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Biomedical subjects

R E Giles

Publications and source records attributed to R E Giles.

At least 19 recordsLinked to original sources
PubMed1999

Hematopoietic retroviral gene marking in patients with follicular non-Hodgkin's lymphoma.

We conducted a double retroviral vector (RV) gene marking trial to test for the possible contribution to relapse of follicular non-Hodgkin's lymphoma (FNHL) cells present in bone marrow (BM) and peripheral blood (PB) grafts used for hematopoietic reconstitution of patients undergoing myelaoblative chemotherapy and autologous transplant. CD34 positive selection using the CellPro Ceprate CD34 column was performed on PB mononuclear cells obtained after cyclophosphamide/G-CSF mobilization. CD34 positive cells were exposed for 4-6 hours to the LNL6 or G1 Na RV in the absence of growth factors or stromal monolayers. One week later, BM mononuclear cells were similarly processed. Patients then received total body irradiation (TBI), cyclophosphamide, and etoposide followed by infusion of both PB and BM CD34 positive cells. Semiquantitative Southern blot analysis of DNA t(14;18) amplification products showed approximately a three log reduction in t(14;18) positive cells after CD34 positive selection. The first patient showed evidence of engraftment with RV positive BM and PB cells for 9 months. He relapsed one year after transplant. At relapse, one year after transplant, he had lost evidence of RV positive cells in ficolled mononuclear BM and PB cells as well as in CD19 positive cells. The second and third patients showed evidence of engraftment with RV positive cells up to 9 and 6 months post BMT respectively. The second and third patients are still in clinical remission. Our results demonstrate engraftment of RV transduced hematopoietic cells in the PB and BM for up to 9 months.

Adult↗
PubMed1999

Simple/rapid test devices for anti-HIV screening: do they come up to the mark?

Thirteen simple/rapid test devices (S/RTDs) for the detection of antibodies to HIV 1 and HIV 2 were assessed. Ninety-two specimens in four categories were used and results with the thirteen S/RTDs were compared with those obtained with six currently available commercial laboratory-based anti-HIV 1/2 EIAs. Seven of the 13 S/RTDs scored all 26 blood donors' specimens as unreactive, and 11 correctly identified all the 25 "straightforward" anti-HIV positive specimens. False negative results arose when testing by Uni-Gold HIV and SeroCard HIV, which gave 72 and 68 correct positive observations, respectively, out of 75. No S/RTD detected seroconversion earlier than the most sensitive EIAs, but four S/RTDs performed similarly to most of the EIAs. On the low-titre panel specimens, six S/RTDs were less sensitive than the least sensitive EIA and, in contrast to four of the six EIAs, only one S/RTD was able correctly to identify all the positive specimens. A manufacturing problem was identified that allowed the HIV antigen-sensitised area on the membrane of two SeroCard HIV devices to be misaligned with the device's reading window so that the reaction was almost entirely obscured. As long as small numbers of specimens were involved, most S/RTDs required considerably less time and less equipment than EIAs, but overall they were slightly less sensitive. Their use in various health settings and for confirmatory procedures is discussed.

Developing Countries↗
PubMed1996

Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive systemic therapy.

To formally test the hypothesis that the granulocyte/macrophage colony-forming unit (GM-CFU) cells can contribute to early hematopoietic reconstitution immediately after transplant, the frequency of genetically modified GM-CFU after retroviral vector transduction was measured by a quantitative in situ polymerase chain reaction (PCR), which is specific for the multidrug resistance-1 (MDR-1) vector, and by a quantitative GM-CFU methylcellulose plating assay. The results of this analysis showed no difference between the transduction frequency in the products of two different transduction protocols: "suspension transduction" and "stromal growth factor transduction." However, when an analysis of the frequency of cells positive for the retroviral MDR-1 vector posttransplantation was carried out, 0 of 10 patients transplanted with cells transduced by the suspension method were positive for the vector MDR-1 posttransplant, whereas 5 of 8 patients transplanted with the cells transduced by the stromal growth factor method were positive for the MDR-1 vector transcription unit by in situ or in solution PCR assay (a difference that is significant at the P = 0.0065 level by the Fisher exact test). These data suggest that only very small subsets of the GM-CFU fraction of myeloid cells, if any, contribute to the repopulation of the hematopoietic tissues that occurs following intensive systemic therapy and transplantation of autologous hematopoietic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Recent advances in the application of gene therapy to human disease.

PURPOSE: To review the recent advances in the application of genetic modification strategies to the therapy of human diseases for which a molecular defect is known. METHODS: A computerized data bank search, the minutes of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee published in the Federal Record, and reports of human clinical trials were used as data sources for this review. Clinical trials included in this review were published in the literature or approved by the NIH Recombinant DNA Advisory Committee. STUDY SELECTION: Evaluations of the efficacy of genetic modification strategies in clinical trials in human and in animal models are summarized. The design and outcome of the genetic modification strategies employed are reviewed for 16 marking trials, 16 gene replacement trials for molecular deficiency diseases, 3 chemoprotection and 4 chemotherapy sensitization trials, 11 cancer vaccine trials, 2 antisense oligonucleotide trials, and 3 molecular immunotherapy trials. DATA SYNTHESIS: The marking trials have shown that residual leukemia cells in the infused autologous marrow can contribute to relapse following autologous bone marrow transplants. The use of genetic modification for the replacement of missing or deficient genes in severe combined immunodeficiency, familial hypercholesterolemia, and cystic fibrosis has been associated with encouraging results so far. Clinical genetic therapy trials involving cancer vaccines, antisense oligonucleotides, adoptive immunotherapy with genetically modified T cells, delivery vectors containing interleukin-1 receptor inhibitor for arthritis, replacement strategies for storage diseases, and genetic suppression of human immunodeficiency viral replication are just commencing. CONCLUSIONS: The clinical application of genetic modification techniques has thus far been successful in the beginning phases of this field. These early results suggest that continuation of gene therapy trials designed to correct the molecular changes that lead to disease states in humans is warranted. Evaluation of such clinical trials in the future may be based on the analysis of assays for short-term surrogate endpoints, as well as on the therapeutic outcomes of the trial, such as survival or remission.

Bone Marrow Transplantation↗
PubMed1992

Renal and antihypertensive effects of a novel eukalemic diuretic, ICI 207,828.

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.

Amiloride↗
PubMed1991

Evaluation of the mutagenic effects of SV40 in mouse, hamster, and mouse-human hybrid cells.

We have examined the ability of SV40 to induce changes in drug or temperature resistance in mouse, hamster, and mouse-human hybrid cells. SV40 induced a substantial increase of cells resistant to 5-bromodeoxyuridine + trifluorothymidine in Balb/c 3T3 cells and induced an increase of hybrid cells resistant to 6-thioguanine. SV40 was found to be nonmutagenic or weakly mutagenic in other test systems. The 3T3 cells were T-antigen positive, exhibited a marked reduction in TK activity, were heterogeneous for [3H]BrdU incorporation by autoradiography, and exhibited instability of the drug-resistance phenotype, suggesting that SV40 may be inducing resistance by an epigenetic process. SV40-induced 6-thioguanine resistance in the hybrids appears to occur predominantly by chromosome loss.

Animals↗
PubMed1991

Biochemistry and pharmacology of ICI 200,880, a synthetic peptide inhibitor of human neutrophil elastase.

ICI 200,880 is representative of a new chemical class of inhibitors of human neutrophil elastase (HNE). The compound demonstrated competitive kinetics vs HNE with a Ki value of 5.0 x 10(-10) M. The selectivity of ICI 200,880 for HNE versus a variety of enzymes ranged from 150- (relative to porcine pancreatic elastase [PPE]) to greater than 360,000-fold in favor of HNE. In pharmacokinetic studies ICI 200,880 displayed a long retention time when administered directly to the lung and was rapidly eliminated when administered intravenously. Aerosol pretreatment of hamsters with ICI 200,880 before intratracheal administration of HNE produced a long-lasting inhibition of enzyme-induced increases in lung weight, total lavageable red cells, and total lavageable white cells. Subcutaneous administration of either 50 or 100 mumol/kg (twice/day) of ICI 200,880 for 14 or 28 days prevented the time-dependent increase in alveolar diameter produced by a single intratracheal dose of PPE when compound dosing was initiated 24 hours following the enzyme. Treatment of hamsters with ICI 200,880 using the same protocol and doses for 8 weeks prevented the destructive lesion induced by a single intratracheal dose of HNE. It is concluded that ICI 200,880 has biochemical, pharmacokinetic, and pharmacologic profiles that make it a useful therapeutic agent for understanding the role of HNE in various diseases. ICI 200,880 is presently being evaluated in man.

Animals↗
PubMed1991

Biologic characterization of ICI 200,880 and ICI 200,355, novel inhibitors of human neutrophil elastase.

ICI 200,880 and its close structural analog, ICI 200,355, are representatives of a new chemical class of inhibitors of human neutrophil elastase (HNE). Both compounds are substituted tripeptide ketones, which demonstrated competitive kinetics versus HNE, with identical Ki values of 5.0 x 10(-10) M. The selectivity of ICI 200,880 for HNE versus a variety of enzymes ranged from 150-fold [relative to porcine pancreatic elastase (PPE)] to greater than 360,000-fold in favor of HNE. The compound effectively inhibited HNE-hydrolysis of bovine ligamentum nuchae elastin. In pharmacokinetic studies, ICI 200,880 and ICI 200,355 displayed long retention times when administered directly to the lung and were rapidly eliminated after intravenous administration. Pretreatment of hamsters with either inhibitor before intratracheal administration of HNE produced dose- and time-dependent inhibition of enzyme-induced increases in lung weight, total lavageable red cells, and total lavageable white cells. Aerosol administration of ICI 200,880 produced similar results. Subcutaneous administration of either 50 or 100 mumol/kg (twice/day) of ICI 200,880 for 14 or 28 days prevented the time-dependent increase in alveolar diameter produced by a single intratracheal dose of PPE when compound dosing was initiated 24 h after the enzyme. Treatment of hamsters with the same protocol and doses of ICI 200,880 for 8 wk prevented the destructive lesion induced by a single intratracheal dose of HNE. It is concluded that ICI 200,880 and ICI 200,355 have biochemical, pharmacokinetic, and pharmacologic profiles that make them useful therapeutic agents for understanding the role of HNE in various diseases. ICI 200,880 is presently being evaluated in humans.

Animals↗
PubMed1990

A novel potent non-benzodiazepine anxioselective agent with reduced dependence liability: ICI 198, 256.

ICI 198,256, a member of the cinnoline series, was shown to be a potent anxiolytic agent in several species of animals. In addition, ICI 198,256 exhibited potent activity as an antagonist of both metrazole and bicuculline-induced convulsions. The salient features of ICI 198,256 are that it possesses minimal sedative liability, lower ethanol interaction and possibly lower dependence liability than benzodiazepines (e.g., diazepam). Neurochemically, this structurally novel anxiolytic compound is potent and selective for the Type 1 (cerebellar) BZ receptors in vivo as well as ex vivo, and in addition shows an agonist BZ-like profile in a variety of systems. Thus, ICI 198,256 may offer several significant advantages in the treatment of anxiety in humans than existing benzodiazepines.

Animals↗
PubMed1989

Biochemical and pharmacological characterization of ICI 198,615: a peptide leukotriene receptor antagonist.

ICI 198,615 is one representative of a new chemical class of peptide leukotriene receptor antagonists that are the most potent and selective described to date. ICI 198,615 antagonized LTC4-, LTD4- and LTE4-induced increases in cutaneous vascular permeability in the guinea pig, with i.v. ED50 values of 0.083, 0.11 and 0.067 mumol/kg, respectively. Against LTD4, ICI 198,615 was 615 and 415 times more potent than LY 171883 and FPL 55712, respectively. L-Serine borate, an inhibitor of the metabolism of LTC4 to LTD4, did not influence the antagonism by ICI 198,615 of LTC4-induced increases in cutaneous vascular permeability. The compound both inhibited and reversed aerosol ovalbumin antigen-induced increases in pulmonary resistance in passively sensitized guinea pigs, but demonstrated little ability to inhibit or reverse ovalbumin antigen-induced decreases in dynamic lung compliance. At concentrations ranging from 10(-8) to 10(-5) M, ICI 198,615 had no significant effect on either the spontaneous or ovalbumin antigen-induced release of histamine, peptide leukotrienes, thromboxane B2 or 6-keto-prostaglandin F1 alpha from chopped guinea pig lung. At 10 microM, the compound did not inhibit 5-, 12- or 15-lipoxygenase. Finally, ICI 198,615 antagonized LTD4-induced increases in TxB2 release from chopped guinea-pig lung.

Animals↗
PubMed1989

Meropenem: evidence of lack of proconvulsive tendency in mice.

The proconvulsive tendency of the novel carbapenem, meropenem was compared to that of imipenem, alone and in combination with cilastatin. The potentiation of metrazole-induced convulsions in mice was measured. Both imipenem and imipenem/cilastatin caused significant potentiation of metrazole-induced convulsions at a dose of 200 mg/kg, i.v. In contrast, meropenem (50-400 mg/kg, iv) failed to exhibit any significant potentiation of metrazole-induced seizures.

Animals↗
PubMed1989

ICI 147,798: a slowly dissociable beta adrenoceptor antagonist that causes insurmountable beta-1 and surmountable beta-2 adrenoceptor antagonism in isolated tissues.

ICI 147,798 has been shown to exhibit both diuretic and beta-antagonist properties in vivo. The present study investigated the nature and selectivity of the beta-antagonism in a variety of isolated tissues. ICI 147,798 produced a concentration-dependent suppression of the maximum chronotropic response of norepinephrine in guinea pig right atria (beta-1 adrenoceptor). ICI 147,798 caused a concentration-dependent shift to the right of the salbutamol concentration-response curve in the guinea pig trachea (beta-2 adrenoceptor), and Schild analysis suggested competitive inhibition. Propranolol produced parallel shifts to the right of the norepinephrine concentration-response curve in guinea pig right atria, except at relatively high concentrations. The inhibitory effects of propranolol in guinea pig right atria were reversed by greater than 95%, whereas the effects of ICI 147,798 were only slightly reversed after a 6-hr washout period. Preincubation of propranolol with ICI 147,798 in guinea pig right atria prevented completely the suppression of the norepinephrine maximum chronotropic response. Postincubation of propranolol with ICI 147,798 partially reversed the suppression of the maximum chronotropic response. ICI 147,798 had no effect on the maximum chronotropic responses of either histamine (H2-receptor) or forskolin (adenylate cyclase activation) in guinea pig right atria and had no effect on agonist responses in a variety of other receptor systems. The insurmountable beta-1 adrenoceptor antagonism was evaluated based on the assumptions of irreversible competitive antagonism, mixed competitive and noncompetitive antagonism and slowly dissociating competitive antagonism ("hemi-equilibrium" conditions). Concentration-dependent changes in norepinephrine KA values suggested the first three possibilities were unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1989

Insurmountable beta receptor blockade by ICI 147,798 in rabbits.

In rabbits, the characteristics of cardiac beta-1 receptor blockade produced by ICI 147,798, a novel beta receptor blocking agent with diuretic properties, were evaluated and compared with those of propranolol. In conscious rabbits, i.v. injections of 0.31, 1.0 and 3.1 mg/kg of ICI 147,798 and 1.0 mg/kg of propranolol caused significant bradycardia. ICI 147,798 produced a dose-dependent shift to the right of the dose-response (chronotropic) curve of isoproterenol with suppression of the maximal tachycardia, an effect characteristic of insurmountable beta receptor blockade. Propranolol also produced a shift to the right of the dose-response curve of isoproterenol without affecting the maximal tachycardia. ICI 147,798-induced antagonism was specific for beta adrenoceptors as it failed to modify the effects of acetylcholine, angiotensin II, phenylephrine, adenosine, histamine and prostaglandin E2 on mean arterial pressure and heart rate. In rabbits with prior autonomic blockade, ICI 147,798, like propranolol, failed to inhibit the positive chronotropic effects of theophylline which are mediated by postreceptor mechanisms. In reserpinized rabbits, ICI 147,798 was found to have no intrinsic sympathomimetic activity. Unlike the effects of propranolol, which were attenuated by first-pass through the hepatic vascular bed, the effects of ICI 147,798 were unaffected suggesting an absence of first-pass metabolism. The effects of propranolol (1.0 mg/kg i.v.) were not detectable at 24 hr after injection, whereas significant beta receptor blocking activity was still present at 24 hr after ICI 147,798 (1.0 mg/kg i.v.). The results suggest that ICI 147,798 is a specific, long-acting, insurmountable beta-1 receptor blocking agent without intrinsic sympathomimetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Preclinical studies with pyrazolopyridine non-benzodiazepine anxiolytics: ICI 190,622.

Tracazolate is a pyrazolopyridine anxiolytic that enhances the binding of [3H]-flunitrazepam [( 3H]FLU) to brain tissue. The discovery that a metabolite of tracazolate, desbutyltracazolate, was a weak inhibitor of [3H]FLU binding led to the synthesis of a series of potent anxiolytics. From this series, ICI 190,622 emerged as a viable drug candidate, being a potent anxiolytic in rats and monkeys. This anxiolytic agent appears to produce only minimal sedation. Furthermore, ICI 190,622 appears less likely to potentiate the actions of ethanol than diazepam. ICI 190,622 is also a potent anticonvulsant (anti-metrazol ED50 = 1.1 mg/kg, PO) in rodents. Neurochemically, ICI 190,622 is similar to the benzodiazepine anxiolytics. In vitro, ICI 190,622 competitively inhibited [3H]FLU binding in cerebral cortex with an IC50 of 81 nM and was 4.3-fold more potent in the cerebellum (IC50 = 19 nM). This suggests a selectivity for the Type 1 benzodiazepine binding site. In contrast, diazepam showed similar affinities in both regions (cerebral cortex = 7 nM and cerebellum = 9 nM). Following oral administration, ICI 190,622 displaced [3H]FLU binding from cerebellar membranes more potently than diazepam (ED50 = 3 and 6 mg/kg, respectively, 1 hour after administration). Thus, ICI 190,622 should be an effective anxiolytic with significant advantages over benzodiazepines.

Animals↗