.

BACKGROUND & AIMS: Imbalances of iron homeostasis are accompanied by alterations of intestinal iron absorption. The identification of divalent-metal transporter 1 (DMT1) and ferroportin 1 (FP1) has improved our understanding of transmembrane iron trafficking. To gain insight into the regulatory properties of these transporters in the duodenum, we studied their expression in patients with hereditary hemochromatosis (HFE-associated and non-HFE-associated), secondary iron overload, and iron deficiency. METHODS: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry. RESULTS: DMT1 and FP1 mRNA levels are positively correlated with each other in all patient groups (P < 0.001). Moreover, DMT1 and FP1 mRNA levels were significantly increased in patients with iron deficiency, HFE and non-HFE hemochromatosis, whereas they were unchanged in patients with secondary iron overload. Alterations in DMT1 and FP1 mRNA levels were paralleled by comparable changes in the duodenal expression of these proteins. In patients with normal iron status or iron deficiency, significant negative correlations between DMT1, FP1 mRNA, and serum iron parameters were found, which were absent in subjects with primary hemochromatosis. CONCLUSIONS: DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload.

Adult↗
PubMed2001

Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia.

BACKGROUND & AIMS: The multidrug resistance protein (MRP) isoforms MRP2 (ABCC2) and MRP3 (ABCC3) play a decisive role in the hepatic secretion of endogenous and xenobiotic conjugates and are differentially expressed in hepatocytes and cholangiocytes. The epithelium of the gallbladder considerably modifies the composition of primary hepatic bile by absorption and secretion; however, the underlying transport mechanisms were largely unknown. Localization of MRP2 and MRP3 may provide an explanation of how the products of phase II conjugation are effluxed from gallbladder epithelia. METHODS: Expression and localization of MRP2 and MRP3 were analyzed by reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence microscopy of human gallbladder tissue. RESULTS: Expression of MRP2 and MRP3 was identified in all gallbladders by RT-PCR followed by sequencing of the amplified fragments. Double immunofluorescence microscopy using 2 specific antibodies for the respective MRP isoform showed the simultaneous expression of MRP2 in the apical membrane and MRP3 in the basolateral membrane of gallbladder epithelia. MRP1 protein expression was not detectable. CONCLUSIONS: Our findings show the expression of MRP2 and MRP3 in distinct plasma membrane domains of gallbladder epithelia and provide evidence for the capacity of the gallbladder to secrete xenobiotic and endogenous anionic conjugates into blood via MRP3 and into bile via MRP2.

Aged↗
PubMed2001

Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway.

Despite the importance of relaxin to normal parturition in various species and its potential as an etiological agent in preterm delivery in women, knowledge regarding the mechanisms by which relaxin alters cervical connective tissue is extremely limited. An established in vitro model for human pregnancy cervix, human lower uterine segment fibroblasts, was used to determine the effects of relaxin as well as those of progesterone on the expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase-1. The results demonstrate that relaxin is a positive regulator of matrix metalloproteinase expression, as it stimulates the expression of procollagenase protein and mRNA levels, stimulates prostromelysin-1 protein and mRNA levels, and inhibits tissue inhibitor of metalloproteinase-1 protein expression. Stimulation of procollagenase and prostromelysin-1 expression by relaxin does not involve phorbol-12-myristate-13-acetate- sensitive PKCs. Relaxin-stimulated tyrosine phosphorylation of the putative receptor and inhibition by a receptor tyrosine kinase inhibitor suggest that the relaxin receptor is probably a tyrosine kinase receptor. Inhibition of c-Raf protein expression using an antisense oligonucleotide inhibits relaxin regulation of matrix metalloproteinase and tissue inhibitor of metalloproteinase-1, suggesting that a signaling pathway involving c-Raf kinase mediates relaxin action.

Cells, Cultured↗
PubMed2001

Kidney cancer: the Cytokine Working Group experience (1986-2001): part I. IL-2-based clinical trials.

The Cytokine Working Group (CWG) was initially established in 1986 as the Extramural IL-2/LAK Working Group. With funding from the National Cancer Institute (NCI), the CWG was mandated to confirming data regarding the efficacy of the high-dose interleukin-2 (IL2)/lymphokine-activated killer cell (LAK cell) regimen piloted at the NCI in the treatment of renal cell cancer. Since those initial studies, the CWG has conducted a series of clinical trials, often with correlative immunologic investigations, to evaluate combination immunotherapy in attempts to enhance the efficacy of IL-2 or to reduce toxicity. Subsequently, the CWG conducted trials to demonstrate the activity of lower-dose outpatient combination cytokine regimens to help determine their role in the armamentarium of treatment for metastatic renal cell cancer. This has culminated in a phase III randomized trial comparing the activity of high-dose IL-2 with the activity of outpatient IL-2 plus interferon-alpha. The CWG also has honed the management of both high-dose IL-2 and outpatient IL-2 regimens to make these safer in the hands of experienced clinicians. In addition, the CWG has produced a series of carefully conducted clinical trials of new cytokines, again attempting to define their clinical efficacy as anticancer agents. These include studies of IL-4, IL-6, and IL-12. Currently, the CWG is conducting studies with new approaches to IL-2 therapy, as well as planning trials with new agents for treatment of renal cell cancer. This review describes these efforts conducted over the past 15 yr.

Antineoplastic Agents↗
PubMed2001

Kidney cancer: the Cytokine Working Group experience (1986-2001): part II. Management of IL-2 toxicity and studies with other cytokines.

The Cytokine Working Group (CWG) was initially established in 1986 as the Extramural IL-2/LAK Working Group. With funding from the National Cancer Institute (NCI), the CWG was mandated to confirming data regarding the efficacy of the high-dose interleukin-2 (IL2)/lymphokine-activated killer cell (LAK cell) regimen piloted at the NCI in the treatment of renal cell cancer. Since those initial studies, the CWG has conducted a series of clinical trials, often with correlative immunologic investigations, to evaluate combination immunotherapy in attempts to enhance the efficacy of IL-2 or to reduce toxicity. Subsequently, the CWG conducted trials to demonstrate the activity of lower-dose outpatient combination cytokine regimens to help determine their role in the armamentarium of treatment for metastatic renal cell cancer. This has culminated in a phase III randomized trial comparing the activity of high-dose IL-2 with the activity of outpatient IL-2 plus interferon-alpha. The CWG also has honed the management of both high-dose IL-2 and outpatient IL-2 regimens to make these safer in the hands of experienced clinicians. In addition, the CWG has produced a series of carefully conducted clinical trials of new cytokines, again attempting to define their clinical efficacy as anticancer agents. These include studies of IL-4, IL-6, and IL-12. Currently, the CWG is conducting studies with new approaches to IL-2 therapy, as well as planning trials with new agents for treatment of renal cell cancer. This review describes these efforts conducted over the past 15 yr.

Antineoplastic Agents↗
PubMed2001

Effects of hydroxyurea on extrachromosomal DNA in patients with advanced ovarian carcinomas.

PURPOSE: In vitro low concentrations of hydroxyurea eliminate double-minute chromosomes (dmins) containing amplified drug-resistance genes and oncogenes from cancer cells. This clinical trial investigated whether a noncytotoxic dose of oral hydroxyurea could reduce the number of dmins in cancer cells in patients with advanced ovarian carcinomas. EXPERIMENTAL DESIGN: The high frequency of ascites associated with ovarian cancer facilitated the monitoring of cytogenetic variations with minimal discomfort in patients who required frequent abdominal paracentesis. Sixteen patients with advanced ovarian carcinomas resistant to conventional cisplatin-based and/or paclitaxel chemotherapy and with ascites requiring frequent abdominal paracentesis were entered in this study. A course of treatment consisted of a single oral dose of 80 mg/kg hydroxyurea every 3 days for 6 weeks. Blood and i.p. levels of hydroxyurea were determined. We monitored the variations of dmins in tumor cells taken from serial abdominal paracenteses. RESULTS: The median number of courses administered to the patients was 1 (range, 1--9). In ascites, hydroxyurea concentrations were 610.3 +/- 76.3, 219.8 +/- 85.6, and 86.1 micromol/liter at 4, 24, and 30 h after oral administration, respectively. Eleven (78.6%) of 14 patient specimens contained dmins before therapy. The number of spreads with tumor cells containing dmins were reduced by more than 50% in 5 (45%) of 11 and 3 (60%) of 5 patients at the completion of the first and second course of chemotherapy, respectively. Using tumor cells taken directly from the patients and grown in soft agar, we documented that concentrations of hydroxyurea in ascites were too low to have any cytotoxic effects. No grade 3--4 hydroxyurea-related toxicities nor any objective responses were observed. However, despite the utilization of a low noncytotoxic dose of hydroxyurea, two patients had prolonged stabilization of their disease for 6 and 10 months, respectively, with concomitant decreases in the number of dmins that remained until progression. CONCLUSIONS: This study showed that, in some circumstances, a noncytotoxic dose of hydroxyurea given to patients with ovarian cancer can decrease the number of metaphase spreads containing dmins in cancer cells.

Administration, Oral↗