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Biomedical subjects

A Markowitz

Publications and source records attributed to A Markowitz.

At least 37 records · Page 2Linked to original sources
PubMed1995

Targeting and initial radioimmunotherapy of medullary thyroid carcinoma with 131I-labeled monoclonal antibodies to carcinoembryonic antigen.

The targeting potential of 131I-labeled NP-4 and MN-14 anti-CEA (carcinoembryonic antigen) monoclonal antibodies (MAbs) was assessed in 19 patients with metastatic medullary thyroid cancer (MTC). Seventeen of these patients also entered pilot radioimmunotherapy studies with nonmyeloablative doses of 131I-anti-CEA MAbs. Tumor targeting was possible in all 19 patients, with an overall lesion sensitivity of 91%. Tumor dosimetry with 131I-MN-14 IgG or F(ab)2 was very favorable, with tumor doses of 14.3 +/- 8.3 cGy/mCi and tumor:red marrow dose ratios exceeding 3:1 for most lesions. Limited antitumor effects lasting up to 26+ months, based on physical exam, tumor markers, computed tomography, or a followup MAb scan, were seen in 5 of 11 assessable patients given relatively low doses of 131I-labeled anti-CEA MAbs. We conclude that anti-CEA MAbs are excellent agents for targeting metastatic MTC. The high tumor uptake of the 131I-anti-CEA antibodies and evidence of tumor response in some patients suggest that radioimmunotherapy with radioiodinated anti-CEA MAbs may be an effective treatment for MTC, particularly when the maximum tolerated dose is given alone or in combination with autologous red marrow or peripheral stem cell support.

Animals↗
PubMed1995

CO binding kinetics of human cytochrome P450 3A4. Specific interaction of substrates with kinetically distinguishable conformers.

The kinetics of CO binding to human cytochrome P450 3A4 was examined by the flash photolysis technique, employing the membrane-bound P450 expressed in baculovirus-infected SF9 insect cells. Triexponential kinetics was observed, indicating that P450 3A4 is composed of multiple, kinetically distinguishable conformers. To define the substrate specificity of individual P450 3A4 conformers we evaluated the effect of a series of substrates of varying sizes and structures on the CO binding kinetics. The rate of CO binding to the total mixture of P450 3A4 conformers was increased in the presence of nifedipine and erythromycin, decreased by quinidine, testosterone, and warfarin, and unaffected by cimetidine and 17 alpha-ethynylestradiol. A recently developed kinetic difference method (Koley, A. P., Robinson, R. C., Markowitz, A., and Friedman, F. K. (1994) Biochemistry 33, 2484-2489) was used to define the kinetic parameters of individual P450 3A4 conformers. The results showed that different conformers have distinct substrate specificities. The substrates had markedly variable effects on the CO binding kinetics of their target P450 3A4 conformers and thus differentially modulate their conformations. These results demonstrate that the interaction of a particular substrate with a specific P450 3A4 conformer can be assessed in the presence of multiple conformers.

Animals↗
PubMed1995

Interaction of polycyclic aromatic hydrocarbons and flavones with cytochromes P450 in the endoplasmic reticulum: effect on CO binding kinetics.

The flash photolysis technique was used to examine the kinetics of CO binding to cytochromes P450 in rat liver microsomes. The effect of polycyclic aromatic hydrocarbons (PAHs) and flavones was used to distinguish the kinetic behavior of the PAH-metabolizing P450 1A1 from that of the remaining multiple microsomal P450s. Applying this approach to microsomes from 3-methylcholanthrene-treated rats showed that although all tested PAHs accelerated CO binding to P450 1A1, the extent varied markedly for different PAHs. The tricyclic PAHs phenanthrene and anthracene enhanced CO binding by 37- and 49-fold, respectively, while several tetracyclic and pentacyclic PAHs increased the rate by 3-16-fold. The results indicate that PAHs exert a dual effect on the rate of CO binding to P450 1A1: a general enhancement via widening of the CO access channel and a reduction that is dependent on PAH size. Although 5,6-benzoflavone increased the rate of CO binding to P450 1A1 by 3.5-fold, it additionally decelerated binding to a constitutive P450 by 15-fold. This flavone thus exerts markedly different effects on two P450s within the same microsomal sample. In contrast, the sole effect of 7,8-benzoflavone was acceleration of CO binding to P450 1A1 by 18-fold. The divergent effects of these isomeric flavones, which only differ in positioning of an aromatic ring, illustrate the sensitivity of CO binding to substrate structure. The varying effects of these PAHs and flavones on CO binding kinetics show that they differentially modulate P450 conformation and access of ligands to the P450 heme and demonstrate that binding of carcinogens to a specific target P450 can be evaluated in its native microsomal milieu.

Animals↗
PubMed1995

Phase II trial of isotretinoin and recombinant interferon alfa-2a in metastatic colorectal carcinoma.

Phase II trials of the novel biologic combination isotretinoin (13-cis-retinoic aid) plus recombinant interferon alfa-2a have demonstrated this combination's major activity against advanced squamous cell carcinoma of the skin and cervix. Because this combination has had limited study in other tumors, we initiated a phase II trial of this regimen in patients with metastatic colorectal adenocarcinoma. Sixteen patients with measurable metastatic colon carcinoma who had received no previous chemotherapy were entered on the trial. Patients received recombinant interferon alfa-2a, 6 million units a day subcutaneously, and isotretinoin, 1 mg/kg per day orally in two divided doses. Patients were evaluated for response after 8 weeks of treatment and then continued on therapy until progressive disease was documented. We did not observe complete or partial responses. Two patients experienced minor responses in measurable pulmonary metastases lasting 12 and 8 weeks. Grade 3-4 toxic reactions included fatigue (5 patients), granulocytopenia (6 patients), neurotoxicity (2 patients), and elevated serum triglyceride levels (2 patients). Although this combination has demonstrated significant activity in squamous cell carcinomas of the skin and cervix, our results suggest that it has little therapeutic activity against advanced colorectal adenocarcinomas.

Adenocarcinoma↗
PubMed1995

Propofol reduces the incidence of vomiting after tonsillectomy in children.

We compared the effect of a propofol-based anaesthetic to an isoflurane-based anaesthetic on the incidence of postoperative vomiting in children following tonsillectomy. Thirty-nine children were enrolled in the study and randomized to receive one of the proposed anaesthetics. All patients underwent a mask induction with halothane, nitrous oxide, and oxygen. Intravenous access was established and all children received fentanyl (2-4 micrograms.kg-1) i.v., mivacurium (0.3 mg.kg-1) i.v. and acetaminophen (10-15 mg.kg-1) p.r. Following tracheal intubation, patients received either isoflurane (0.8-1.6%) or propofol (120-180 micrograms.kg-1 min-1) i.v. with nitrous oxide 70%/oxygen 30% for maintenance of anaesthesia. Vital signs were maintained within 20% of baseline. All patients were extubated in the operating room. PACU nursing staff recorded episodes of vomiting for 4-6 h prior to discharge. A telephone interview the following day was also used for data recovery. Age, sex, and duration of the procedure were not significantly different between the two study groups. Of 19 patients who received propofol, four vomited (21%); in contrast, of the 20 patients who received isoflurane, 11 vomited (55%). This difference is significant (P = 0.048 two-tailed Fisher's Exact Test). These data suggest that using propofol for anaesthesia can diminish the incidence of vomiting following tonsillectomy.

Anesthesia↗
PubMed1994

Kinetics of CO binding to cytochromes P450 in the endoplasmic reticulum.

The kinetics of CO binding to cytochromes P450 in rat liver microsomes were examined using the flash photolysis technique. Modulation of the kinetics by P450 form-specific effectors such as anti-P450 monoclonal antibodies and substrates was used to elucidate the kinetic behavior of individual P450s within the endoplasmic reticulum. The problem of attributing a kinetic parameter to a single P450 in the presence of multiple microsomal P450s was overcome with a difference method that employs the difference of the kinetic profiles obtained in the presence and absence of a P450 effector. Applying this approach to study the conformation/dynamics of P450 2B1 in microsomes from phenobarbital-treated rats revealed that the substrate benzphetamine enhances while testosterone inhibits the rate of CO binding to this P450. Similar experiments with P450 1A1 in microsomes from 3-methylcholanthrene-treated rats showed that the substrate benzo[a]pyrene accelerates CO binding. These results show that the access channel between solvent and heme in the P450 interior can be altered in a substrate- and P450-dependent manner to either hinder or facilitate CO diffusion to the heme iron. These results also demonstrate that analytical difference methods may be employed to characterize the conformation of individual P450s in their native membrane environment in the endoplasmic reticulum.

Animals↗
PubMed1994

Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature.

Vasculitis is characterized by inflammatory changes and necrosis of blood vessels. Involvement of arteries and veins of diverse sizes throughout the body is possible and results in a multiplicity of clinical manifestations. Primary and secondary forms of vasculitis exist. Secondary vasculitis has been linked to several processes, including infections, drugs, and allergic, rheumatologic, and neoplastic disease. The majority of patients with malignant neoplasm-associated vasculitis who have been described had hematologic neoplasms. We report a patient with adenocarcinoma of the colon and vasculitis and review the 36 cases of vasculitis in patients with solid tumors documented in the world literature. The most common malignant neoplasms were non-small-cell lung cancer and prostate, breast, colon, and renal cancer. Cutaneous leukocytoclastic vasculitis and nerve and muscle microvasculitis were the most frequently observed vasculitic subtypes. Importantly, in 71% of the cases, manifestations of vasculitis appeared before or concurrent with the initial recognition or the relapse of the tumor. Management strategies that met with success in at least half the patients in whom they were used included corticosteroids, cyclophosphamide, and treatment of the underlying cancer. Prognosis may be primarily related to the ability to control the malignant neoplasm, as most of the patients who died did so because of tumor progression.

Adenocarcinoma↗
PubMed1993

Role of In-111 labeled CYT-103 immunoscintigraphy in the evaluation of patients with recurrent colorectal carcinoma.

An immunoconjugate of the whole antibody, B72.3, has been approved by the FDA. It is labeled with indium-111, which allows imaging studies intended for the diagnosis and staging of colorectal and recurrent ovarian carcinoma. The new diagnostic imaging agent (CYT-103), Oncoscint CR/OV, has found particular use in evaluating patients with recurrent carcinoma. The three major indications for the study are: 1) occult disease--unexplained rise in serum tumor markers (e.g. CEA), with negative work-up including CT; 2) known local recurrence (e.g. liver or rectal area)--surgery is planned, but there is a need to rule out other areas of involvement; 3) clarify equivocal CT or MRI finding--to distinguish whether an abnormality is due to recurrent tumor or scar tissue, fibrosis, or unopacified bowel loop. Oncoscint has proven to be more sensitive than CT in the detection of disease in the pelvis and extrahepatic abdomen. CT remains the modality of choice for the detection of liver metastases. The combined sensitivity of the two modalities is 88% on a per-patient basis.

Adult↗
PubMed1993

Granulocyte-macrophage colony-stimulating factor as a cause of paraneoplastic leukaemoid reaction in advanced transitional cell carcinoma.

Increasing evidence suggests that paraneoplastic syndromes may be mediated by tumour-related cytokine release, although the specific factor(s) involved remain poorly defined. Colony-stimulating factors (CSF) and interleukins (IL) promote colony growth in semi-solid media and, when administered in recombinant form, increase blood counts in patients. However, normal serum CSF levels in individuals with physiologic blood counts and the relationship between specific serum CSF levels and paraneoplastic leukaemoid reaction are not well established. In this study, we found that normal serum levels of granulocyte-macrophage CSF (GM-CSF), as measured by ELISA, were generally < 55 pg ml-1; IL-3, < 30 pg ml-1; and granulocyte CSF (G-CSF), < 50 pg ml-1. In contrast, high levels of GM-CSF (132 pg ml-1), but not G-CSF or IL-3, were found in a patient with a transitional cell carcinoma of the renal pelvis and increased leukocytosis correlating with the tumour burden. The GM-CSF was biologically active, as demonstrated by its ability to stimulate colony growth in vitro. Based on these results it appears that autonomous production of GM-CSF is one possible pathophysiologic mechanism underlying leukaemoid reaction in cancer patients.

Aged↗
PubMed1993

Collecting duct carcinoma of the kidney.

Collecting duct carcinoma (CDC) is a recently recognised histological variety of renal carcinoma (RC) considered to arise from the epithelium of the collecting ducts. Diagnosis of this entity depends on well defined gross and microscopic criteria and is supported by a characteristic immunostaining pattern. The clinical features of these patients, the natural course of the disease and its response to treatment have not been clearly established. Between 1980 and 1990 we treated 12 patients (median age 43 years, range 16-62) with collecting duct carcinoma of the kidney. In addition to being relatively young, each patient had a strong family history of associated malignancies. Survival was short (median 22 months) and 11 patients presented with locally advanced or metastatic disease.

Adolescent↗
PubMed1990

Phase II study of recombinant alpha-interferon in malignant melanoma.

Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days. Eight patients responded objectively and six patients (6%) had a complete response. The median duration of complete response was 11 months. Patients achieving complete response had only cutaneous, nodal, or pulmonary disease; some had extensive prior therapy; some could tolerate no more than three million units per day. Few patients could tolerate the target dose of 36 million units daily for 70 days. Limiting toxicity was primarily fatigue. Interferon in tolerable doses is effective in a small subset of patients with melanoma. Comparison of published trials of dacarbazine and recombinant alpha interferon indicates the two drugs have similar activity.

Adult↗
PubMed1990

Hearing after retrolabyrinthine vestibular neurectomy.

Thirty-four patients underwent vestibular neurectomies between September 1984 and January 1989. The first 15 patients operated on through January 1987 (and followed for a minimum of 2 years) were evaluated separately for long-term hearing preservation and freedom from vertigo spells. Audiograms taken at 1 postoperative month revealed no change in the pure tone averages of 25 patients and showed improved hearing of 20 to 30 dB in 5 patients. Two patients sustained losses of 18.5 dB and 21 dB, respectively. The speech discrimination scores remained the same in 17 patients, improved in 9, and were reduced in 6. Audiograms performed 12 to 40 months postoperatively showed preservation of the pure tone averages and speech discrimination scores when compared with the earlier 1-month postoperative audiograms in 73% of the patients. The speech discrimination scores, however, tended to fluctuate with the symptomatic course of each disease. Two patients developed major vertigo spells 1 1/2 years following surgery. Postoperative ice-caloric testing revealed no responses in 25 patients and markedly reduced responses in 6. There were no major complications or facial paralysis. The retrolabyrinthine vestibular neurectomy is an effective way to control vertigo with preservation of hearing and an acceptably low incidence of complications and side effects.

Adult↗
PubMed1987

A system for measuring the angular response of hemiparkinsonian monkeys to a food stimulus.

A Zenith Z-100 PC system was used to control an automated feeding system for determining the angular limits at which a monkey would respond to a food stimulus. Raisins secured to the end of a rotating arm by means of vacuum pressure were delivered to the monkey alternately from clockwise and counterclockwise directions at a fixed radius. The point at which the monkey took a raisin from the end of the arm was determined by an increase in negative pressure. The arm position was measured by using a potentiometer mounted in the arm gear train. The computer system controlled the experiment as well as the on-line recording and plotting of data.

Analog-Digital Conversion↗
PubMed1987

Parenteral antibiotic therapy at home: experience with intramuscular cefonicid.

Patients with serious infections often remain hospitalized solely to continue parenteral antibiotic therapy although many who are afebrile and medically stable could complete treatment in an outpatient setting. Potential advantages of outpatient treatment include lower costs and greater efficiency in the use of hospital beds, and economic and psychological benefits to patients. Cefonicid, a parenteral cephalosporin with an extended antibacterial spectrum and a prolonged serum half-life, was used to treat 39 patients with serious infections, mostly those of bone or soft tissues. Staphylococcus aureus was the predominant pathogen isolated (18 patients); nine gram-negative aerobes were observed in single instances. After indicated surgical procedures and inpatient intravenous antibiotic therapy, the patients were discharged to continue parenteral therapy at home with once-daily intramuscular doses of cefonicid. Mean duration of outpatient therapy was 16 days. The clinical response was satisfactory in all but two patients, one with relapse of a S aureus wound infection, the second with a gram-negative reinfection at the site of a bone cyst. Systemic and local tolerability of cefonicid were good. It is concluded that outpatient antibiotic therapy with intramuscular cefonicid can benefit both patients and hospitals.

Adolescent↗
PubMed1984

Treatment of superficial bladder tumors in a controlled trial with thio-TEPA versus adriamycin.

Forty-six patients with superficial transitional cell carcinoma of the bladder were randomized into two groups. Thio-TEPA or adriamycin were instilled periodically into the bladder and cystoscopic follow up was carried out. Both thio-TEPA and adriamycin proved to have similar efficacy in delaying tumor recurrence. Further investigations to establish better dose and interval schedules are indicated.

Administration, Topical↗
PubMed1977

Differentiation of several isolates of Peptococcus magnus by counterimmunoelectrophoresis.

Uniform sonicated suspensions of three clinical isolates of Peptococcus magnus that were morphologically, chromatographically, and biochemically identical were used to produce hyperimmune antisera in rabbits. Similar hyperimmune serum was prepared to a single strain of Peptostreptococcus anaerobius. When these antisera and antigens were tested by counterimmunoelectrophoresis, the three isolates of Peptococcus magnus were immunologically distinct. None of the antisera to Peptococcus magnus formed precipitin lines with Peptostreptococcus anaerobius.

Animals↗