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Biomedical subjects

J Cummings

Publications and source records attributed to J Cummings.

At least 145 records · Page 8Linked to original sources
PubMed1988

The distribution of doxorubicin in mice following administration in niosomes.

Large multilamellar non-ionic surfactant vesicles (niosomes) with diameters of around 800-900 nm prepared from a C16 triglyceryl ether with and without cholesterol and containing doxorubicin (Adriamycin) were administered to S180 tumour-bearing NMRI mice by bolus injection. Although in-vitro drug release from cholesterol-containing niosomes is delayed, in-vivo there was little difference between the two preparations when plasma levels were compared. As previously observed, half-lives of the drug were prolonged compared with free solution profiles. Liver uptake was not significantly affected by niosome encapsulation of doxorubicin. There is minor accumulation of drug in the lung, perhaps because of aggregation of the vesicles and their physical entrapment. Tumour levels of drug were higher following administration of cholesterol-containing niosomes and this was reflected in the more effective reduction in tumour growth. Metabolism of doxorubicin is altered by niosomal administration, but more studies are required before the significance of the metabolic data can be assessed.

Animals↗
PubMed1987

Comparative cardiotoxicity and antitumour activity of doxorubicin (adriamycin) and 4'-deoxydoxorubicin and the relationship to in vivo disposition and metabolism in the target tissues.

4'-Deoxydoxorubicin (4'-DOX) is an analogue of the anticancer drug Adriamycin (ADR) believed to lack its cardiotoxicity. Bioreduction to a semi-quinone free radical has been implicated in the etiology of ADR induced cardiotoxicity. We have studied (in a rat model) acute cardiotoxicity (after 16 mg/kg i.v. of both drugs), antitumour activity (after 5 mg/kg i.v.) and the relationship to disposition and metabolism in the target tissues (after 5 mg/kg i.v.). 7-Deoxyaglycones, which are considered inactive lipophilic metabolites derived from ADR semi-quinone, were utilised as markers of in vivo tissue free radical generation. Both drugs produced toxicity of equal severity to hearts after 24 hr, associated with high cardiac levels of 7-deoxyaglycones in the case of ADR (AUC0-48 hr, micrograms/g X hr: ADR, 47; ADR 7-deoxyaglycone (ADR-DONE), 24; and adriamycinol 7-deoxyaglycone (AOL-DONE), 35) compared to low cardiac levels of 7-deoxyaglycones but a times five higher peak cardiac concentration of parent drug in the case of 4'-DOX (AUC0-48 hr, micrograms/g X hr: 4'-DOX, 68; 4'-DOX-DONE, 3.8; and 4'-DOL-DONE, 0.8). 4'-DOX displayed superior antitumour activity to ADR against the MC 40A sarcoma growing sub-cutaneously, achieving higher concentrations of parent drug in tumour (AUC0-48 hr, micrograms/g X hr: 4'-DOX, 150; ADR, 60). There was an absence of 7-deoxyaglycones of both drugs in the tumour. These data suggest that drug bioreduction is involved principally only in ADR induced cardiotoxicity and that the level of unchanged parent drug achieved in the tumour is the most important pharmacokinetic determinant of antitumour activity for both ADR and 4'-DOX.

Animals↗
PubMed1987

Increased anti-tumor effect of adriamycin-loaded albumin microspheres is associated with anaerobic bioreduction of drug in tumor tissue.

Anti-tumor activity and fate of adriamycin incorporated into biodegradable albumin microspheres was examined in vivo after direct intratumoral injection. Adriamycin in microspherical form displayed superior anti-tumor activity to a comparable dose of drug in solution. This was associated at later time points (40 hr, 50 hr and 72 hr after injection) with higher median parent drug concentrations in tumor tissue (4.1, 3.6, 2.6 micrograms/g respectively for microspheres and 1.6, 1.7 and 1.0 micrograms/g for solution) and the consistent detection of 7-deoxyaglycone metabolites, end products of reduction of adriamycin under anaerobic conditions (1.1, 1.0, 1.0 micrograms/g respectively for microspheres and less than 0.1 micrograms/g at all time points for solution). It is generally considered that the redox properties of anthracyclines are responsible for their toxicity to normal tissues whereas other mechanisms are responsible for antineoplastic activity. In this study we show that inducing metabolism of Adriamycin via reductive pathways is associated with increased anti-tumor effect.

Albumins↗
PubMed1987

Phase II clinical and pharmacological study of oral 4-demethoxydaunorubicin in advanced non-pretreated small cell lung cancer.

4-Demethoxydaunorubicin (4-DMDNR) is an oral anthracycline with antitumour activity demonstrated in a number of clinical studies. We have assessed the usefulness of 4-DMDNR in 16 patients with advanced small cell lung cancer, none of whom had received previous chemotherapy. There were no complete or partial responders among the 14 evaluable patients, but 9 patients showed a minor radiographic improvement and 6 reported transient symptomatic improvement. Side effects were mostly minor or moderate, although one patient succumbed to septicaemia during neutropenia following treatment. There was no evidence of cardiotoxicity in any patient. Pharmacological studies were undertaken in 8 patients. A previously undescribed metabolite, identified as the 7-deoxyaglycone of 4-demethoxydaunorubicinol, was detected in 3 patients and these 3 patients all showed some anti-tumor response.

Administration, Oral↗
PubMed1987

Method for the determination of 4-demethoxydaunorubicin, its quinone and hydroquinone metabolites in human plasma and urine by high-performance liquid chromatography.

4-Demethoxydaunorubicin (4-DMDNR) is a new orally active analogue of daunorubicin (DNR). We have developed a high-performance liquid chromatography (HPLC) method capable of separating and identifying 4-DMDNR, five possible fluorescent quinone metabolites and three possible non-fluorescent hydroquinone metabolites. Methods are described for high-yield synthesis of reference metabolites. The limit of detection of the fluorescence assay was less than 1 ng/ml after extraction of 1 ml plasma or urine with chloroform/propan-2-ol (2:1), with coefficients of variation in k' (HPLC column capacity factors) of less than 3% throughout the day. Efficiency of the extraction method described exceeded 80% in control experiments. Blood and urine samples were analysed from four cancer patients who had received 50 mg/m2 orally as three divided doses every 8 h. A typical urinary profile of the drug and its metabolites was: parent drug, 13%; 4-demethoxydaunorubicinol (4-DMDNOL), 80%; 4-DMDNR 7-hydroxyaglycone, 4% and 4-DMDNOL 7-hydroxyaglycone, 3%. 4-DMDNOL was the major metabolite detected in plasma. A further metabolite identified as the 7-deoxyaglycone of 4-DMDNOL was detected in plasma of two patients at concentrations equal to or greater than the parent drug. In the other two patients no trace of the metabolite was detected.

Carcinoma, Small Cell↗
PubMed1987

Occurrence of circulating 7-deoxyaglycone metabolites of 4'-deoxydoxorubicin in man.

In five cancer patients we have determined the pharmacokinetics of 4'-deoxydoxorubicin (4'-DOX), its alcoholic metabolite 4'-deoxydoxorubicinol and the occurrence of circulating 7-deoxyaglycone metabolites. The 7-deoxyaglycone of the alcohol metabolite, the major aglycone of Adriamycin (ADR) present in man, was not detected in any serum sample. The 7-deoxyaglycone of the parent drug, which appears in concentrations in excess of 30 ng/ml after ADR administration, was detected in only 2/5 patients in trace amounts. These preliminary data indicate a difference in biotransformation between ADR and 4'-DOX despite their close structural similarities.

Biotransformation↗
PubMed1987

Meningocerebral hemangiomatosis resembling Sturge-Weber disease in a horse.

A 3-year-old horse presented with intermittent generalized seizures of 2-month duration. During interictal periods, the horse appeared normal and a cause for the seizures could not be identified. Necropsy revealed opacity of the leptomeninges, covering most of one cerebral hemisphere along with thinning and collapse of the cortex in the ipsilateral pyriform lobe. Histopathology demonstrated leptomeningeal vascular proliferation and meningothelial hyperplasia. Prominent tortuous vessels of the gyri and sulci extended into some regions of the subjacent cortex, where there was neuronal loss, ectopia, and disorganization. Clusters of prominent arterioles were found in the sclerotic choroid plexus of the lateral and fourth ventricles. Milder vascular lesions were present in the leptomeninges of the ventral brain stem, right cerebrum, spinal cord, and in the eye. The left trigeminal nerve was distorted by swollen fasicles containing onion bulb-like structures. Most bulbs contained central axons surrounded by myelin sheaths of variable thickness. Electron microscopy demonstrated concentrically arranged cells with continuous basal laminae and rare pinocytotic vesicles. S-100 immunohistochemistry showed strong positive staining in these cells. This is an unusual combination of lesions to which analogies can be drawn with the human neuroectodermal dysplasias, specifically Sturge-Weber disease. The relationship of the neuropathy to the leptomeningeal hemangiomatosis is unclear, but a compound anomaly in embryological development resulting in dysplasia and neoplasia may be involved.

Angiomatosis↗
PubMed1986

Determination of anthracycline purity in patient samples and identification of in vitro chemical reduction products by application of a multi-diode array high-speed spectrophotometric detector.

We describe the application of a high-speed spectrophotometric detector and high-performance liquid chromatography to the determination of anthracycline purity in extracted patient specimens and to the identification of chemical reduction products. Blood contained pure anthracyclines whilst in urine, tissue and tumour there was evidence of co-eluting endogenous peaks and complexation. Aerobic reduction yielded two main products: a C13 alcohol and a fully reduced, non-fluorescent, yellow hydroquinone. Anaerobic reduction in the presence of DNA yielded a 7-deoxyaglycone metabolite end product instead of the fully reduced hydroquinone. Eight other separate chromatographic species were identified, all of which showed unique absorbance characteristics, having a visible lambda max at 530 nm and being coloured purple/blue.

Anaerobiosis↗
PubMed1986

The effect of verapamil on the pharmacokinetics of adriamycin.

The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.

Administration, Oral↗
PubMed1986

Influence of polysorbate 80 (Tween 80) and etoposide (VP-16-213) on the pharmacokinetics and urinary excretion of adriamycin and its metabolites in cancer patients.

Polysorbate 80 (Tween 80) is present in the IV pharmaceutical preparation of VP-16-213 marketed as VePesid (Bristol-Myers) (etoposide 100 mg, benzylalcohol 150 mg, polyethylene glycol 300 3250 mg, citric acid 10 mg, Tween 80 400 mg and absolute alcohol to 5 ml per 100 mg ampule of VP16), to increase its miscibility with blood. We have examined the effects of 400 mg/m2 Tween 80 IV and 100 mg/m2 VP16 on the pharmacokinetics of Adriamycin (ADR, 30 or 40 mg/m2). ADR and metabolite concentrations were measured by HPLC. ADR plasma profiles were best fitted to a bi-exponential decay and a two-compartment open model. Tween 80 did not alter the values of the two ADR half-lives, nor did it affect metabolite kinetics of their urinary excretion. However, in a similar manner and consistently in all patients, both Tween 80 and VP16 increased the volume of distribution of the central compartment for ADR up to 3-fold, decreased the AUC of ADR up to 2-fold and increased its clearance by exactly the same amount. These effects were due to reduced plasma ADR concentrations during the early phase of its kinetics. Urinary excretion of ADR was also increased. In conclusion, VP16 is likely to affect the kinetics of drugs administered with it: early plasma concentrations will fall due to a general physiological effect of Tween 80 on the apparent volume of circulation.

Adult↗
PubMed1986

Etoposide: a pharmacokinetic profile including an assessment of bioavailability.

The pharmacokinetics of intravenous etoposide (50-150 mg m-2) have been studied in 17 patients. Bioavailability studies on either the capsule or intravenous (i.v.) formulation were performed in 13 patients, 7 of whom received both oral formulations given in the dose range 50-250 mg m-2. After i.v. administration the mean +/- SD half-lives were t1/2 alpha 0.62 +/- 1.01 h and t1/2 beta 6.04 +/- 2.5 h. The bioavailability of etoposide was extremely variable: for the capsule it was 38 +/- 14% (range 10-55) and for the i.v. formulation it was 53 +/- 25% (range 31-88). The i.v. formulation was not significantly better than the capsule. The results confirm the low and variable bioavailability of oral etoposide.

Administration, Oral↗
PubMed1986

Marked inter-patient variation in adriamycin biotransformation to 7-deoxyaglycones: evidence from metabolites identified in serum.

Several factors are known to modulate the clinical pharmacokinetics of adriamycin (ADR). Biotransformation has not been studied in this context because of problems identifying serum metabolites. We have studied patterns of ADR biotransformation in 25 patients with normal liver and kidney function and in most cases receiving ADR for the first time. Three major serum metabolites were identified by HPLC, TLC and mass spectrometry and their pharmacokinetics were followed over a 24-hr period. The relative amount of each metabolite present in a patient was quantitated by calculating its AUC. Adriamycinol was the major metabolite detected in the majority of patients. Adriamycin 7-deoxyaglycone was detected in the serum of 15 patients where it accounted for a small percentage of the total ADR concentration (1-5%). Its apparent half-life was normally less than 30 min. Adriamycinol 7-deoxyaglycone was detected in the serum of only 13 patients where it accounted for a greater percentage of the total ADR concentration (10-20%). Its pharmacokinetics exhibited marked inter-patient variations, with apparent half-lives ranging from 0.1 to 24 hr. There was a correlation between the AUC of ADR and the relative amount of metabolites present in each patient (r = 0.73). Thus, biotransformation may explain, partly, inter-patient variations in ADR pharmacokinetics. In turn, variations in biotransformation are dictated by whether or not ADR is converted to 7-deoxyaglycones.

Biotransformation↗
PubMed1986

Disposition kinetics of adriamycin, adriamycinol and their 7-deoxyaglycones in AKR mice bearing a sub-cutaneously growing ridgway osteogenic sarcoma (ROS).

Disposition kinetics of Adriamycin (ADR), adriamycinol (AOL) and their 7-deoxyaglycones (ADR-DONE and AOL-DONE) have been studied in AKR mice bearing a s.c. growing ROS tumour after i.v. administration of 10 mg/kg. ADR and its metabolites were extracted from tissues by two different methods, separated and identified by HPLC. Tissue 7-deoxyaglycones were isolated, purified and then identified by HPLC, TLC and mass spectrometry. Kinetic profiles of ADR showed rapid equilibration of the drug with well perfused tissues but a slower and complex equilibration of the drug with the ROS tumour. Serum and tissue profiles of AOL were similar to the parent drug. From the kinetic profiles of the 7-deoxyaglycones it appeared that in the tissues their formation was rapid, with ADR-DONE always appearing first. Maximum concentrations of ADR-DONE were reached in the liver and heart only 10 min after drug administration. Estimated half lives of ADR-DONE were in liver, 1.1 hr and in heart, 2.8 hr and for AOL-DONE in liver, 5.4 hr, in heart, 5.1 hr and in serum, 4.1 hr.

Animals↗
PubMed1986

Fermentation of dietary fibre in the intestinal tract: comparison between man and rat.

1. The breakdown and faecal bulking capacity of dietary fibre preparations from wheat bran, apple, cabbage, carrot, and guar gum were compared in man and rat. 2. The degradation of the fibre showed good correlation between man and rat (r 0.99, regression coefficient 0.86). Wheat bran was the least well-digested, 66 and 59% of the neutral sugars being excreted in faeces of man and rat respectively. The breakdown of the fibre in apple, cabbage, carrot and guar gum was more complete and 4-29% of the neutral sugars were recovered in faeces. 3. The main dietary fibre constituents in each preparation were degraded to a similar extent in man and rat. The main dietary fibre constituents of apple, carrot, cabbage and guar gum were almost completely degraded. Of the xylose in wheat bran 45% (man) and 48% (rat) were recovered in faeces. However, the percentage excretion of glucose and arabinose from bran was higher in man. 4. A faecal glucan other than cellulose was identified in human faeces after guar gum, and has been provisionally identified as starch. No such glucan occurred in rat faeces. 5. A good correlation between the faecal bulking capacity in man and rat was seen (r 0.97, regression coefficient 0.56). Wheat bran had the best bulking capacity, while that of apple, cabbage, carrot and guar gum was less pronounced. Faecal bulking was inversely related to the amount of fibre which was water-soluble in each preparation. 6. It is concluded that this rat experimental model is useful for the prediction of fermentative breakdown and bulking capacity of dietary fibre in man. However, more comparative studies are needed to evaluate animal experiments regarding other physiological effects of dietary fibre.

Adult↗
PubMed1985

Method for the determination of 4'-deoxydoxorubicin, 4'-deoxydoxorubicinol and their 7-deoxyaglycones in human serum by high-performance liquid chromatography.

4'-Deoxydoxorubicin (4'-DOX) is a new and structurally similar analogue of the anti-cancer drug adriamycin (ADR). Based on known pathways of metabolism of ADR a high-performance liquid chromatographic method for the separation and identification of 4'-DOX and five possible metabolites was developed. Sensitivity for serum is 10 ng/ml for 4'-DOX and its alcoholic product 4'-deoxydoxorubicinol (4'-DOL) and 2 ng/ml for four of its aglycone products with coefficients of variation in k' of less than 5% throughout the day. An extraction step with better than 80% recovery of 4'-DOX and five reference metabolites from serum is described. Analysis of patient sera identified two metabolite peaks. These co-eluted with the reference metabolites of 4'-DOL and the 7-deoxyaglycone of 4'-DOX. Pharmacokinetics of the parent drug followed a two-compartment model. Both the metabolites were produced quickly and disappeared quickly.

Biotransformation↗