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Biomedical subjects

M E Gore

Publications and source records attributed to M E Gore.

At least 127 records · Page 7Linked to original sources
PubMed1989

In vitro studies of ways to overcome resistance to VAMP--high dose melphalan in the treatment of multiple myeloma.

Myeloma colonies (MY-CFUc) from 7/24 patients undergoing treatment with VAMP (vincristine, adriamycin and methyl prednisolone) and high dose melphalan (HDM) were melphalan-resistant. It was not possible to conclude that VAMP induced melphalan resistance in MY-CFUc, but that resistance is endogenous in some myeloma cell populations. In 12/13 of the same patients of whom four had MY-CFUc which were melphalan resistant, the sensitivity of MY-CFUc and GM-CFUc to busulphan was similar. Thus resistance of MY-CFUc to melphalan did not confer resistance to busulphan. MY-CFUc from 1/7 of a second group of patients were adriamycin-resistant. This resistance was removed when the cells were treated with a combination of verapamil (3 micrograms/ml) and adriamycin. Verapamil also enhanced the toxicity of adriamycin to MY-CFUc from two patients where there was no evidence for adriamycin resistance. In these three patients the sensitivity of both MY-CFUc and GM-CFUc was similar after treatment with verapamil. Verapamil did not affect the uptake or efflux of 3H-daunorubicin in sensitive and resistant RPMI-8226 cells (myeloma) and peripheral blood mononuclear cells from a normal donor; neither did it affect the binding of 3H-daunorubicin to nucleic acid. It is concluded that verapamil may be a useful adjuvant to VAMP chemotherapy and that busulphan may provide an alternative to melphalan in patients whose myeloma cells are melphalan resistant.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

High-dose chemotherapy and autologous bone marrow transplantation for myeloma.

In three studies we have attempted to increase the complete remission rate in a series of patients with multiple myeloma under the age of 69. A CR rate of 27% was seen in 63 patients treated with intravenous high-dose melphalan 140 m/m2 with or without the addition of high-dose methyl prednisolone 1 g/m2 for 5 days (in 22 patients). In a third study a CR rate of 50% was seen in 50 patients treated in a programme in which vincristine, adriamycin and methyl prednisolone was first given and patients then received high-dose melphalan 140-200 mg/m2 with an autologous bone marrow transplant where possible. Median remission duration in the first two studies was 19 months with a median survival of 5 years. A definition of complete remission in myeloma is proposed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Antineoplastic Agents↗
PubMed1989

VAMP followed by high dose melphalan and autologous bone marrow transplantation for multiple myeloma.

Fifty previously untreated patients with myeloma were entered into a 2-phase treatment programme: vincristine, adriamycin and methyl prednisolone (VAMP) followed by high dose intravenous melphalan (HDM) with autologous bone marrow transplantation where possible. The complete remission rate of 50% was associated with very good quality of life and the reversal of humoral immunosuppression. Complete remission is important in younger patients with myeloma as it represents a first step in achieving long, symptom- free survival.

Adult↗
PubMed1989

Lymphomas: the impact of chemotherapy on survival.

Hodgkin's disease and non-Hodgkin's lymphoma are among the most sensitive tumours to chemotherapy. Response, even if complete, does not invariably result in cure. Chemotherapy has had a major impact on survival for patients with advanced Hodgkin's disease and in patients with both early and advanced high grade lymphoma. However, even in these two categories only 30-50% of patients can expect to be cured. Chemotherapy has had a major influence on the palliation of disease in patients with low grade lymphoma; however, it has not much influenced the long natural history of this group of diseases and no patients are cured by this or any other modality.

Antineoplastic Agents↗
PubMed1988

Phase I and pharmacokinetic studies with the pentacyclic pyrroloquinone mitoquidone.

Mitoquidone (MTQ) is the first member of a new group of pentacyclic pyrroloquinones developed for clinical evaluation as a potential anticancer agent. MTQ demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. Twenty-seven patients were treated with MTQ given as a 4-h infusion either once every 21 days (150-600 mg/m2), once a week (200 mg/m2 per week), or as 5 daily doses repeated every 28 days (60-180 mg/m2 per day). The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies. Temporary remission of B-symptoms occurred in two patients with lymphoma. The plasma pharmacokinetics of MTQ were investigated using an HPLC assay with fluorescence detection. Linear pharmacokinetics were observed with a terminal plasma half-life of 2.9 +/- 2.1 h (n = 18 doses). The volume of distribution was 3.4 +/- 2.6 l/kg and plasma clearance was 629 +/- 469 ml/min per m2. Several soluble analogues with similar antitumour activity are currently under investigation.

Carcinoma↗
PubMed1987

High dose carboplatin in the treatment of lung cancer and mesothelioma: a phase I dose escalation study.

Sixteen patients with lung cancer or mesothelioma have been treated with escalating doses of carboplatin. Five patients (10 courses) were given 800 mg/m2, four patients (five courses) 1200 mg/m2 and seven patients (eight courses) 1600 mg/m2. Myelosuppression was the major toxicity encountered. The median duration of grade 4 neutropenia ranged from 1 day (800 mg/m2) to 11 days (1600 mg/m2) and the median duration of grade 4 thrombocytopenia ranged from 1 day (800 mg/m2) to 7 days (1600 mg/m2). The median fall in haemoglobin (Hb) ranged from 2.2 g/l (800 mg/m2) to 3.6 g/l (1600 mg/m2). Nephrotoxicity was encountered at all dosages and was in part, though not entirely, dose related. 2/9 patients receiving 800 mg/m2 and 4/6 of the patients receiving 1600 mg/m2 had a fall in glomerular filtration rate (GFR) greater than 25% but less than 50%. 800 mg/m2 of carboplatin was well tolerated, the performance status in 9/10 (90%) courses being 0-1 (ECOG scale). At 1600 mg/m2 in 6/8 (75%) courses the performance status was 2-4. There was one treatment-related death from neutropenia at this dose level. The severity of nausea and vomiting was not dose related but other toxicities including diarrhoea, alopecia, mild neuropathy and ototoxicity and possible CNS toxicity occurred at doses of 1200 mg/m2 and over. 5/7 patients with small cell lung cancer achieved a complete or partial response to treatment.

Adult↗
PubMed1987

Plasma free platinum pharmacokinetics in patients treated with high dose carboplatin.

Plasma free platinum (less than 50,000 mol. wt) pharmacokinetics have been studied in eight patients treated with high-dose (800-1600 mg/m2) carboplatin as a 1 h infusion with moderate hydration. Following the infusion, levels decayed biphasically with half-lives (means +/- S.D.) of 83 +/- 15 min and 6.1 +/- 2.8 h. The plasma free platinum area under the concentration vs. time curve (AUC) at 1600 mg/m2 in five patients was 23 +/- 2 mg carboplatin/ml.min. Comparison with data at conventional doses (less than or equal to 500 mg/m2) gave no indication of non-linear kinetics. Total body clearance of free platinum was found to correlate with glomerular filtration rate (r = 0.769, P = 0.03), and haematological toxicity, white cell nadir and duration of thrombocytopenia, correlated with plasma free platinum AUC (r = 0.784, P = 0.02 and r = 0.885, P = 0.01, respectively). Persistence of platinum was demonstrated in tissues removed at autopsy from a patient who had received carboplatin 14 days earlier. Highest platinum levels were found in the liver, kidney, skin and small cell lung tumour.

Adult↗
PubMed1987

Priming reduces the bone marrow toxicity of carboplatin.

A dose of 170 mg/kg of carboplatin is lethal in mice, death occurring through bone marrow failure. This lethality can be avoided by giving the animals 200 mg/kg cyclophosphamide 1 or 2 days before this dose of carboplatin. The improved normal tissue tolerance cannot be explained by altered pharmacokinetics of carboplatin. Increased survival appears to be associated with a more rapid regeneration of the haemopoietic stem cells. Tumour tissue is not protected in the same way and thus a therapeutic gain can be achieved using this protocol.

Animals↗
PubMed1987

Propylene glycol pharmacokinetics and effects after intravenous infusion in humans.

Knowledge of the pharmacokinetics of propylene glycol (PG) is scarce, though it is used in a number of preparations for intravenous use. Although systemic toxicity appears to be uncommon, PG has been reported to cause lactic acidosis and other adverse effects. We describe a rapid gas chromatographic assay method for PG and the plasma pharmacokinetics after intravenous administration to six patients on nine occasions. The pharmacokinetics were nonlinear, based on a saturable clearance. The apparent first-order half-life was 2.3 +/- 0.7 h. There was no evidence of lactic acidosis, hemolysis, or increase in osmolality at 3-15 g/m2 PG infused over periods of 4 h.

Adult↗
PubMed1987

Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer.

Fifty-two previously untreated patients with small-cell lung carcinoma (SCLC) were treated with a combination of carboplatin 300 mg/m2 intravenously (IV) on day 1 and etoposide 100 mg/m2 IV on days 1 through 3 every 28 days for four courses. Patients with limited disease (LD) subsequently received thoracic radiotherapy; no prophylactic cranial radiotherapy was used. Forty-four patients (85%) achieved an objective response, including 82% (29% complete remissions) of LD patients and 88% (13% complete remissions) of extensive-disease (ED) patients. Median response duration for LD patients was 7 months and 5.5 months for ED patients. Median survival for both LD and ED patients was 9.5 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3/4 leucopenia occurring in 44% of patients. There was one (2%) treatment-related neutropenic death. Treatment was otherwise well tolerated, and in particular no renal toxicity, neurotoxicity, or ototoxicity was seen. This new combination is highly active in terms of response rate, but response duration and survival is disappointing, and might be improved by prolonged treatment or by the use of additional drugs in combination.

Adult↗
PubMed1987

Antiviral chemotherapy.

Specific antiviral chemotherapy now has an established role in the treatment of many virus infections, particularly those caused by herpesviruses. This change is one of the major medical developments of the last decade. There is reason to believe that further advances will occur, and we can look forward to a range of antiviral drugs comparable to those available for bacterial infections.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Monoclonal antibodies recognizing epitopes carried on both glycolipids and glycoproteins of the human milk fat globule membrane.

The molecules of the human milk fat globule membrane (MFGM) which bind four murine monoclonal antibodies (LICR LON M3, M8, M18 and M24) raised against the human MFGM have been identified. By using 'Western' blotting [Burnette (1981) Anal. Biochem. 112, 195-203] it was shown that each antibody reacted with a different set of proteins. M3 and M24 were similar in their pattern of reaction with the membrane proteins, but were quite distinct from M8 and M18, which also differed from each other. Glycopeptides prepared from the MFGM by exhaustive Pronase digestion were able to inhibit partially the binding of M3 and M24, and prevent totally the binding of M8 and M18, to the MFGM in an enzyme-linked immunoabsorbent assay. Oligosaccharides obtained by the deproteination of human milk also completely inhibited the binding of M3, M18 and M24 to the MFGM. However, the binding of M8 was not inhibited by these saccharides, and therefore M8 may not be recognizing a simple carbohydrate determinant. By using an enzyme-linked assay, M8 and M18 were shown not to bind to MFGM glycolipid, whereas M3 and M24 did, and this was confirmed by overlaying thin layer chromatograms of MFGM lipids with these antibodies. Both M3 and M24 showed a similar complex pattern of reaction, binding to more than one glycolipid moiety. By these means all four antibodies have been shown to react with antigens which involve carbohydrate side chains carried on different proteins, and two were also shown to react with such determinants on glycolipids.

Antibodies, Monoclonal↗
PubMed1984

A monoclonal antibody which differentiates between bound and free human secretory component.

In this study a mouse monoclonal antibody ( LICR -LON- LC28 ) to human secretory component (SC) is reported. This antibody binds to free SC or to SC associated with IgA or IgM. It exhibits a 10-fold higher affinity for SC bound to IgA than for free SC. The affinity of the antibody for SC associated with IgM is equivalent to that seen for free SC. LICR -LON- LC28 appears to be species specific and does not cross-react with other human milk proteins.

Antibodies, Monoclonal↗
PubMed1979

Identification of the paraproteins and clinical significance of more than one paraprotein and clinical significance of more than one paraprotein in serum of 56 patients.

Sera from 56 patients with more than one paraprotein were investigated for immunoglobin class and light chain type of each paraprotein. The patients were divided into two groups according to the diagnosis, that is myeloma and macroglobulinaemia or others. The frequency of combinations of paraproteins was considered in the whole series and in the two groups. The laboratory and clinical findings were analysed to investigate the diagnostic and prognostic significance of more than one paraprotein in a serum. It is concluded that a lower percentage of patients with more than one paraprotein can definitely be shown to have myeloma than might be expected from studies on monoclonal paraproteinaemia, that patients having IgA paraproteins in the serum had the poorest prognosis, and that paraproteins with lambda light chains were more likely to be associated with myeloma or macroglobulinaemia. A discriminant analysis of ESR and total paraprotein levels in the two groups of patients showed that combinations of the two parameters were not more effective at distinguishing the groups than the ESR alone.

Blood Sedimentation↗