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Biomedical subjects

S Hodges

Publications and source records attributed to S Hodges.

At least 37 records · Page 2Linked to original sources
PubMed1999

Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors.

PURPOSE: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d. RESULTS: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response. CONCLUSION: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.

Administration, Oral↗
PubMed1998

A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea.

Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2, 000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19. 5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration-36. 84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.

Administration, Oral↗
PubMed1998

The ecology of outcomes: system accountability in children's mental health.

This article provides a conceptual and practical framework called the Ecology of Outcomes. Based on this framework, agencies that serve children and families build and use outcome-oriented information systems to respond to their clients in a more flexible manner. The goal is to improve promising programs by involving stakeholders in outcome identification and in utilization of results. Problems addressed include the emphasis human services place on rules compliance, lack of feedback to program staff to allow for midcourse correction, and lack of input by key stakeholders in the identification of outcomes to be measured. The following components of the framework are described: principles of outcome accountability, prerequisites and building blocks, implementing an outcome information system, and utilizing the results. Key elements of the framework are the integration of outcome information into a service system's decision-making process and the inclusion of client, stakeholder, and provider satisfaction information.

Child↗
PubMed1998

Cognitive characteristics of seasonal affective disorder: a preliminary investigation.

Light therapy, the current treatment for Seasonal Affective Disorder (SAD), does not help everyone suffering from SAD. This paper examines whether patients with SAD potentially might benefit from cognitive behaviour therapy by investigating whether they show a similar cognitive profile to those with non-seasonal depression for whom cognitive therapy has been shown to be effective. Ten subjects with SAD were compared to 11 non-seasonally depressed and 10 normal controls on a range of measures including the Automatic Thoughts Questionnaire and the Dysfunctional Assumptions Scale. One-way analysis of variance showed that the SAD group reported significantly more negative automatic thoughts and dysfunctional attitudes than a non-depressed control group but did not differ from a group with non-seasonal depression. The results suggest that patients with SAD may respond to cognitive behaviour therapy like those with non-seasonal depression. Further research is therefore recommended to examine the efficacy of cognitive therapy as a complementary addition to light therapy in the treatment of SAD and to examine other cognitive aspects of SAD.

Adult↗
PubMed1998

Detection of GB virus C by the RT-PCR LCx system.

The recent publication of representative genomic sequences of GBV-C has permitted the selection of PCR primers for detection of GBV-C in clinical samples by PCR techniques. Traditional amplification methodologies which couple reverse transcription polymerase chain reaction (RT-PCR) and Southern blot detection are slow, cumbersome, and can be technique dependent. This has hampered studies to determine the clinical significance of GBV-C. We report the selection of highly conserved PCR primers and a probe useful for semi-automated RT-PCR using the Abbott LCx system. This adaptation of the LCx system expands its capabilities to include the detection of RNA by RT-PCR, in addition to DNA detection by ligase chain reaction (LCR).

Automation↗
PubMed1998

A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide.

Because topoisomerase (topo) I- and topo II-targeting agents exert their principal effects on the two major classes of enzymes involved in regulating DNA topology in the cell, there has been considerable interest in evaluating combinations of these classes of agents. In preclinical studies of inhibitors of topo I and topo II in combination, drug scheduling and sequencing have been critical determinants of antitumor activity, with a greater magnitude of cytotoxicity generally occurring when treatment with the topo I inhibitor precedes treatment with the topo II-targeting agent. The underlying mechanism that has been proposed to explain this schedule dependency is compensatory up-regulation of topo II and, therefore, enhanced cytotoxicity of topo II inhibitors in cells treated initially with topo I inhibitors. The feasibility of sequentially administering the topo I inhibitor topotecan (TPT) followed by the topo II inhibitor etoposide to patients with advanced solid malignancies was evaluated in this Phase I and translational laboratory study. Fifty patients with solid neoplasms were treated with TPT doses ranging from 0.17 to 1.05 mg/m2/day as a 72-h continuous (i.v.) infusion on days 1-3 followed by etoposide, 75 or 100 mg/m2/day as a 2-h i.v. infusion daily on days 8-10. The combined rate of severe neutropenia and thrombocytopenia was unacceptably high above the TPT (mg/m2/day)/etoposide (mg/m2/day) dose levels of 0.68/100 and 0.68/75 in minimally and heavily pretreated patients, respectively, and these dose levels are recommended for further disease-directed evaluations of TPT/etoposide on this administration schedule. Successive biopsies of accessible tumors were obtained for quantitation of topo I and II levels prior to and immediately after treatment with TPT and prior to and immediately after treatment with etoposide in seven patients. The results of these limited studies in tumors did not fully support the proposed mechanistic rationale favoring the development of this particular sequential TPT/etoposide regimen, because only two of the six patients' tumors in whom topo I was successively measured had either modest or substantial decrements in topo I levels following treatment with TPT, and the principal effect of interest, up-regulation of topo II following treatment with TPT, was clearly documented in the tumors of only one of six subjects in whom successive measurements of topo I were performed. Even in view of the notable objective antitumor activity in three subjects, including a complete response in a patient with colorectal carcinoma and partial responses in one patient each with non-small cell lung and gastric carcinomas, the toxicity and ancillary laboratory results do not provide substantial evidence that sequential treatment with TPT and etoposide might be more advantageous than either TPT or etoposide administered as a single agent.

Adult↗
PubMed1998

Transverse expansion in the upper arch.

The decision as to when to refer patients with transverse problems and when to undertake expansion can be confusing. This paper explains the situations when expansion should be undertaken and also covers the methods of treatment currently available.

Humans↗
PubMed1997

Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia.

Multistep alterations of chromosome 17 in the progression of human urinary bladder neoplasia were studied by superimposed histologic and genetic mapping. The p53 gene was included in the analysis as a model tumor suppressor gene that is frequently involved in urothelial carcinogenesis. The strategy provided a systematic approach to the study of multistep genomic alterations that occur as neoplasia progresses from precursor intraurothelial conditions to invasive cancer. This was accomplished by sampling the entire mucosa of the organ and displaying microscopically identified invasive cancer and precursor conditions in the form of a histologic map. Subsequent isolation of DNA provided a set of samples in which the search for genetic alterations was performed and superimposed on the histologic map. This approach disclosed multifocal allelic losses of chromosome 17 in the early preinvasive phases of urothelial neoplasia. The alterations were predominantly confined to the p12-13, q22-11 and q24-25 regions. Mutations and allelic losses of the p53 gene were mapped to early preinvasive phases of urothelial neoplasia. The data provide detailed analysis of chromosome 17 allelic losses that occur in the development and progression of urothelial neoplasia and represent the first step for genome-wide modeling of multistep human urothelial carcinogenesis.

Alleles↗
PubMed1996

Surface-associated material from the bacterium Actinobacillus actinomycetemcomitans contains a peptide which, in contrast to lipopolysaccharide, directly stimulates fibroblast interleukin-6 gene transcription.

The oral commensal Gram-negative bacterium Actinobacillus actinomycetemcomitans is believed to be the causative organism of localized juvenile periodontitis, a disease in which there is rapid loss of alveolar bone supporting the teeth. Previously, we have reported that gentle saline extraction of this bacterium removed a loosely adherent proteinaceous fraction from the cell surface of the bacterium, which we have termed surface-associated material. This material contained potent bone-resorbing activity. We now report that surface-associated material is also a potent stimulator of cytokines, and in particular, interleukin-6 (IL-6) synthesis, while the lipopolysaccharide from this bacterium is only a weak stimulator of IL-6 synthesis by fibroblasts and monocytes. In contrast to enteric lipopolysaccharide (LPS), which induces fibroblast IL-1, IL-6 and tumour necrosis factor (TNF) alpha synthesis, surface-associated material stimulated gingival fibroblasts to synthesize only IL-6, with no induction of IL-1 or TNF (the normal inducers of IL-6 synthesis). Reverse transcriptase PCR also failed to detect mRNA for IL-1 or TNF in surface-associated-material-stimulated fibroblasts, although both mRNAs were present in Escherichia coli LPS-stimulated cells. Neutralizing antibodies to IL-1 and/or TNF or the natural IL-1 receptor antagonist (IL-1ra) inhibited enteric LPS-induced IL-6 synthesis, but did not inhibit surface-associated-material-induced synthesis. In addition, dexamethasone, which completely suppressed LPS-induced IL-6 synthesis, only inhibited surface-associated-material-induced IL-6 synthesis by 50%. This suggests that the active constituent in the surface-associated material stimulates IL-6 gene transcription by a transcriptional control mechanism distinct to that of E. coli LPS. The IL-6 stimulating activity of the surface-associated material is inhibited by both heat and trypsin, suggesting that it is proteinaceous. The activity has been isolated using anion-exchange, reverse-phase and size-exclusion HPLC. The active moiety is a peptide of molecular mass 2kDa which may be the product of a bacterial short open reading frame.

Aggregatibacter actinomycetemcomitans↗
PubMed1996

Educational reform in health administration.

The transformation of the health care marketplace now demands transformation of the academy. The stakeholders--students, industry leaders, business, government, consumers--are all demanding managed care education now for the students of health administration. The authors describe a graduate course on managed health organizations initially offered to students at a Southwestern university during 1994.

Curriculum↗
PubMed1995

Hysterectomy and psychiatric disorder: are the levels of psychiatric morbidity falling?

This paper compares the findings of three studies carried out at intervals over the years 1975-1990. The three studies were concerned with different issues, but each study examined psychiatric morbidity among women undergoing hysterectomy for menorrhagia of benign origin. In all three studies levels of psychiatric morbidity were measured before the operation and 6 months after the operation. Psychiatric morbidity was measured with the Present State Examination (PSE) (Wing et al. 1974), and with established self-report questionnaires. Levels of psychiatric morbidity fell significantly across the three studies. In Study 1, the proportions of psychiatric cases were 58% before hysterectomy and 26% after; in Study 2, 28% before and 7% after; and in Study 3, 9% before and 4% after. The decline in psychiatric morbidity was not associated with demographic and social characteristics, previous psychiatric history, family psychiatric history, the nature of the women's menstrual complaints, or the women's understanding and expectations of the operation. In Study 3 anti-menorrhagic drugs were prescribed twice as frequently as in the two previous studies; while the prescribing of psychotropic medication was significantly higher in Study 1 than in Study 2 or Study 3. The implications of these findings are discussed.

Adaptation, Psychological↗
PubMed1995

Successful outcome with serial amniocenteses for polyhydramnios complicating cystic adenomatoid malformation of the lung.

Hydrops fetalis secondary to congenital cystic adenomatoid malformation of the fetal lung is almost invariably a lethal condition. This poor prognosis may be attributed to the combined effects of tissue compression from the thoracic space occupying lesion and premature delivery of a hydropic baby following rupture of the membranes in the presence of polyhydramnios. We describe a successful outcome with serial amniocenteses. Partial in utero resolution of the lung lesion with complete return to normal of the aberrant liquor volume was documented, and a live infant was delivered at term.

Adult↗
PubMed1994

Oxygen free radicals in idiopathic facial pain.

Chronic idiopathic oro-facial pain has become a common complaint, resulting increasingly in referral to the pain clinics world-wide, about 90% of the psychologically stress-related patients of the psychiatric clinic of Eastman Dental Hospital, London have been found to have associated idiopathic oro-facial pain. Psychological stress may produce a situation where oxidative stress might enhance the production of free radicals, especially OH radicals, in human biological fluids. Furthermore, it has been suggested that. OH radicals are responsible for the production of many systemic and local tissue injury diseases which may initially manifest as pain syndrome. It has been suggested that the oxygen free radical production of sailcloth, 2,3-dihydroxybenzoic acid (DHB) is a biological marker for the detection and quantification of OH radicals. Analyses of plasma samples collected from patients with chronic idiopathic orofacial pain and an equal number of age and sex matched control subjects revealed that the patient group had significantly increased evidence for circulating levels of 2,3-DHB after aspirin ingestion than control subjects. There was no significant difference in 2,5-DHB levels between the two groups. The urine samples from the same individuals showed evidence of measurable amounts of 2,3 and 2,5-DHB in both pre- and post-aspirin samples. These results suggest that OFRs may be involved in the aetiology of pain in patients that present with facial pain.

Adult↗
PubMed1993

A phase I trial of carboplatin and etoposide given as continuous infusions to adults with leukemia.

Thirty-two adult patients with acute leukemia were treated with continuous infusion carboplatin and etoposide at eight different dose levels. Dose limiting toxicity was encountered at doses of carboplatin of 310 mg/m2 per day for 5 days (total 1550 mg/m2 per course) and etoposide 150 mg/m2 per day for 5 days (total dose 750 mg/m2 per course) and consisted primarily of gastrointestinal toxicity. Of the five courses given at the highest dose level, three were complicated by grade 4 gastrointestinal toxicity. The recommended dose for further phase II evaluations in acute leukemia is carboplatin 250 mg/m2 per day for 5 days by continuous infusion and etoposide 150 mg/m2 per day for 5 days given by continuous infusion. The response to treatment was notable for a single complete remission achieved in a patient with acute undifferentiated leukemia. None of the patients with chronic myeloid leukemia in blast crisis (n = 12) or with acute lymphocytic leukemia (n = 4) or acute myeloid leukemia (AML) (n = 15) achieved complete remission (CR), although all patients with AML entered on this trial had prior complete remissions that were less than 1 year in duration, and many were refractory, either to primary therapy or to the most recent attempt to obtain CR.

Acute Disease↗
PubMed1992

Lafora disease: a progressive myoclonus epilepsy.

Lafora disease is a rare inborn error of metabolism resulting in storage of a polyglucosan in tissues including the brain, skin and liver. Four children are described with progressive myoclonus epilepsy and intellectual deterioration in whom this diagnosis was made. In two the diagnosis was confirmed by the presence of periodic acid schiff (PAS) positive, diastase resistant, colloidal iron staining inclusion material in the liver when they were referred to a paediatric gastroenterologist with abnormal liver function tests. In one, the diagnosis was made from cerebellar biopsy, although on retrospective review the liver biopsy performed at this time was abnormal. In a fourth child, whose sibling was affected, histological diagnosis was confirmed by skin biopsy, although clinical and EEG findings had been highly suggestive for several years. The disease has autosomal recessive inheritance, is progressive and the prognosis is poor. Paediatricians should be aware of this diagnosis, which is often delayed, as early histological diagnosis allows prognostic and genetic counselling and optimal treatment. Although the diagnosis was made by liver or brain biopsy in three cases, skin biopsy offers a reliable, less invasive means of diagnosis.

Adolescent↗