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S Waxman

Publications and source records attributed to S Waxman.

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

Influence of ruminal distribution on norfloxacin pharmacokinetics in adult sheep.

Norfloxacin (NF) ruminal distribution after intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administration was determined in order to assess the influence of the rumen on the pharmacokinetic behaviour of NF in sheep. Norfloxacin concentrations in rumen were detected after i.v. and i.m. administrations between 4 and 48 h in all animals studied. The experimental distribution ratios after i.v. and i.m. administration expressed as area under the concentration-time curve ratios AUC(rumen)/AUC(plasma) were 0.24 and 0.39, respectively, and thus lower than corresponding predicted value of 5.06. Apparently, drug persisted in the rumen content longer than in plasma. The experimental mean residence time ratios MRT(rumen)/MRT(plasma) after i.v. and i.m. administrations were 2.33 and 1.66, respectively. After p.o. administration, NF concentrations in the rumen content were extremely high compared with the respective plasma concentrations, resulting in mean peak concentrations ratio C(max-rumen)/C(max-plasma) of 383.66 and AUC(rumen)/AUC(plasma) experimental ratio of 402.32. This value was considerably higher (approximately 79 fold) than the predicted distribution ratio of 5.06. Our results suggest that the limited p.o. bioavailability of NF in ruminants could not be attributed to ruminal degradation.

Administration, Oral↗
PubMed2001

Pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in adult goats.

The pharmacokinetic behavior of marbofloxacin was studied in goats after single-dose intravenous (i.v.) and intramuscular (i.m.) administrations of 2 mg/kg bodyweight. Drug concentration in plasma was determined by high performance liquid chromatography (HPLC) and the data collected were subjected to compartmental and noncompartmental kinetic analysis. This compound presented a relatively high volume of distribution (Vss=1.31 L/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.23 L/kg small middle doth, which is related to a long elimination half-life (t1/2beta=7.18 h and 6.70 h i.v. and i.m., respectively). Pharmacokinetic parameters were not significantly different between both routes of administration. Marbofloxacin was rapidly absorbed after i.m. administration (Tmax=0.9 h) and had high bioavailability (F=100.74%).

Animals↗
PubMed2001

Urgent coronary bypass surgery for failed percutaneous coronary intervention in the stent era: Is backup still necessary?

BACKGROUND: Current practice guidelines for performance of percutaneous coronary intervention (PCI) in the United States mandate availability of on-site surgical backup. With the decreasing frequency of urgent coronary bypass surgery (UCABG) with newer technologies, it is unclear whether such backup continues to be necessary. METHODS: A database of 5655 consecutive patients undergoing PCI at a single center between August 1, 1992, and December 31, 1997, was analyzed. Outcomes were determined as well as clinical, lesion, and procedural characteristics of patients during 4 time periods preceding and during use of coronary stenting. RESULTS: Frequency of UCABG for failed PCI decreased from 2.2% to 0.6% in the most recent time period (P <.01) with no change in incidence of in-hospital death or myocardial infarction. Incidence of stenting progressively increased to 72% in the latest period. Patients requiring UCABG had a higher prevalence of acute coronary syndromes (95%) and type B lesions (79%), but these characteristics were also common in patients who did not undergo UCABG. Although coronary stents were available during the last 3 periods studied, only 30% of UCABG patients had lesions or complications amenable to stenting, and stenting attempts in these patients were all unsuccessful. Despite stenting and use of perfusion balloons and intra-aortic balloon pumps, only 40% of patients having UCABG were stable and pain free on transfer to the operating room. CONCLUSIONS: Although use of UCABG for a failed PCI is currently very low, there are no satisfactory predictors, patients requiring UCABG are frequently clinically unstable, and availability of stenting does not reliably eliminate the need for UCABG or result in a decrease in mortality. This small group of patients continues to require readily available surgical standby.

Angioplasty, Balloon, Coronary↗
PubMed2001

Transatrial access to the normal pericardial space for local cardiac therapy: preclinical safety testing with aspirin and pulmonary artery hypertension.

The reliability, rapidity, and safety of nonsurgical, transatrial pericardial access for local cardiac therapy have been demonstrated in healthy animals. Since many patients take aspirin or have increased right-sided pressures, we evaluated the procedure's safety under these conditions. Transatrial pericardial access was performed in anesthetized pigs following aspirin administration (162 mg p.o., n = 6) or during experimental pulmonary artery hypertension (n = 4 different animals) and required only 3 minutes following guide catheter positioning. Platelet aggregability testing with arachidonic acid confirmed aspirin effectiveness. Mean pericardial fluid hematocrit was 0.1 +/- 0.1% after 2 days of aspirin therapy and 1.9 +/- 1.1% at sacrifice 24 hours later (NS). Mean pericardial fluid hematocrit was 1.0 +/- 0.5% after 45 minutes of pulmonary artery hypertension and 4.3 +/- 0.8% at sacrifice 30 minutes later (NS). Histologic analysis in both groups revealed a small thrombus and localized inflammation at the site of puncture. Neither aspirin use nor pulmonary artery hypertension causes significant bleeding into the pericardial space following transatrial access and thus does not preclude this route for local cardiac drug delivery.

Animals↗
PubMed2001

History of the development of arsenic derivatives in cancer therapy.

Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation and cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease.

Antineoplastic Agents↗
PubMed2000

Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells.

To elucidate the molecular mechanism of all-trans-retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells, the gene expression patterns in the APL cell line NB(4) before and after ATRA treatment were analyzed using complementary DNA array, suppression-subtractive hybridization, and differential-display-polymerase chain reaction. A total of 169 genes, including 8 novel ones, were modulated by ATRA. The ATRA-induced gene expression profiles were in high accord with the differentiation and proliferation status of the NB(4) cells. The time courses of their modulation were interesting. Among the 100 up-regulated genes, the induction of expression occurred most frequently 12-48 hours after ATRA treatment, while 59 of 69 down-regulated genes found their expression suppressed within 8 hours. The transcriptional regulation of 8 induced and 24 repressed genes was not blocked by cycloheximide, which suggests that these genes may be direct targets of the ATRA signaling pathway. A balanced functional network seemed to emerge, and it formed the foundation of decreased cellular proliferation, maintenance of cell viability, increased protein modulation, and promotion of granulocytic maturation. Several cytosolic signaling pathways, including JAKs/STAT and MAPK, may also be implicated in the symphony of differentiation. (Blood. 2000;96:1496-1504)

Antineoplastic Agents↗
PubMed2000

Regrowth of 5-fluorouracil-treated human colon cancer cells is prevented by the combination of interferon gamma, indomethacin, and phenylbutyrate.

We previously reported that phenylbutyrate (PB), a differentiation agent, retarded the regrowth of fluoropyrimidine-treated HT29 cells to a greater extent in a well-differentiated subclone as compared with a poorly differentiated subclone (Y. Huang and S. Waxman, Clin. Cancer Res., 4: 2503-2509, 1998). To extend these results and to overcome the known heterogeneity of human colon carcinoma (HCC) cells, the effect of cytostatic agents reported to inhibit HCC growth [IFN-alpha and IFN-gamma, indomethacin, and PB alone or in combination] on clonogenicity and HCCs recovery from 5-fluorouracil (FUra) treatment was studied in eight different HCCs. IFN-alpha proved to be ineffective in all eight HCCs, whereas IFN-gamma induced marked growth inhibition in four HCCs that expressed wild-type K-ras. Despite large differences in HCC response to the other individual agents, strong growth inhibition was observed when PB was added in combination with indomethacin. The inhibition was even more pronounced when IFN-gamma was included in the regimen. Most importantly, after treatment with the combination of three agents, the clonogenic potential was severely inhibited (92-100%) in the IFN-gamma-sensitive cell lines, whereas in the IFN-gamma-insensitive cell lines, comparable loss of clonogenecity was obtained when the cells were pretreated with FUra. As known and described in detail, the three cytostatic agents inhibit different processes necessary for cell growth, thus requiring the cells to repair multiple pathways to restore growth. The induction of STAT1 DNA binding activity by IFN-gamma and p21WAF1 by PB, alone or in combination, correlated with growth inhibition and loss of clonogenicity. The finding that the readily reversible growth inhibition and decrease in clonogenicity of FUra-treated HCC are prolonged by subsequent treatment with the three cytostatic agents in all HCCs may be of clinical importance because FUra continues to be the most widely used cytotoxic agent in the treatment of colon carcinoma.

Antimetabolites, Antineoplastic↗
PubMed2000

Cellular retinol-binding protein expression and breast cancer.

BACKGROUND: The biologic activity of vitamin A depends, in part, on its metabolism to active nuclear receptor ligands, chiefly retinoic acid. The cellular retinol-binding protein (CRBP) binds vitamin A with high affinity and is postulated to regulate its uptake and metabolism. In this report, we analyze the expression of CRBP in normal and malignant breast tissues. METHODS: We evaluated CRBP expression by in situ hybridization in six reduction mammoplasty specimens and 49 human breast carcinoma specimens by use of digoxigenin-labeled RNA probes and in nine cultured mammoplasty specimens by northern or western blot analysis. Statistical significance was evaluated with the chi(2) test or Fisher's exact test if the sample sizes were small. All P values are from two-sided tests. RESULTS: CRBP was expressed in all 15 mammoplasty specimens (normal breast tissue) and in 33 of 35 available specimens of normal tissue adjacent to carcinoma. In contrast, 12 (24%) of 49 carcinoma lesions were uniformly negative for CRBP (P =.023 for comparison with adjacent normal breast tissue). The loss of CRBP expression was as frequent in ductal carcinoma in situ (six [27%] of 22) as in invasive lesions (six [22%] of 27), suggesting that it is a relatively early event in carcinogenesis and not associated with patient age, tumor grade, and expression of steroid receptors or c-Myc. Preliminary experiments did not find an association between CRBP and retinoic acid receptor beta loss, but most (four of five) CRBP-negative tumors were also retinoic acid receptor beta negative. CONCLUSION: CRBP is underexpressed in 24% (95% confidence interval = 12.5%-36.5%) of human breast carcinomas, implying a link between cellular vitamin A homeostasis and breast cancer. We hypothesize that the loss of CRBP restricts the effects of endogenous vitamin A on breast epithelial cells.

Blotting, Northern↗
PubMed2000

Preclinical safety testing of percutaneous transatrial access to the normal pericardial space for local cardiac drug delivery and diagnostic sampling.

The safety of a percutaneous method and streamlined catheter system to access the normal pericardial space via the right atrial appendage for drug delivery and diagnostic sampling was demonstrated in 20 anesthetized pigs. Access was successfully accomplished in all animals within 3 min of guide catheter positioning and was documented by fluoroscopic imaging and pericardial fluid sampling. The animals were sacrificed at 24 hr (n = 10) and 2 weeks (n = 10) for histopathologic analysis. Mean pericardial hematocrit was 1.1% +/- 0.3% at initial sampling, 4.3% +/- 1.4% at 24 hr (P = 0.005 vs. baseline), and 0.4% +/- 0.2% at 2 weeks (P = 0.13 vs. baseline). At 24 hr, there was local inflammatory reaction in the atrial wall and a small thrombus at the site of puncture. At 2 weeks, no significant inflammatory changes or pericarditis were evident. The technique is well tolerated with no apparent adverse complications. Advances in intrapericardial therapeutics and diagnostics will direct the clinical application of this novel approach in human subjects.

Animals↗
PubMed2000

Differentiation therapy in acute myelogenous leukemia (non-APL).

Successful treatment of acute promyelocytic leukemia (APL) has identified several novel approaches to induce leukemic cell differentiation and selective apoptosis by overcoming the site-specific transcriptional repression by dominant fusion leukemogenic proteins characteristic of APL and other forms of acute myelogenous leukemia (AML). These therapeutic approaches include the use of site-specific ligands, receptors and cytokines, disruption of dominant fusion leukemogenic proteins, chromatin remodeling and combining the above with cytotoxic chemotherapy. With the exception of cytotoxic chemotherapy, the above therapeutic strategies do not significantly affect normal hematopoiesis and their combinations have been shown to be synergistic in inducing myeloid differentiation and apoptosis in several AML cell lines and in patients with APL. These approaches are, in general, non-cross resistant and should be well tolerated particularly in elderly patients with AML. Clinical studies which include biologic end points for differentiation induction, histone acetylation and selective apoptosis are presently in development to evaluate these strategies in the treatment of AML.

Acute Disease↗
PubMed2000

Intrapericardial beta-adrenergic blockade with esmolol exerts a potent antitachycardic effect without depressing contractility.

Hyperadrenergic states of various etiologies can contribute to tachycardias. Systemic beta-adrenergic blockade suppresses sinus tachycardia but may adversely affect arterial blood pressure and contractility, because the drug gains access to myocardial cells as well as to the sinoatrial node. We examined whether intrapericardial beta-adrenergic blockade with esmolol could suppress tachycardia without reducing contractility as a result of limited drug diffusion, which would be sufficient to penetrate the superficial sinoatrial node but not the deeper myocardial layers. In five anesthetized pigs, we provoked a reflex heart rate increase of 50 beats/min with hemorrhage. The rapidly acting beta-adrenergic blocking agent esmolol (1 mg/kg) was administered intrapericardially using a new percutaneous transatrial access method and a catheter system that can be rapidly and safely introduced. Esmolol equivalently suppressed hemorrhage-induced sinus tachycardia when administered intrapericardially (from 192 to 158 beats/min at 5 min, p < 0.05) or intravenously (from 177 to 151 beats/min at 1 min, p < 0.05). The antitachycardic effect of intrapericardial esmolol was prolonged compared with intravenous esmolol (10 min vs. 3 min, p < 0.05). Intrapericardial esmolol did not affect blood pressure or left ventricular dP/dt max, an index of contractility, whereas intravenous esmolol decreased blood pressure at 1 min for 2 min (p < 0.05) and simultaneously decreased left ventricular dP/dt max at 1 min for < 2 min (p < 0.05). Intrapericardial esmolol suppresses adrenergically induced sinus tachycardia without decreasing contractility or blood pressure. The transatrial approach for intrapericardial delivery of certain 1-adrenergic blocking agents could be employed to control tachycardias in emergency care and surgical settings in patients with impaired cardiac contractility and propensity to hypotension.

Adrenergic beta-Antagonists↗
PubMed1999

Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients.

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RARalpha fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RARalpha expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 x 10(9)/L at relapse had better survival than those with WBC count over 10 x 10(9)/L (P =.038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P =.01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

Adult↗
PubMed1999

Genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene.

The promyelocytic leukemia zinc finger gene (PLZF) is involved in chromosomal translocation t(11;17) associated with acute promyelocytic leukemia. In this work, a 201-kilobase genomic DNA region containing the entire PLZF gene was sequenced. Repeated elements account for 19.83%, and no obvious coding information other than PLZF is present over this region. PLZF contains six exons and five introns, and the exon organization corresponds well with protein domains. There are at least four alternative splicings (AS-I, -II, -III, and -IV) within exon 1. AS-I could be detected in most tissues tested whereas AS-II, -III, and -IV were present in the stomach, testis, and heart, respectively. Although splicing donor and acceptor signals at exon-intron boundaries for AS-I and exons 1-6 were classical (gt-ag), AS-II, -III, and -IV had atypical splicing sites. These alternative splicings, nevertheless, maintained the ORF and may encode isoforms with absence of important functional domains. In mRNA species without AS-I, there is a relatively long 5' UTR of 6.0 kilobases. A TATA box and several transcription factor binding sites were found in the putative promoter region upstream of the transcription start site. PLZF is a well conserved gene from Caenorhabditis elegans to human. PLZF paralogous sequences are found in human genome. The presence of two MLL/PLZF-like alignments on human chromosome 11q23 and 19 suggests a syntenic replication during evolution. The chromosomal breakpoints and joining sites in the index acute promyelocytic leukemia case with t(11;17) also were characterized, which suggests the involvement of DNA damage-repair mechanism.

Alternative Splicing↗
PubMed1999

Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway.

Low concentrations of As(2)O(3) (</=1 micromol/L) induce long-lasting remission in patients with acute promyelocytic leukemia (APL) without significant myelosuppressive side effects. Several groups, including ours, have shown that 0.5 to 1 micromol/L As(2)O(3) induces apoptosis in APL-derived NB4 cells, whereas other leukemic cells are resistant to As(2)O(3) or undergo apoptosis only in response to greater than 2 micromol/L As(2)O(3). In this report, we show that the ability of As(2)O(3) to induce apoptosis in leukemic cells is dependent on the activity of the enzymes that regulate cellular H(2)O(2) content. Thus, NB4 cells have relatively low levels of glutathione peroxidase (GPx) and catalase and have a constitutively higher H(2)O(2) content than U937 monocytic leukemia cells. Glutathione-S-transferase pi (GSTpi), which is important for cellular efflux of As(2)O(3), is also low in NB4 cells. Moreover, As(2)O(3) further inhibits GPX activity and increases cellular H(2)O(2) content in NB4 but not in U937 cells. Selenite pretreatment of NB4 cells increases the activity of GPX, lowers cellular H(2)O(2) levels, and renders NB4 cells resistant to 1 micromol/L As(2)O(3). In contrast, concentrations of As(2)O(3) that alone are not capable of inducing apoptosis in NB4 cells induce apoptosis in the presence of the GPx inhibitor mercaptosuccinic acid. Similar effects are observed by modulating the activity of catalase with its inhibitor, aminotriazol. More important from a therapeutic point of view, U937 and HL-60 cells, which require high concentrations of As(2)O(3) to undergo apoptosis, become sensitive to low, clinically acceptable concentrations of As(2)O(3) when cotreated with these GPx and catalase inhibitors. The induction of apoptosis by As(2)O(3) involves an early decrease in cellular mitochondrial membrane potential and increase in H(2)O(2) content, followed by cytochrome c release, caspase 3 activation, DNA fragmentation, and the classic morphologic changes of apoptosis.

Amitrole↗
PubMed1999

Genomic structure of the human PLZF gene.

The human PLZF (promyelocytic leukaemia zinc finger) gene encodes a Krüppel-like zinc finger protein, which was identified via the reciprocal translocation t(11;17)(q23;q21) fusing it to the retinoic acid receptor alpha (RARalpha) gene in promyelocytic leukaemia. To determine its complete genomic organisation, we constructed a cosmid-map fully containing the hPLZF gene. The gene has seven exons, including a novel 5' untranslated exon, varying in size from 87 to 1358bp and spans at least 120kb. Flanking intronic sequences were identified and all splice acceptor and donor sites conformed to the gt/ag rule. Five polymorphic markers could be fine located in its vicinity. These data will facilitate mutation analysis of hPLZF in t(11;17) leukaemia cases, as well as assist mapping and loss-of-heterozygosity analysis. Here we have tested hPLZF as a possible candidate for the PGL1 locus involved in hereditary head and neck paragangliomas. However, mutation analysis revealed no aberration in 12 paraganglioma patients from different families.

Base Sequence↗