Search PubMed⌕ Search

Biomedical subjects

R A Newman

Publications and source records attributed to R A Newman.

At least 91 records · Page 5Linked to original sources
PubMed1992

Analgesic activity of anticancer agent suramin.

Suramin exhibited morphine-like analgesic activity in mice. It antagonized both thermal (hot-plate) and acetic acid-evoked writhing responses with ED50 values 1/100 and 1/68, respectively, that of morphine. The suramin- and morphine-induced hot-plate analgesia was suppressed by administration of 0.5 mg/kg naloxone. However, lower doses (5-30 micrograms/kg) of naloxone produced dose-related potentiation or suppression of suramin and morphine analgesia. This potentiation effect may be due to the inhibition of writhing by naloxone itself rather than be a direct antagonism of the morphine effect.

Analgesia↗
PubMed1991

Protective effect of ICRF-187 against normal tissue injury induced by adriamycin in combination with whole body hyperthermia.

The use of [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) as a protective agent against normal tissue toxicity caused by combined Adriamycin (ADR) and whole body hyperthermia (WBH; 2 h at 41.5 degrees C) was assessed in a rat model. The effect of ICRF-187 on the antitumor response induced by the combination of ADR and WBH was also investigated in order to assess alterations in the therapeutic index of this combined therapeutic modality treatment. ICRF-187 significantly reduced ADR-mediated body weight loss, renal toxicity, and cardiomyopathy under both normothermic and hyperthermic conditions as shown by morphological and functional assays. ADR-induced neuropathy (seen only in normothermic rats) was also ameliorated by ICRF-187. Although this study did not show a pronounced effect of ICRF-187 on ADR-induced acute myelosuppression, ADR-mediated chronic anemia, leukocytosis, and thrombocytosis were reduced by ICRF-187 in both normothermic and WBH-treated rats. The effect of ICRF-187 on antitumor response was evaluated with a tumor growth delay assay using an in vivo transplantable fibrosarcoma. ICRF-187 caused no significant change in tumor growth delay induced by either ADR alone or ADR combined with WBH. Indeed, the only complete tumor regression following treatment resulted from the combination of ICRF-187 plus ADR plus WBH. Thus, ICRF-187 significantly increases the therapeutic index of the combined modality treatment of ADR and WBH by selectively reducing normal tissue toxicity without interfering with antitumor efficacy.

Animals↗
PubMed1991

Effect of adriamycin combined with whole body hyperthermia on tumor and normal tissues.

Thermal enhancement of Adriamycin-mediated antitumor activity and normal tissue toxicities by whole body hyperthermia were compared using a F344 rat model. Antitumor activity was studied using a tumor growth delay assay. Acute normal tissue toxicities (i.e., leukopenia and thrombocytopenia) and late normal tissue toxicities (i.e., myocardial and kidney injury) were evaluated by functional/physiological assays and by morphological techniques. Whole body hyperthermia (120 min at 41.5 degrees C) enhanced both Adriamycin-mediated antitumor activity and toxic side effects. The thermal enhancement ratio calculated for antitumor activity was 1.6. Thermal enhancement ratios estimated for "acute" hematological changes were 1.3, whereas those estimated for "late" damage (based on morphological cardiac and renal lesions) varied between 2.4 and 4.3. Thus, while whole body hyperthermia enhances Adriamycin-mediated antitumor effect, normal tissue toxicity is also increased, and the potential therapeutic gain of the combined modality treatment is eroded.

Animals↗
PubMed1991

Preparation, characterization, and antitumor activity of water-soluble aminoalkanol platinum(II) complexes.

A new series of highly water-soluble aminoalkanol platinum(II) complexes have been synthesized and characterized by elemental analysis, conductance, IR, and 195Pt NMR. Preliminary in vitro and in vivo screening tests for antitumor activities of these complexes against L1210 murine leukemia were performed. In general, these compounds were far less cytotoxic than cisplatin and possessed only a moderate degree of antitumor activity.

Animals↗
PubMed1991

Circadian infusion of floxuridine in patients with metastatic renal cell carcinoma.

A total of 42 patients with metastatic renal cell carcinoma received floxuridine infusion for 14 days at monthly intervals. The drug was delivered via an external programmable pump on a time-modified or circadian schedule; the highest dose of 68% was given between 3 and 9 p.m. Of the 42 patients 25 (60%) had undergone prior nephrectomy. Of the 40 evaluable patients 4 (10%, 95% confidential interval 3 to 24%) achieved a partial response: 3 of the 4 had undergone prior nephrectomy, while 1 had undergone renal angioinfarction. Another 4 patients (10%) had responses at metastatic sites but no response in the primary kidney tumor. The median duration of response for these 2 groups of patients was 65 and 27 weeks, respectively, and the most responsive site was the lungs. The treatment was generally well tolerated and could be administered on an outpatient basis. Our study confirms the limited but definite activity of floxuridine infused on a circadian schedule in patients with metastatic renal cell carcinoma. We observed responses in metastasis equally in patients with or without prior nephrectomy.

Adult↗
PubMed1991

Doxorubicin analogues incorporating chemically reactive substituents.

Doxorubicin (1) analogues 2-5, incorporating the following alkylating or latent alkylating substituents, R, on the 3'-position of the daunosamine sugar have been synthesized as potential antitumor agents: 2, R = NHCOC6H4(p)SO2F; 3, R = NHCOCH2Br; 4, R = NHCOCH2Cl; 5, R = NHCON(NO)CH2CH2Cl. These compounds were designed on the premise that alkylating anthracyclines might bind covalently to critical intracellular target macromolecules and overcome resistance to the parent agent attributable to reduced cellular drug accumulation. Growth inhibitory studies of the analogues were conducted in vitro against mouse leukemia cells (L1210 and P388) and human uterine sarcoma cells that are sensitive (MES-SA) and resistant (MES-SA/DOX) to doxorubicin. The analogues were 5-100-fold less potent than doxorubicin against the sensitive cell lines. However, they were only marginally cross-resistant with doxorubicin against MES-SA/DOX. Compounds 3 and 5 were also evaluated against a human myelocytic cell line (KBM-3) and a subline (KBM-3/DOX) resistant to doxorubicin. They were equally potent against both cell lines, indicating a complete lack of cross-resistance with doxorubicin. Alkylating anthracyclines may have potential for the treatment of tumors resistant to the parent agents.

Animals↗
PubMed1991

Pitch effects on vowel roughness and spectral noise for subjects in four musical voice classifications.

This study was designed to investigate the effects of vocal fo on vowel spectral noise level (SNL) and perceived vowel roughness for subjects in high- and low-pitch voice categories. The subjects were 40 adult singers (10 each sopranos, altos, tenors, and basses). Each produced the vowel /a/ in isolation at a comfortable speaking pitch, and at each of seven assigned pitches spaced at whole-tone intervals over a musical octave within his or her singing pitch range. The eight /a/ productions were repeated by each subject on a second test day. The SNL differences between repeated test samples (different days) were not statistically significant for any subject group. For the vowel samples produced at a comfortable pitch, a relatively large SNL was associated with samples phonated by the subjects of each sex who manifested the relatively low singing pitch range. Regarding the vowel samples produced at the assigned-pitch levels, it was found that both vowel SNL and perceived vowel roughness decreased as test-pitch level was raised over a range of one octave. The relationship between vocal pitch and either vowel roughness or SNL approached linearity for each of the four subject groups.

Acoustics↗
PubMed1991

Hepatic arterial infusion chemotherapy with complete hepatic venous isolation and extracorporeal chemofiltration: a feasibility study of a novel system.

When chemotherapeutic drugs with low liver extraction are used for hepatic arterial infusion (HAI), dosage limits are usually determined by systemic rather than hepatic toxicity. If such agents could be administered by HAI at dosages limited by hepatic toxicity, regional drug exposure and therapeutic efficacy might be significantly enhanced. We report herein a novel system that achieves complete hepatic venous isolation using a dual-balloon vena cava catheter that can be inserted percutaneously. This catheter is connected to a carbon filter in an extracorporeal venous bypass circuit to recover drug that is not absorbed by the liver after HAI. The hemodynamic response to this system was evaluated in six pigs. When the animals were placed on the extracorporeal circuit, we observed a 22% decrease in cardiac output that was well tolerated without significant change in blood pressure. When the filter was incorporated into the circuit, cardiac output was significantly reduced (50%); however, continuous infusion of phenylephrine rapidly normalized blood pressure, heart rate, cardiac output, and left ventricular filling pressures. Initial testing of chemofiltration efficacy was performed in four of the six animals, the remaining two animals being used only to assess hemodynamic response. One each of the four tested animals received either doxorubicin (3 or 9 mg/kg), mitomycin C (1 mg/kg), or cisplatin (1 mg/kg) by HAI. The filter removed over 90% of hepatic venous doxorubicin and mitomycin C and 65% of hepatic venous cisplatin. This feasibility study confirms that hepatic venous isolation with chemofiltration can significantly reduce systemic exposure to high-dose chemotherapeutic agents given by HAI.

Animals↗
PubMed1990

Significance of C1q-binding macromolecules within the head and neck cancer patient.

Elevated levels of macromolecules, within the peripheral blood of head and neck cancer patients, capable of binding the first component of complement (C1qBM) in vitro have prognostic implication. Namely, elevated levels of C1qBM have been associated with nonresponse to induction chemotherapy. In this investigation, a series of in vitro studies regarding the biological properties of C1qBM were combined with a longitudinal analysis of 112 previously untreated head and neck cancer patients. Our purpose was to shed light on the biological significance of this circulating macromolecule, a substance composed, in part, of IgG and IgM. A potential confounding influence of C1qBM with induction chemotherapy, which could contribute to observed prognostic findings, was negated by two in vitro observations: the macromolecule failed both to bind the chemotherapeutic agents cisplatin, bleomycin, and 5-fluorouracil and to impede the cytotoxic effect of these same drugs on a cultured human head and neck cancer cell line. The clinical relevance of C1qBM was reinforced by the observation that elevated levels predicted a high probability of death with disease (P = 0.005 by Cox's proportional hazards model). The prognostic implication was independent of the use of induction chemotherapy, i.e., patients with high C1qBM levels treated with multimodality therapy not composed of anticancer drugs did equally poorly. Thus, the prognostic significance of C1qBM in patients undergoing induction chemotherapy appears independent of drug effect and appears reflective of tumors that are more rapidly progressive and potentially less responsive to therapeutic intervention, including combinations of surgery, radiation, and/or chemotherapy.

Antigen-Antibody Complex↗
PubMed1990

Liblomycin-mediated DNA cleavage in human head and neck squamous carcinoma cells and purified DNA.

Liblomycin (LBM), a novel bleomycin analogue, and bleomycin A2 (BLM A2) were compared with respect to their relative potential to inhibit growth in a human head and neck squamous carcinoma cell line and to produce DNA damage within cellular DNA and nuclei DNA and against isolated naked DNA. Against the BLM-sensitive cell line 183A, the concentration of LBM that inhibits cell growth by 50% was 1.1 microM for a 30-min drug exposure, while it was 23 microM for BLM A2. Drug-mediated DNA double-strand cleavage within cells was compared with the relative ability of these drugs to produce DNA cleavage in isolated 183A cell nuclei. Though 30-min exposures of cells to equimolar concentrations of both drugs resulted in 4-fold greater cellular DNA damage by LBM than BLM A2, the two drugs were nearly equipotent in producing DNA injury within isolated nuclei. Against Simian virus 40 DNA, however, LBM was 10-fold less effective than BLM A2 in producing Forms II and III DNA from Form I DNA. Radioactivity from either [3H]BLM A2 or 125I-LBM found associated with cells after a 30-min incubation period was also assessed in the 183A cell line. The exposure of cells to radiolabeled drug (1 microM) resulted in a 71-fold greater amount of cell-associated radioactivity for LBM than for BLM A2. The relative abilities of the 183A cell line to partially reseal LBM- or BLM A2-mediated DNA double-strand breaks were also assessed. No preferential repair of overall drug-mediated DNA injury, however, was observed. Finally, drug-mediated specific cleavage sites on pBR322 DNA were determined. At doses that gave the same extent of DNA cleavage, both BLM A2 and LBM gave similar patterns of strand scission, although minor differences were observed. Taken together, these data demonstrate that the greater efficacy of LBM against the BLM-sensitive head and neck squamous cell line is due mainly to LBM's greater association with cells over a defined time period, even though the DNA cleaving ability of LBM is relatively lower than that of BLM A2.

Base Sequence↗
PubMed1990

Ligneous conjunctivitis with ear involvement.

We report the association of ligneous conjunctivitis with middle-ear and tympanic membrane involvement in two children. Eye and ear specimens revealed histopathologic and ultrastructural findings consistent with ligneous conjunctivitis, characterized by an amorphous, eosinophilic material with acute and chronic nongranulomatous inflammation. Ear specimens demonstrated granulation tissue along with the above features. Conjunctival and ear lesions from these patients were studied histochemically, immunohistochemically, and ultrastructurally. Our studies demonstrate fibrin and albumin deposition as a common feature in all lesions. Deposition of other components, such as mucopolysaccharides, amyloid, immunoglobulins, and mast cells, were, however, variable. The diversified nature of these lesions, together with the association of eye and ear disease, substantiates the existence of an underlying systemic disorder of unknown cause.

Amyloid↗
PubMed1990

Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer.

Fifteen patients with previously untreated extensive non-small cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (4-DMDR) at the dose of 10 mg/m2/day x 5 days every 3 weeks with routine administration of antiemetic drugs. They received a median of two courses of treatment with the cumulative dose range from 50-712.5 mg/m2. One patient achieved partial remission with a duration of 14 weeks. Two patients had minor responses with durations of 14 and 24 weeks. Stable disease occurred in three patients (21, 22, and 27 weeks). Median survival was 33 weeks (range 3-73+ weeks). Toxicities were tolerable. Neutropenia (less than 1,000 mm3) occurred in only 16% of all treatment courses. Three patients developed correctable arrhythmias (two with atrial fibrillation and one with accelerated junctional rhythm). The cause of arrhythmia was unclear. No clinical evidence of congestive heart failure or decreased cardiac ejection fraction was observed. Nausea and vomiting were common but tolerable. Alopecia and mucositis were uncommon. Clinical pharmacokinetic studies were done in nine patients. However, plasma 4-DMDR levels were below the limit of detection (3 ng/ml). Because 4-DMDR has shown some activity in previously untreated E-NSCLC and the toxicities at this dose schedule are mild, we suggest that further studies of this drug at a higher dose in this schedule are indicated.

Adult↗
PubMed1990

Assessment of pulmonary and hematologic toxicities of liblomycin, a novel bleomycin analog.

The antitumor efficacy as well as hematologic and pulmonary toxicity of Liblomycin, a new lipophilic analog of bleomycin, was evaluated in BDF1 mice. In comparison to bleomycin which was without any antitumor efficacy against P388 leukemia, a dose of 10 mg/kg Liblomycin administered on a daily schedule for 10 consecutive days resulted in a significant increase in animal survival (% T/C of 190). This therapeutic dose and schedule of drug administration did not produce any evidence of pulmonary histopathologic injury; at a similar dose and schedule bleomycin resulted in greater than 40% consolidation of alveolar lung space. Mouse lung collagen synthesis measured as rate of [3H]hydroxyproline formation was increased almost 4-fold by bleomycin 7 days following a single maximally tolerated i.v. injection (133 mg/kg); in contrast, Liblomycin (60 mg/kg) did not significantly alter the rate of lung collagen synthesis compared to saline injected control animals. Lung function was assessed by whole body plethysmography. Bleomycin produced an increase in breathing rates above control values by day 15 following administration of drug at 10 mg/kg (d1-10). Mice treated with Liblomycin did not exhibit an increased rate of breathing. Liblomycin, in contrast to bleomycin, produced mild and transient leukopenia and thrombocytopenia suggesting that this toxicity will be a limiting one in future clinical trials. The only other toxicity noted in this study was the appearance after repeated intraperitoneal administration of Liblomycin of a hepatic collagenous fibrous capsule. The capsule formation resulted in an abnormal and grossly lobulated liver which was believed to have affected animal survival. Intravenous administration of Liblomycin, however, was not associated with any detectable hepatic injury.

Animals↗
PubMed1990

Modification of methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum(II) pharmacology using a platinum-specific monoclonal antibody.

Platinum complexes are extremely active chemotherapeutic agents. A murine monoclonal antibody designated 1C1 was developed that binds to the third-generation platinum complex methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum(II) (MIDP). Competitive enzyme-linked immunosorbent assay (ELISA) shows that antibody 1C1 binds preferentially to the 1,2-diamminocyclohexane (DACH) side-chain of the platinum complex, although non-DACH-containing platinum complexes can compete for binding at high concentrations. When tested against MCF-7 breast carcinoma cells, the 1C1-MIDP complex caused 50% growth inhibition at 0.63 micrograms Pt/ml, whereas MIDP alone caused 50% growth inhibition at a concentration of 0.16 micrograms Pt/ml. Pharmacokinetic studies in rats using [3H]-MIDP showed that the drug was cleared triphasically from plasma, with elimination-phase half-lives (t1/2) of 1.2, 10.2, and 243 min for alpha, beta, and gamma phases, respectively. The MIDP-1C1 complex was cleared with longer half-lives of 5, 26, and 291 min, respectively. The overall clearance rate from plasma of the MIDP-1C1 complex was 10-fold lower than that of MIDP alone (0.37 vs 3.01 ml/kg x min). Tissue concentrations of [3H]-MIDP 3 h after administration showed that 1C1 antibody prevented MIDP distribution to most organs and dramatically reduced [3H] concentration in the intestine, liver, kidney, heart, and skeletal muscles. Studies are under way to determine the relative therapeutic activity of the 1C1 antibody-MIDP complex and assess whether the 1C1 antibody may be useful for antibody-directed delivery of platinum complexes to tumors.

Animals↗
PubMed1990

Intrapleural etoposide for malignant effusion.

The pharmacology, toxicity, and therapeutic effectiveness of etoposide (VP-16) given by the intrapleural route were examined in a phase I trial. Ten patients with malignant pleural effusion received 100, 150, or 225 mg/m2 VP-16 infused over 2 h into the pleural space after drainage of pleural fluid. The administration of VP-16 was tolerated well, with no local pain, increase in cough, dyspnea, or infection. Myelosuppression was mild at doses of 150 mg/m2 or less but severe at 225 mg/m2. Drug levels were followed in both plasma and pleural fluid for up to 12 h. Clearance of VP-16 from the pleural cavity was low at 2 ml/min m2. Peak pleural-fluid drug levels in patients receiving 225 mg/m2 exceeded 300 micrograms/ml, whereas peak drug concentrations in corresponding plasma samples obtained at the same time amounted to less than 10 micrograms/ml. Serial chest X-rays showed no disappearance of pleural effusion in nine evaluable patients. However, follow-up investigation of pleural fluid characteristics [carcinoembryonic antigen (CEA), lactic dehydrogenase (LDH), and cytologic examination] suggested some evidence of local therapeutic benefit.

Adult↗
PubMed1990

Beta-adrenoceptor binding studies with LY195448 and metabolites.

LY195448(R) (a phenethanolamine derivative that has demonstrated cytotoxic activity against cell cultures in vitro but that exhibited a hypotensive side effect during phase I trials), its p-hydroxy and acid metabolites, and a noncytotoxic S-stereoisomer were evaluated with respect to competitive binding against the beta-adrenergic antagonist [3H]dihydroalprenolol in rat brain cortex and human cardiac tissues. When IC50 and Ki values were compared, the R-isomer of LY195448 in general was more potent than the S-stereoisomer. While LY195448(R) was about 10-fold more active than the p-hydroxy metabolite in cardiac tissues, the two compounds were nearly equipotent both in blocking the binding of radioligand to the brain and in reducing blood pressure in rats. In the cerebral preparation, the binding of the acid metabolite was weak, with its activity being equal to that of the S-stereoisomer.

Animals↗
PubMed1990

Detection of cellular platinum using the monoclonal antibody 1C1.

A monoclonal antibody, 1C1, developed using a trans-R,R-1,2-diamminocyclohexane (DACH) modified platinum analog (DACH-Pt-SO4) complexed with DNA was shown, using the enzyme-linked immunosorbent assay (ELISA), to have the ability to bind to both free drug DACH-Pt-SO4 and to the drug-DNA complex. Using competitive ELISA, 1C1 was found to recognize non-DACH-containing platinum compounds, such as cis-dichlorodiammine platinum (II) (CDDP). 1C1 exhibited strong binding to slot-blotted, DACH-Pt-SO4-treated DNA and moderate binding to the CDDP-DNA complex, but was unable to detect DACH containing methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum (II) (MIDP)-modified DNA. Immunocytochemical staining studies using 1C1 antibody on CDDP-treated BRO melanoma cells showed preferential staining of the cytosol compared with the nucleus. Although the extent of staining was dose dependent, a heterogeneous staining pattern was observed. Multicellular spheroids of MDA886LN squamous carcinoma cells treated with CDDP showed intense staining on the growing periphery compared with weak but homogeneous staining within the spheroid. Cell cycle-dependent uptake of CDDP in synchronized BRO cells may partly explain the observed heterogeneity of platinum distribution.

Antibodies, Monoclonal↗