Managing the patient with fractured femur.
Explore the source record for details and available documents.
Emergencies↗
Biomedical subjects
J Cummings
Publications and source records attributed to J Cummings.
Chromatographic characterisation of six human metabolites of the new anticancer drug GR63178A.
GR63178A is the second pentacyclic pyrroloquinone to enter clinical trials as an anticancer drug. We developed a reversed-phase, gradient-elution high-performance liquid chromatography (HPLC) method along with a Bond Elut C2 mini-column sample-preparation technique for the analysis of GR63178A, its 9-hydroxy-metabolite GR54374X and internal standard GR70440A in human plasma and urine. The limit of detection is 2 ng/ml for both GR63178A and GR54374X. Analysis of GR63178A is complicated by its light instability, whereby a number of chromatographically distinct, stable degradation products can form. These can be practically eliminated if clinical specimens are frozen immediately and all subsequent sample preparation is performed in a darkroom. Using this methodology, a total of six metabolites (including GR54374X) were detected in human plasma and urine specimens. The five new metabolites were characterised according to polarity (HPLC retention time), UV-visible absorption maxima and the effect of incubation with beta-glucuronidase and aryl-sulphatase. Application of this methodology to the analysis of GR63178A will aid in the development of this novel synthetic anticancer drug.
Antineoplastic Agents↗
Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology.
In a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r = 0.924) over the full range of doses studied (4-36 mg/m2) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1 +/- 7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of greater than 18 mg/m2 and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m2. No response were seen in this patient population.
Adolescent↗
Determination of covalent binding to intact DNA, RNA, and oligonucleotides by intercalating anticancer drugs using high-performance liquid chromatography. Studies with doxorubicin and NADPH cytochrome P-450 reductase.
An HPLC method is described which can determine covalent binding to intact nucleic acid by intercalating anticancer drugs and at the same time remove noncovalently bound intercalated drug. The method uses a column containing a nonporous 2-microns DEAE anion-exchange resin capable of chromatographing nucleic acids greater than 50,000 bases in size in under 1 h. After priming with 1 mg of DNA, the column behaves as an intercalator affinity column, strongly retaining the drug while allowing the nucleic acid to pass through normally. Retained drug is released with an injection of 0.1 M potassium hydroxide. Incubations were performed with the intercalator doxorubicin, which is also believed to bind covalently to DNA. When [14C]doxorubicin was mixed with DNA, at a concentration where all the drug would bind by intercalation, the column retained 82% of the total radioactivity, only 18% migrated with the nucleic acid. If the DNA was mildly denatured by treatment with 2 M sodium chloride at 50 degrees C for 45 min before chromatography, then 99.8% of total radioactivity was retained, only background counts migrated with the nucleic acid, as was the case with single-stranded DNA and RNA without any treatment. Purified NADPH cytochrome P-450 reductase was used to activate doxorubicin. DNA inhibited the metabolism of the drug by the enzyme, no covalent binding occurred with RNA, low levels occurred with single-stranded DNA (34 pmol/100 micrograms), and the highest levels were recorded with oligonucleotides (243 pmol/100 micrograms). The assay was sufficiently sensitive to measure covalent binding to DNA extracted from MCF-7 human breast cancer cells treated with 50 microM [14C]doxorubicin (18.6 pmol/100 micrograms). Thus, covalent binding to DNA, RNA, and oligonucleotides by intercalators can be measured quickly (20 min) without the need to either digest the nucleic acid or subject it to long sample preparation techniques.
Animals↗
The molecular pharmacology of doxorubicin in vivo.
Explore the source record for details and available documents.
Binding Sites↗
Dealing with writer's block in an older man: depression, Parkinson's disease, or both?
Explore the source record for details and available documents.
Depression↗
Method for the determination of gamma-L-glutamyl-L-dihydroxyphenylalanine and its major metabolites L-dihydroxyphenylalanine, dopamine and 3,4-dihydroxyphenylacetic acid by high-performance liquid chromatography with electrochemical detection.
A high-performance liquid chromatographic method for the analysis of gamma-L-glutamyl-L-dihydroxyphenylalanine (gludopa) and its major metabolites L-dihydroxyphenylalanine (L-DOPA), dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) is described. High sensitivity is achieved with a multi-cell coulometric detector utilising the specific electrochemical properties of gludopa (limit of detection 10 pg on-column). The retention time of gludopa was both pH-dependent and sensitive to negatively charged ion-pairing agents. An alumina-based solid-phase sample preparation technique with dihydroxybenzylamine as internal standard is described for plasma and urine (limit of detection 40 pg/ml) and an ultrafiltration technique is described for tissues (limit of detection 1-10 ng/g). After treatment with 50 mg/kg gludopa, in excess of twenty separate catecholic metabolic peaks can be detected in rat urine, whereas in humans after 9 mg/kg the only catechols detected were L-DOPA, dopamine and DOPAC.
3,4-Dihydroxyphenylacetic Acid↗
Relationship between reductive drug metabolism in tumour tissue of anthracyclines in microspherical form and anti-tumour activity.
Increased activity against a rat solid tumour of doxorubicin incorporated into protein microspheres and administered intratumourally was associated with both increased duration of exposure of tumour tissue to native drug and anaerobic bioreduction of doxorubicin to 7-deoxyaglycones, indicating formation of reactive drug intermediates within tumour tissue. To investigate which of these aspects of drug disposition determined activity we have compared the in vivo fate (clearance from and metabolism by tumour tissue) of doxorubicin in microspherical form with the analogue 4'-deoxydoxorubicin and related this to the tumour growth delay recorded for these drugs. Within the dose range 42 to 55 micrograms, growth delay (14-18 days) of doxorubicin in microspherical form was markedly superior to drug in solution, whereas growth delay of 4'-deoxydoxorubicin in microspherical form (4.3-7.2 days) was not greater than drug in solution. Metabolism to 7-deoxyaglycones by tumour tissue was not a prominent feature of either drug when administered in solution. However, in microspherical form both drugs were extensively metabolized (peak concentrations: 3.6 micrograms/g doxorubicin 7-deoxyaglycone; 2.5 micrograms/g 4'-deoxydoxorubicin 7-deoxyaglycone). Native drug concentrations in tumour tissue were similar after administration in microspherical form at 48 hr (doxorubicin 3.8 micrograms/g; 4'-deoxydoxorubicin 3.7 micrograms/g) and 72 hr (doxorubicin 2.4 micrograms/g; 4'-deoxydoxorubicin 2.7 micrograms/g). At both time points, following administration in microspherical form, tumour tissue concentrations of doxorubicin were significantly greater than when drug was administered in solution, whereas no significant differences were observed for 4'-deoxydoxorubicin. The results are inconsistent with the process of anaerobic bioreduction of doxorubicin to 7-deoxyaglycones being an important component of its anti-tumour activity in microspherical form and point to the importance of increased duration of exposure to native drug.
Animals↗
A randomized trial of Veterans Administration home care for severely disabled veterans.
This randomized study screened hospital admissions to all wards except Psychiatry and Spinal Cord Injured during a 3-year period to identify 233 severely disabled patients (2 impairments on the Katz Index of ADL) and caregivers who were willing to participate in a pretest-multiple posttest trial of the Hines VA Hospital-based Home Care (HBHC) Program. Patient functional status, morale, and satisfaction with care were measured at baseline, 1 month and 6 months post discharge. Caregiver satisfaction and morale were assessed at the same time periods. All health care services used by both groups were tracked over the 6-month period and converted to cost. Findings include improved 1-month satisfaction with care (P = 0.04) and improved 6-month cognitive functioning (P = 0.04) among HBHC patients and improved 1-month (P = 0.04) and 6-month satisfaction with care (P less than 0.01) among their caregivers. A nonsignificant 10% decrease in net cost of care, was found in the treatment group, largely due to lower use of private sector hospital care.
Aftercare↗
Pharmacokinetics, bioavailability, metabolism, tissue distribution and urinary excretion of gamma-L-glutamyl-L-dopa in the rat.
gamma-L-Glutamyl-L-dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg-1 intravenously (i.v.) and 60 mg kg-1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2 alpha of 7 min and terminal half-life of 67 min. After i.p. administration absorption was rapid (t 1/2 ab 6 min), elimination was monophasic with a terminal half-life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L-dopa, dopamine, DOPAC and gamma-L-glutamyl-dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L-dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man.
3,4-Dihydroxyphenylacetic Acid↗
Characterization of the major metabolites of flavone acetic acid and comparison of their disposition in humans and mice.
Flavone acetic acid represents a novel chemical structure currently undergoing clinical investigation. Broad spectrum activity has been observed in preclinical animal screens, but at doses close to toxic in mice. Phase I clinical trials have established that equivalent plasma drug levels can be achieved in humans, but to date Phase II trials have not demonstrated significant activity in a range of tumor types. Little is known about the drug's biotransformation, although metabolites have been implicated in proposed mechanisms of action. In this paper, we have purified the two major human metabolites present in urine (also the only two metabolites detected in plasma) and characterized their structure, chemical properties, activity, and pharmacokinetics. Metabolite 1 (M1) was a glucuronide conjugated to the 8-acetic acid grouping (Mr 456), was chemically labile, and showed a strong tendency to undergo chemical rearrangement at mildly alkaline pH. Metabolite 2 (M2) was also a glucuronide (Mr 456) but appeared to be an unusual isomer of M1. Both were noncytotoxic. In patients, biotransformation represented the predominant mechanism of drug clearance with as much as 80% of a low dose (0.5 g/m2) recovered in urine as M1 and M2 after only 6 h. At high dose (4.8 to 8.6 g/m2, 1- to 6-h infusion) the appearance of peak concentrations of metabolites in plasma and urine was delayed, apparently due to saturation of glucuronidation pathways. This resulted in an overall reduction in drug clearance by 3- to 4-fold. Mice cleared flavone acetic acid much more slowly than patients (289 ml/h/m2 after 600 mg/m2 i.p. versus 2.3 liters/h/m2 after 4.8 g/m2-1-h i.v. infusion) without producing M1 or M2. A different metabolite, exhibiting characteristics of a conjugate, was detected at low concentrations in plasma, tissues, and tumor. Extensive metabolism to inactive products followed by their rapid clearance may contribute to the lack of activity so far seen in humans.
Animals↗
Flavone 8-acetic acid: our current understanding of its mechanism of action in solid tumours.
Flavone 8-acetic acid (FAA) represents a novel chemical structure undergoing clinical trials as an anticancer drug. Its unusual properties tend to distinguish it from a conventional cytotoxic compound, particularly in the response of solid murine tumours; as a consequence, novel mechanisms of action are currently under investigation. In this review we summarised these mechanisms into one of the three categories (a) direct cytotoxicity, (b) biologic response modifier and (c) pharmacologic effector and considered the evidence for and against each. FAA is cytotoxic to tumour cells in vitro, but only at high concentrations and after long exposures. In vivo it is considerably more cytotoxic to the same cells, and it is unlikely that direct cytotoxicity alone can account for this difference. FAA stimulates NK cell activity, induces interferon alpha and synergises with interleukin 2 in the treatment of murine renal cancer. However, a definite link between immunomodulation and antitumour activity has still to be confirmed. Perhaps FAA's most unusual property is its ability to reduce tumour blood flow dramatically, which may provide the appropriate conditions for reactive chemistry to occur. Finally, a combination of the above mechanisms probably work together in producing the drug's unique spectrum of antitumour activity.
Adjuvants, Immunologic↗
Voice perception deficits: neuroanatomical correlates of phonagnosia.
Voice perception (recognition of familiar voices and discrimination of unfamiliar voices) was studied in brain-damaged patients and normal controls. Left- and right-brain-damaged subjects were tested on familiar voices (25 famous males) and 26 pairs of unfamiliar voices. Deficits in recognizing familiar voices were significantly correlated with right-hemisphere damage; discrimination of unfamiliar voices was worse in both clinical groups than in normal controls. Computerized tomographic scans indicated that an intact right parietal-lobe was present in all cases of normal voice recognition, while right parietal-lobe damage was significantly correlated with a deficit in voice recognition. Temporal-lobe damage of either hemisphere was associated with a voice discrimination deficit.
Adult↗
Recruiting and training home care attendants. A response to the AIDS crisis.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Optimisation of a reversed-phase high-performance liquid chromatographic method for the determination of flavone acetic acid and its major human metabolites in plasma and urine.
A high-performance liquid chromatographic method for the determination of flavone acetic acid (FAA) and its major human metabolites in plasma and urine is described. Two factors were identified as being the key to resolving the metabolites; pH and buffer ionic strength. Run at optimal conditions of 10 mM ammonium acetate, pH 5.5-propan-2-ol (80:20) and a column temperature of 40 degrees C on a muBondapak C18 10 microns particle column (30 cm X 3.8 mm I.D.), two major metabolites were identified [FAA, retention time (tR) 6.02 min +/- 0.5% coefficient of variation (C.V.); metabolite 1, tR 4.13 min +/- 1.1% C.V.; metabolite 2, tR 5.10 min +/- 0.5% C.V. and hesperidin, internal standard, tR 4.69 min +/- 1.6% C.V.]. A solid-phase technique using Bond Elut C2 40-microns particles is described which extracts FAA, metabolites and internal standard with efficiencies in excess of 90%. Considerable attention has to be paid to sample preparation: FAA has poor aqueous solubility at acidic pH and the metabolites degrade back to FAA via intermediates at alkaline pH. Both problems can be avoided by buffering and diluting samples with 10 mM ammonium acetate, pH 5.5.
Antineoplastic Agents↗
Target organ disposition and plasma pharmacokinetics of doxorubicin incorporated into albumin microspheres after intrarenal arterial administration.
We synthesized doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-loaded human albumin microspheres (containing approximately 1% doxorubicin w/w) between 15 and 20 micron in diameter. Intrarenal arterial administration of 99mTC-labeled microspheres demonstrated a high renal entrapment ratio (97% of recovered radioactivity). The pharmacokinetics and metabolism of doxorubicin are different when it is administered in microspherical form. Peak plasma levels are lower (16 ng/ml versus 135 ng/ml) compared with treatment by a doxorubicin solution. Histologic studies showed that the microspheres were trapped within capillaries and small arterioles in the renal vascular arcade. It is apparent that chemoembolization with doxorubicin-loaded microspheres significantly reduces systemic exposure to the antineoplastic agent, and maintains intrarenal drug levels.
Albumins↗
The pharmacokinetics of high dose cyclophosphamide and high dose etoposide.
We have studied the pharmacokinetics of single agent high dose cyclophosphamide (HDC) (160-240 mg kg-1) given as repeated intravenous (i.v.) infusions to six patients with small cell lung cancer (SCLC), and HDC (180 mg kg-1) combined with etoposide (750-1000 mg m-2) as repeated i.v. infusions to five patients with SCLC and two patients with teratoma. HDC has a similar pharmacokinetic profile to low dose cyclophosphamide, with a half-life of 4.83 +/- 1.3 h. Repeated administration of HDC produced a small but significant shortening of the half life (P = 0.02). The terminal half-life of high dose etoposide was 7.7 +/- 2 h which is similar to our previous results with low dose etoposide (50-300 mg m-2), but the volume of distribution which was 35.5 +/- 11.6 1. was significantly increased (P less than 0.001). Plasma steady state concentrations of 26.2 +/- 11.7 micrograms ml-1 were achieved. The possible mechanism for the alteration of volume of distribution of etoposide will be discussed.
Carcinoma, Small Cell↗
Pharmacology of adriamycin: the message to the clinician.
In attempting to describe the human pharmacology of ADR, one is aware of the gaps in our knowledge and shortcomings of the available data. Nevertheless, such information is essential if we are ever to be able to convert rationally in vitro observations into clinical pharmacologic effect or, as is more often the case, explain why the desired effect has not been produced. Clinical pharmacokinetic studies to-date suggest that there is a clear relationship between ADR blood levels and toxicity. No such relationship between ADR blood levels and therapeutic response has been shown. The 7-deoxyaglycone tissue metabolites of ADR, which also appear in blood, may be more closely related to ADR cardiotoxicity and therefore may provide a better pharmacokinetic marker of its development. It appears that the only accurate pharmacokinetic indicator of response is the level of drug in the tumour itself.
Animals↗