ABSTRACT
Perianal Crohn's disease can cause significant morbidity for patients affected by the disease. However, diagnostic modalities and treatment options have progressed changing the goals of treatment from fistula "improvement" to complete cessation of drainage. Fistula closure and fibrosis of the fistula track is achieved in some patients. Furthermore, treatment has become a combined effort between medical physicians and surgeons. Simple disease can be treated with medical therapy alone consisting of antibiotics and immunomodulators. Infliximab should be added to refractory simple disease or simple disease with the presence of inflammation. If complex fistula disease is evident a surgical evaluation should also be done to determine if intervention is indicated. Complex disease should be treated with antibiotics, immunomodulators and biologic therapy from the onset. This review will summarise current data regarding medical options for treatment of fistulising Crohn's disease.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Anus Diseases/therapy , Crohn Disease/therapy , Digestive System Surgical Procedures/methods , Immunosuppressive Agents/therapeutic use , Algorithms , Anus Diseases/diagnosis , Anus Diseases/etiology , Congresses as Topic , Crohn Disease/complications , Crohn Disease/diagnosis , Humans , Treatment OutcomeABSTRACT
Brainstem auditory evoked potential (BAEP) recording was used to screen presymptomatically the hearing of 200 neonates treated with ampicillin (100 mg/kg daily) and gentamicin sulfate (5 mg/kg daily). The study included 130 male and 70 female neonates; post-conceptional age ranged from 34 to 57 weeks (mean 42.36 weeks). We divided neonates into 2 groups according to duration of antibiotic treatment; group 1 consisted of 179 patients who were treated with antibiotic agents for < or = 7 days. Although 15 (8.4%) in this group initially manifested abnormal BAEP recordings, only 8 of these brain-damaged neonates (4.5%) (6 with peripheral and 2 with central dysfunction) later manifested abnormal recordings. Group 2 consisted of 21 neonates who were treated for 10 to 30 days; BAEP recordings were abnormal in 7 patients (33.3%) (4 with peripheral and 3 with central dysfunction). We conclude that BAEP is indicated only for neonates treated with gentamicin sulfate for > 10 days. In this group, infants so treated usually have underlying disease or severe infection, including birth asphyxia, hypoxia, sepsis, and meningoencephalitis, all of which are clinically significant indicators of high risk for auditory pathway dysfunction.
Subject(s)
Anti-Bacterial Agents/adverse effects , Evoked Potentials, Auditory, Brain Stem/drug effects , Gentamicins/adverse effects , Hearing Loss/chemically induced , Neonatal Screening/methods , Female , Gestational Age , Humans , Infant, Newborn , MaleABSTRACT
Limonene is a farnesyl transferase inhibitor that has shown antitumor properties. The drug had been given orally to cancer patients. Plasma and urine samples collected from the patients were examined by reversed-phase HPLC-atmospheric pressure chemical ionization and electrospray ionization MS. The drug underwent rapid conversion to hydroxylated and carboxylated derivatives. Characterization and structural elucidation of the metabolites were achieved by LC/MS and NMR. Five major metabolites were detected in the plasma extracts, namely limonene-1,2-diol, limonene-8,9-diol, perillic acid, an isomer of perillic acid, and dihydroperillic acid. Urinary metabolites comprised the glucuronides of the two isomers of perillic acid, dihydroperillic acid, limonene-8,9-diol, and a monohydroxylated limonene.
Subject(s)
Alkyl and Aryl Transferases , Antineoplastic Agents, Phytogenic/metabolism , Breast Neoplasms/metabolism , Colorectal Neoplasms/metabolism , Terpenes/metabolism , Adult , Aged , Antineoplastic Agents, Phytogenic/blood , Antineoplastic Agents, Phytogenic/urine , Chromatography, Liquid , Cyclohexenes , Farnesyltranstransferase , Female , Humans , Limonene , Male , Mass Spectrometry , Middle Aged , Molecular Structure , Terpenes/blood , Terpenes/urine , Transferases/antagonists & inhibitorsABSTRACT
Idoxifene, a novel antiestrogen with reduced estrogenic activity when compared to tamoxifen, has been given to 20 women with metastatic breast cancer, 19 of whom had received tamoxifen previously, in doses between 10-60 mg. Idoxifene had an initial half-life of 15 h and a terminal half-life of 23.3 days. At a maintenance dose of 20 mg, a mean steady-state level of 173.5 ng/ml was achieved. Significant falls in luteinizing hormone and follicle-stimulating hormone were seen, but the falls were not dose related. Idoxifene was well tolerated, with 11 patients complaining of mild symptoms similar to those seen with tamoxifen. Fourteen patients continued idoxifene therapy for 1-56 weeks; 4 patients showed stabilization of disease for 6-56 weeks and 2 patients showed a partial response.
Subject(s)
Breast Neoplasms/drug therapy , Estrogen Antagonists/therapeutic use , Tamoxifen/analogs & derivatives , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Endocrine Glands/drug effects , Estrogen Antagonists/adverse effects , Estrogen Antagonists/pharmacokinetics , Female , Humans , Middle Aged , Neoplasm Metastasis , Postmenopause , Tamoxifen/adverse effects , Tamoxifen/pharmacokinetics , Tamoxifen/therapeutic useABSTRACT
While the presence of oestrogen receptors (ERs) in human breast cancer may determine the biological response to tamoxifen, the extent to which ER status governs tumour tamoxifen accumulation is unclear. We investigated the intra-tumoural disposition of tamoxifen (TAM) and its major metabolite N-desmethyltamoxifen (DMT) in 36 human breast carcinomas following short-term therapy. Steady-state serum concentrations appeared to be reached following 2 weeks therapy, after which no significant difference in the intra-tumoural concentrations of TAM between ER-ve and ER+ve tumours was observed (717.9 +/- 166.4 ng/gm, and 518.6 +/- 109.4 ng/gm, respectively). In patients treated for less than 2 weeks, there was significantly less intra-tumoural TAM in ER-ve compared with ER+ve tumours (120.9 +/- 49.9 ng/gm and 450.1 +/- 75.3 ng/gm, respectively; p < 0.04). The rate of tumour TAM accumulation correlated with duration of therapy only for ER-ve tumours (r = 0.72, p < 0.02), whereas for ER+ve tumours the absolute ER value appeared to be weakly associated with TAM accumulation (r = 0.41; p < 0.05). The intra-tumoural ratio of TAM to DMT reflected the serum concentrations in ER-ve tumours, but in ER+ve tumours relatively more TAM to DMT was observed. A similar intracellular distribution of both TAM and DMT was observed, although following 2 weeks therapy relatively less of each compound was found in the cytosol of ER-ve compared with ER+ve tumours (18% vs 34%). These results demonstrate that ER status may influence the rate of accumulation and intra-cellular distribution of tamoxifen and its metabolites, but not the final concentrations which are achieved. Following steady-state, both ER+ve and ER-ve tumours, not all of which would be expected to respond to the drug, achieve intra-tumoural concentrations 5-7 fold greater than serum. Unlike recent reports on acquired resistance, therefore, de novo resistance to tamoxifen is unlikely to represent an inability of the tumour to achieve adequate intra-tumoural concentrations of the drug or its metabolites.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/ultrastructure , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/ultrastructure , Receptors, Estrogen/physiology , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacokinetics , Tamoxifen/therapeutic use , Aged , Breast Neoplasms/drug therapy , Drug Administration Schedule , Drug Resistance , Female , Humans , Middle Aged , Neoplasms, Hormone-Dependent/drug therapy , Subcellular Fractions/metabolism , Tamoxifen/bloodABSTRACT
Video EEG monitoring for 1-2 hours was performed on 100 outpatients (57 females and 43 males) with refractory seizures or frequent paroxysmal events. Patients' ages ranged from 8 days to 67 years (mean age 21). At least one clinical seizure or paroxysmal event was observed in 66 patients; 24 of these patients had subtle seizures that would be difficult to observe without videotape monitoring. The combination of videotape and EEG monitoring was able to confirm the diagnosis in 80 cases. The referral diagnosis was changed in 37 patients; they included changes in seizure types in 17 epileptic patients; 10 patients were found to have pseudoseizures and 10 patients had nonepileptic neurological disorders. The yield of EEG seizure activity differed significantly between video EEG monitoring and routine EEG recording (p < 0.001). EEG seizure activity was reported in 77 patients with video EEG monitoring compared to 49 patients with routine EEG recording. We conclude that outpatient video EEG monitoring yields more information on the presence or absence of seizures and their types, improving patient management, and averting the need for prolonged inpatient intensive monitoring.
Subject(s)
Electroencephalography/methods , Epilepsy/physiopathology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Monitoring, Physiologic/methods , Time Factors , Videotape RecordingABSTRACT
The identification of metabolites from the pyridylglutarimide 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (PG, Rogletimide) was achieved using liquid chromatography-mass spectrometry with a thermospray interface (LC-TSP-MS). The urinary metabolites include PG N-oxide, the products of 4- and 5-hydroxylation in the piperidine residue (4- and 5-hydroxy-PG) and a gamma-butyrolactone derived via terminal hydroxylation in the ethyl residue. In addition to the above metabolites, several products of glutarimide ring-opening could be detected in the plasma extracts after multiple-dose treatment. Thus LC-TSP-MS is potentially a simple and rapid technique in studies of drug metabolism for the important glutarimide class of drug.
Subject(s)
Aminoglutethimide/analogs & derivatives , Antineoplastic Agents/metabolism , Aminoglutethimide/blood , Aminoglutethimide/metabolism , Aminoglutethimide/therapeutic use , Aminoglutethimide/urine , Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/urine , Breast Neoplasms/drug therapy , Chromatography, High Pressure Liquid , Female , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Reference StandardsABSTRACT
By modification of a recently developed method for separation of radio-labelled urinary oestrogens we were able to separate oestrogen metabolites and measure their isotope ratios in urine following injections of [3H]delta 4-androstenedione and [14C]oestrone. This method provides a useful tool for studying in vivo aromatisation of delta 4-androstenedione into oestrone in breast cancer patients before and during treatment with aromatase inhibitors.
Subject(s)
Aromatase Inhibitors , Aromatase/metabolism , Breast Neoplasms/metabolism , Estrogens/urine , Aminoglutethimide/therapeutic use , Androstenedione/metabolism , Breast Neoplasms/drug therapy , Estrone/biosynthesis , Female , HumansABSTRACT
The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3-4 days, oestradiol levels fell to 31.1% +/- 6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 micrograms/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates for Co (21.7 +/- 1.82 micrograms/ml), Km (2.66 +/- 0.68 micrograms/ml) and Vmax (0.86 +/- 0.06 micrograms ml-1 h-1). On subsequent repeated dosing with PyG, both the Km (4.31 +/- 0.48 micrograms/ml) and the Vmax (1.83 +/- 0.13 micrograms ml-1 h-1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.
Subject(s)
Aminoglutethimide/analogs & derivatives , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/blood , Estradiol/blood , Aminoglutethimide/pharmacokinetics , Aminoglutethimide/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogens, Conjugated (USP)/blood , Estrone/analogs & derivatives , Estrone/blood , Female , Humans , Middle Aged , Time FactorsABSTRACT
3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione (1) is a strong competitive inhibitor of human placental aromatase (Ki = 1.1 microM; testosterone as substrate) that, unlike the structurally related aromatase inhibitor aminoglutethimide (2), is not also an inhibitor of the cholesterol side-chain cleavage enzyme desmolase. An improved synthesis of 1 is described, which was readily adapted to the preparation of homologues in a series of 3-alkyl-3-(4-pyridyl)-piperidine-2,6-diones (6-13). Alkylation of 1 afforded a second series, comprising 1-alkyl-3-ethyl-3-(4-pyridyl)-piperidine-2,6-diones (14-23). Inhibitory activity toward aromatase was maximal in both series for the octyl derivatives. Respective Ki values for the competitive inhibition exerted by the 3-octyl (12) and the 1-octyl (21) analogues with testosterone as substrate were 0.09 and 0.12 microM. The compounds 1, 2, 12, and 21 differed in their relative potencies as inhibitors of the aromatization of testosterone and androstenedione. Respective Ki values were as follows: for 1, 1.1 and 14 microM (ratio 12.7); for 2, 0.6 and 1.8 microM (3); for 12, 0.09 and 0.20 microM (2.2); and for 21, 0.12 and 0.48 microM (4).
Subject(s)
Aminoglutethimide/analogs & derivatives , Antineoplastic Agents/pharmacology , Aromatase Inhibitors , Alkylation , Aminoglutethimide/pharmacology , Chromatography, High Pressure Liquid , Mathematics , Structure-Activity RelationshipABSTRACT
Pyridoglutethimide [3-ethyl-3-(4-pyridyl)piperidine-2,6-dione] has been developed as an analogue of aminoglutethimide [3-(4-aminophenyl)-3-ethyl-piperidine-2,6-dione] possessing specific aromatase activity with potency comparable to aminoglutethimide. This study investigates the pharmacokinetics of pyridoglutethimide in the rat and the rabbit: the plasma half-life is 6 hr in the rat and 16.4 hr in the rabbit. The sole metabolite found in urine (rat) and plasma (rat and rabbit) is pyridoglutethimide N-oxide.
Subject(s)
Aminoglutethimide/analogs & derivatives , Antineoplastic Agents/metabolism , Aminoglutethimide/metabolism , Animals , Chromatography, Thin Layer , Female , Half-Life , Humans , Kinetics , Male , Mass Spectrometry , Rabbits , Rats , Rats, Inbred StrainsABSTRACT
The inheritance of A-V conduction time in Polynesians has been examined, using ECGs taken from the population of the Tokelau Islands. As has been demonstrated in other racial groups, A-V conduction time was influenced by sex, age, and heart rate. Complex segregation analysis provides evidence for a significant polygenic influence on A-V conduction, but no evidence for a major gene. Familial correlations and commingling analysis are in agreement with this conclusion. The heritability of A-V conduction time was 0.46. The hypothesis of Møller & Heiberg (1980a) that a major gene could be influencing A-V conduction, is not supported by these data.
Subject(s)
Atrioventricular Node/physiology , Genetics, Medical , Heart Conduction System/physiology , Native Hawaiian or Other Pacific Islander , Female , Humans , Male , New Zealand , Regression Analysis , Time FactorsABSTRACT
Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 h urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily). AG therapy is known to alter the metabolic rate and plasma half-life of a number of coadministered compounds including dexamethasone and warfarin. Clinicians should remain alerted to this phenomenon.
Subject(s)
Aminoglutethimide/analogs & derivatives , Aminoglutethimide/metabolism , Breast Neoplasms/metabolism , Aminoglutethimide/therapeutic use , Aminoglutethimide/urine , Breast Neoplasms/drug therapy , Chromatography, High Pressure Liquid , Colorimetry , Female , Humans , MaleABSTRACT
Four new metabolites of aminoglutethimide have been identified in the urine of patients being treated chronically with the drug. These were products of hydroxylation of the 3-ethylpiperidine-2,6-dione residue, namely 3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione and its acetylamino analog, 3-(4-aminophenyl)-3-(1-hydroxyethyl)piperidine-2,6-dione, and 3-(4-aminophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, the lactone formed by rearrangement of 3-(4-aminophenyl)-3-(2-hydroxyethyl)piperidine-2,6-dione. The metabolites were isolated by reverse-phase thin layer chromatography and characterized by comparison of their mass spectra either with those of synthetic samples or with the mass spectra of analogous metabolites previously identified in the urine of rats. These new metabolites were minor constituents compared with aminoglutethimide and with the previously identified major metabolites 3-(4-acetylaminophenyl)-3-ethylpiperidine-2,6-dione and 3-(4-hydroxylaminophenyl)-3-ethylpiperidine-2,6-dione. There were marked species differences between rat and human inasmuch as almost all the metabolites in the urine of the rat were N-acetylated whereas most of the human metabolites were not. However, 5-hydroxylation of the piperidinedione residue was stereoselective in the same sense in both species, the cis isomer being formed exclusively. Synthetic cis-3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione did not inhibit the activity of the target enzyme systems desmolase and aromatase in vitro, and therefore, like other metabolites so far described, is an inactivation product of the drug.
Subject(s)
Aminoglutethimide/urine , Acetylation , Biotransformation , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Humans , Hydroxylation , Mass SpectrometryABSTRACT
Hydroxylaminoglutethimide (3-ethyl-3-(4-hydroxylaminophenyl)-2,6-piperidinedione) has been identified as a novel metabolite of aminoglutethimide (3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione) in the urine of patients treated chronically with this drug. The metabolite was isolated by reverse-phase thin-layer chromatography, and characterized by comparison of its mass spectrum and chromatographic properties with those of the synthetic compound. Hydroxylaminoglutethimide is unstable; it is readily oxidized to nitrosoglutethimide and disproportionates in the mass spectrometer into this compound and aminoglutethimide. In none of four patients studied was the metabolite detected in the urine after the first dose of the drug. In one patient it appeared after the second dose and in two more within seven to eight days suggesting that its formation is drug-induced, and that it may be the metabolite responsible for the diminished half-life of aminoglutethimide during chronic therapy. The profile of metabolites from one patient, examined by high-performance liquid chromatography after the first dose and again after six weeks of therapy afforded evidence that the formation of hydroxylaminoglutethimide was at the expense of a major metabolite N-acetylaminoglutethimide. Hydroxylaminoglutethimide was not an induced metabolite in the rat.