Biomedical subjects

M A Stephens

Publications and source records attributed to M A Stephens.

At least 37 records · Page 2Linked to original sources

PubMed1995

Synthesis and biological activity of thiazolylindolequinones, analogues of the natural product BE 10988.

A number of analogues of the naturally occurring thiazolylindolequinone BE 10988, a reported potent inhibitor of topoisomerase II, have been prepared and evaluated. The compounds were synthesized from 4-(benzyloxy)-5-methoxy-1-methylindole by appropriate substitution at the indole 3-position followed by standard thiazole ring-forming reactions. The toxicity of these potentially bioreductively activated indolequinones was measured in Chinese hamster V79 cells under aerobic and hypoxic conditions. In addition, toxicity was measured in a human breast cancer cell line that shows amplification of the topo II alpha gene and hypersensitivity to known topo II inhibitors such as mAMSA and mitoxantrone. Using a DNA decatenation assay, a comparison was also made of the inhibitory effects of BE 10988 and mitoxantrone on topo II activity.

Aerobiosis↗

PubMed1995

Educational and long-term therapeutic intervention in the ED: effect on outcomes in adult indigent minority asthmatics.

Minorities have increased morbidity and mortality rates resulting from asthma. The segment of minorities that is socioeconomically depressed often uses the emergency department (ED) as their primary site of medical care. For these reasons, we provided major long-term therapeutic intervention as well as intensive education in the ED for indigent adult African American asthmatics. We intervened in the cases of 30 patients who were frequent visitors to the ED over the previous 2 years. The intervention consisted of 1 hour of education in the ED before discharge regarding the prevention of asthma, the importance of decreasing inflammation as a means of improving asthma control, self-monitoring with a peak flow meter, and a demonstration of correct inhalation technique with metered-dose inhalers and a spacer device. Further, the intervention included management consistent with recent NIH Guidelines, stressing inhaled corticosteroids. After the intervention in the ED, patients were scheduled for follow-up asthma clinic visits. Outcome measures were ED visits and hospitalizations for 1 year after the ED intervention. Using the same inclusion/exclusion criteria, a retrospective control group of 22 patients for the same time period was compared with the intervention group. Before our intervention, the mean number of ED visits per patient for the previous 2 years was 4.4 +/- 2.7, and after the intervention, 2.6 +/- 2.6 (P < .01). The control group did not show a difference in the number of ED visits (3.4 +/- 2.6 before and 3.5 +/- 2.7 after, P = .96). After the intervention, the mean number of hospitalizations decreased significantly in the study group (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Spillover between daughters' roles as caregiver and wife: interference or enhancement?

This research examined how the roles of caregiver and wife affect one another, both positively and negatively, and how such "spillover" effects are related to caregivers' well-being. Spillover was assessed both from the perspective of 125 adult daughter caregivers and their husbands. Husbands reported less negative spillover and more positive spillover from the caregiver role to the wife role than did caregivers. Caregivers reported less positive spillover and more negative spillover from their parent-care role to their wife role than in the opposite direction (wife role to caregiver role). After controlling for caregivers' dispositional optimism, positive and negative spillover were related to several aspects of caregivers' well-being (depression, positive affect, and marital satisfaction), but not to physical health. Findings extend research on number and types of women's roles by suggesting that caregivers' well-being also is influenced by the ways their roles interfere with or enhance each other.

Adult↗

PubMed1995

Fused pyrazine mono-N-oxides as bioreductive drugs. III. Characterization of RB 90740 in vitro and in vivo.

RB 90740 is the lead compound in a series of aromatic mono-N-oxide bioreductive drugs. The compound shows considerably greater toxicity towards hypoxic verses aerobic mammalian cells in vitro. The differential in concentration required to give the same level of cell killing under these conditions ranges from 3.5 in a human bronchio-alveolar tumor cell line up to 120 in a rodent cell line defective in the repair of DNA strand breaks. The ability of RB 90740 to cause DNA strand breaks under hypoxic conditions was confirmed by alkaline sucrose gradient and pulsed field gel electrophoresis techniques. Despite these properties demonstrated in vitro, RB 90740 was shown not to be cytotoxic to hypoxic cells in experimental murine tumors in vivo. This may be due, in part, to the level of hypoxia (< 0.02% O2) necessary to produce toxicity in vitro.

Animals↗

PubMed1994

Cyclopropamitosenes, novel bioreductive anticancer agents. Synthesis, electrochemistry, and biological activity of 7-substituted cyclopropamitosenes and related indolequinones.

The synthesis of the indolequinones 8 and 9 starting from methyl 4-(benzyloxy)-5-methoxy-indole-2-carboxylate (10) is described. The methoxy group in the indolequinones 1, 2, 4, 5, and 7-9 can be displaced by various nitrogen nucleophiles (ammonia, 2-methoxyethylamine, aziridine, 2-methylaziridine, pyrrolidine) in 22-88% yield. The resulting amino-substituted quinones, together with their methoxy precursors, were studied by cyclic voltammetry to determine their reduction potentials, which, in DMF solution, lie in the range -1.355 to -1.597 V (vs ferrocene). The cytotoxicity of the compounds towards aerobic and hypoxic mammalian cells was also determined; in general, under aerobic conditions, the cyclopropamitosenes are more toxic than the corresponding pyrrolo[1,2-a]indolequinones, which are in turn more toxic than the simple 1,2-dimethylindolequinones, with many of the compounds in each series showing greater toxicity toward hypoxic cells.

Animals↗

PubMed1994

The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233).

PURPOSE: To determine the dependency of the aerobic and hypoxic toxicity of tirapazamine on the intracellular activity of DT-diaphorase. METHODS AND MATERIALS: A panel of 18 human cell lines comprising predominantly small cell and nonsmall cell lung cancer and breast cancer lines were used. The activity of DT-diaphorase was determined in cytosolic preparations from cell lysates. The toxicity of tirapazamine was determined using the MTT assay after either 96 or 3 h aerobic exposure or 3 h treatment in hypoxia. RESULTS: The cell lines exhibited a 5000-fold range in DT-diaphorase activity. In toxicity experiments, values of IC50 range from 10.2-120 microM and from 155-1230 for 96 and 3 h aerobic exposures, respectively. In N2, IC50s ranged from 8-55 microM. None of the toxicity values correlate with activity of DT-diaphorase, neither did the ratio of aerobic:hypoxic toxicity (differential toxicity). CONCLUSION: The expression of DT-diaphorase in human tumor cells does not affect the toxicity of tirapazamine.

Antineoplastic Agents↗

PubMed1994

Stress and rewards in women's multiple roles: the case of women in the middle.

This research examined stress and rewards experienced by 95 women who were simultaneously occupying the roles of caregiver, mother, and wife. The study examined role-specific stress and rewards as predictors of well-being (physical health, positive affect, negative affect, and role overload) and examined the effects of an accumulation of role stress and role rewards across these 3 roles. Role rewards contributed unique variance to well-being, even after role stress had been considered. An accumulation of role stress across roles was related to poorer well-being, whereas an accumulation of role rewards was related to better well-being. Findings indicated that caregivers' experiences in multiple roles could both detract from and enhance their mental and physical health.

Adaptation, Psychological↗

PubMed1994

Cyclopropamitosenes: novel bioreductive anticancer agents--mechanism of action and enzymic reduction.

The mechanism of action of cyclopropamitosenes, novel bioreductive anticancer agents, has been investigated using a unique combination of chemical and biochemical techniques. The compounds 4 function as reductively activated alkylating agents under chemical reducing conditions, and the biochemical experiments establish that the methoxy- and aziridinyl-derivatives 4a and 4b behave differently upon bioreduction.

Alkylating Agents↗

PubMed1993

Synthesis of the enantiomers of the bioreductively-activated cytotoxin RSU-1069 and its prodrug RB6145 and lack of stereoselectivity in their cytotoxicity and radiosensitization in vitro.

The R(+)- and S(-)-enantiomers of the radiosensitizer and bioreductively-activated cytotoxin RSU-1069 and their prodrugs have been synthesised. The parent drugs were evaluated as radiosensitizers and bioreductively-activated cytotoxins in vitro. No stereoselectivity in the activities in vitro of the two enantiomers was evident and both compounds were potent hypoxia-selective agents.

Antineoplastic Agents↗

PubMed1993

Heterocyclic mono-N-oxides with potential applications as bioreductive anti-tumour drugs: Part 1. 8-Alkylamino-substituted phenylimidazo [1,2-a] quinoxalines.

A series of imidazo [1,2-a] quinoxaline mono-N-oxides and their 6- and 9-aza analogues have been substituted in the 8-position with a variety of secondary and tertiary amines, and the compounds evaluated as bioreductively activated cytotoxins. Cytotoxic action against hypoxic cells in vitro was critically dependent upon the structural nature of the 8-substituent and its basicity, with little dependence upon reduction potential. 1,2-Dihydro-8-(4-methylpiperazin-1-yl)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide (11) had differential hypoxic:oxic toxicity of 15.3 and some novel analogues had differential hypoxic:oxic toxicities of 7.5-17. Other related compounds with either substituted or unsubstituted 8-piperazinyl substituents, or certain straight-chain aminoalkyl substituents, show comparable activity in vitro. Less basic 8-substituents abolished activity, although the 8-morpholinyl derivatives (7 and 8) had differential hypoxic:oxic toxicities of 3-4. Substitution of the 4-phenyl ring with an electron-withdrawing group (F) improved hypoxic potency, but only with a small effect on hypoxic:oxic toxicity, whereas an electron-donating substituent (MeO) reduced hypoxic potency. Perhaps significantly, the 8-unsubstituted analogue 3 was 6-fold less potent, but had comparable differential cytotoxicity in vitro. The most effective novel hypoxia-selective cytotoxins synthesized were the bifunctional 2-nitro-imidazole derivative 1,2-dihydro-8-((4-(3-(2-nitro-1-imidazoyl)-1-hydroxypropyl)- piperazin-1-yl))-4-phenylimidazo [1,2-a] quinoxaline 5-oxide bishydrochloride (37) and its 9-aza analogue 38. These compounds also exhibited the lowest aerobic toxicities in vitro of the new compounds.

Antineoplastic Agents↗

PubMed1992

2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives.

A series of 2-nitroimidazoles bearing side chains terminating in or containing aziridinyl and oxiranyl groups has been prepared, and the compounds were evaluated in vitro as hypoxia-selective bioreductively-activated cytotoxins and selected compounds tested for their radiosensitizing properties toward hypoxic mammalian cells. Compounds were either the regioisomers of analogues of the potent dual-functional 2-nitroimidiazole alpha-[(1-aziridinyl)-methyl]-2-nitro-1H-imidazole-1- ethanol (RSU-1069, 1) with additional methyl groups or related oxiranes of varying side-chain length and type. Oxiranyl derivatives showed little differential toxicity, and those tested were less effective as radiosensitizers, and although these properties were influenced by side-chain length, differences were not great. Aziridinyl compounds related to 1 but with increased side-chain lengths were unstable. Methylation of 1 in various regions had little effect on radiosensitization and no clear advantages over 1 as differential cytotoxic drugs. Progressive methylation at C-3 was found to increase toxicity but decrease hypoxia selectivity. Incorporation of a cyclohexane side chain in 1,2-cis-2,3-trans-3-aziridin-1-yl-2-hydroxy-1-(2-nitroimidazol+ ++-1- yl)cyclohexane (26) abolished hypoxia-selective toxicity and unexpectedly reduced radiosensitizing efficiency. Of the aziridines, 1-(2-nitro-1-imidazolyl)-2-methyl-3-(1-aziridinyl)-2-propanol (20) was comparable in efficacy to 1 as a bioreductively-activated cytotoxin with slightly lower aerobic toxicity; however, the prodrugs of 1 remain as preferred candidates for clinical evaluation.

Antibiotics, Antineoplastic↗

PubMed1992

Assessment of a range of novel nitro-aromatic radiosensitizers and bioreductive drugs.

In a directed search for the best compounds for clinical evaluation, some 150 selected nitroaromatic compounds, representing 6 distinct types, namely, furans, thiophenes, imidazoles, pyrazoles, pyrroles, and triazoles, have been synthesized and tested as hypoxic cell radiosensitisers and bioreductive drugs. These compounds have a wide range of one-electron redox potentials, ranging from -700 mV for 3-nitropyrroles to -250 mV for 5-nitrofurans. Within each series, those agents bearing alkylating moieties on the side chain are generally the more effective radiosensitisers in vitro. Studies in vivo demonstrated that the bifunctional nitroimidazoles were superior to the other nitroarenes tested. In terms of bioreductive cell killing, the best differential between oxic and hypoxic cell toxicity was shown for the bifunctional 2-nitroimidazoles, which had values greater than 20. In contrast, the other classes of nitroarines generally showed differential toxicities of less than 10.

Animals↗

PubMed1992

Multiple roles of middle-generation caregivers: contextual effects and psychological mechanisms.

Caregiver role experiences of 106 women in the context of their other role experiences as mother and wife were investigated. The study examined role-specific stressors as predictors of well-being (physical health, positive and negative affect), and investigated role-specific feelings of adequacy as a mediator between stress in a given role and well-being. Hierarchical regression analyses revealed that different patterns of role stress were important in explaining different indices of well-being, and that the mother and wife roles contributed unique variance beyond the caregiver role. Path analyses indicated that feelings of adequacy served as a mediator in the role-specific stress process, especially that involving the caregiver and wife roles and the affective indices of well-being. This study suggests the importance of examining caregivers' role experiences in the context of their other family roles and identifies a psychological mechanism through which chronic role stress is related to well-being.

Adult↗

PubMed1992

Evaluation of a pharmacy-managed warfarin-monitoring service to coordinate inpatient and outpatient therapy.

The effects of implementing a warfarin-monitoring service for inpatients were evaluated. The pharmacy-managed service includes chart review, laboratory interpretation, recommendations for warfarin dosage adjustments, physician and patient education, and coordination of follow-up in the outpatient anticoagulation clinic. In a before-after trial, 52 patients monitored by the warfarin-monitoring service were compared with 97 patients who received warfarin before the service was implemented. Significantly fewer determinations of prothrombin time (PT) and partial thromboplastin time (PTT) were ordered for after-trial patients compared with before-trial patients. PT stability at hospital discharge was significantly improved in after-trial patients. After-trial patients were 12.2 times more likely to be referred to the anticoagulation clinic. No difference was found between the before and after groups in overall compliance with follow-up; however, among patients with no history of substance abuse, after-trial patients were 6.7 times more likely to be compliant. The warfarin-monitoring service had no significant effect on the number of hospital visits and readmissions related to toxicity and recurrence of thrombosis. After-trial patients were 5.4 times more likely to have a therapeutic PT at the initial follow-up appointment. The warfarin-monitoring service improved warfarin dose determination, improved PT stability, and increased referrals to the anticoagulation clinic; among patients with no history of substance abuse, it also improved clinic compliance.

Drug Monitoring↗

PubMed1991

Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins.

A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(omega-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) omega-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethyl-amino)ethyl]-3-nitrothiophene-5- carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.

Animals↗

PubMed1991

Stressors and well-being among caregivers to older adults with dementia: the in-home versus nursing home experience.

We examined differences in stressors and well-being for caregivers who care for a relative with dementia at home and those who had placed their relative in a nursing home. The groups did not differ in depression or somatic complaints, but nursing home caregivers had fewer social and interpersonal disruptions. Controlling for caregiving problems, nursing home caregivers reported more stressors due to ADL (activities of daily living) assistance, their relatives' behavioral and cognitive functioning, and lack of caregiving support from family and friends.

Aged↗

PubMed1991

Sources of stress for family caregivers of institutionalized dementia patients.

Although many caregivers place their relative in a nursing home in an attempt to reduce their own burden, caregiving stress often continues after institutionalization. This research examined sources of stress for 66 caregivers who cared for their impaired relative at home and later placed that individual in a nursing home. We hypothesized that although these caregivers no longer had primary responsibility for direct care, they would continue to experience distress because of the stressors associated with the nursing home. Results ran counter to our expectations. Although many caregivers reported stressors related to nursing home care, stressors stemming from the patient's Alzheimer's disease (AD) symptoms accounted for more variance in caregivers' levels of anxiety and depression, and in the quality of their interpersonal relations. Even though caregivers were assisted in their caregiving responsibilities by the nursing home staff, their relative's AD symptoms continued to prompt distress.

Alzheimer Disease↗

PubMed1991

Aziridinyl nitropyrroles and nitropyrazoles as hypoxia-selective cytotoxins and radiosensitizers.

A series of 1- and 2-substituted 4- and 5-nitropyrroles and 3- and 4-nitropyrazoles has been prepared and evaluated in vitro as radiosensitizers of hypoxic cells and as bioreductively-activated cytotoxins. Both the nitropyrroles and the nitropyrazoles were considerably less effective, based upon the differential between hypoxic and aerobic toxicity, than were similar 2-nitroimidazoles bearing alkylating moieties. The trends in radiosensitizing efficiency observed for both classes of drugs corresponded with their one-electron reduction potentials (E1(7] as measured by pulse radiolysis, although they were generally more effective than predicted from previous correlations of E1(7] with sensitizing efficacy and reactivities. Furthermore, the enhancement of sensitizing efficiency by the incorporation of alkylating groups is considerably greater than has been observed for nitroimidazoles. alpha-[(1-Aziridinyl)methyl]-3-nitropyrazole- 1-ethanol (10, E1(7) = -456 mV) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25, E1(7) = -326 mV) were the most effective radiosensitizers in vitro. Only 3-[cis-2,3-dimethyl-1-aziridinyl) methyl)-1-oxo-3,4-dihydro-6-nitro-1-H-pyrrolo [2,1-c] oxazine (22) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25) showed significant bioreductively-activated cytotoxicity, with differentials of 3.5. Although these differential toxicities were coupled with significantly lower aerobic toxicity compared with similar 2-nitroimidazoles, this series was not deemed effective enough to warrant further evaluation. The electron affinity and radiosensitization could be manipulated by chemical design but hypoxia-selectivity was not clearly related to these properties.

Animals↗