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Biomedical subjects

V Miller

Publications and source records attributed to V Miller.

At least 91 records · Page 5Linked to original sources
PubMed1999

Gender-related differences in vascular smooth muscle cell proliferation: implications for prevention of atherosclerosis.

Premenopausal women have a significant reduction in coronary artery disease compared to age-matched males. Little is known about the mechanism underlying this cardioprotective effect of estrogen. Contradictory evidence has been published and our lack of basic understanding of hormone interactions and bioavailability of different estrogens prevents definitive interpretation of these data. We demonstrate gender-specific effects in the proliferation of coronary artery vascular smooth muscle cells obtained from a sexually mature animal model. Vascular smooth muscle cells are an integral component of the atherosclerotic plaque, and inhibition of cell proliferation by estrogen may be one mechanism by which estrogen exerts its cardioprotective effect. Various types of estrogen may also have different mechanistic actions on the vascular system. No differences are demonstrated in overall estradiol binding in vascular smooth muscle cells obtained from male or female animals: however, differences in c-jun, c-fos and TIEG gene expression were gender related. Inhibition of vascular smooth muscle cell proliferation may have important implications in the prevention of atherosclerotic disease and these studies may provide evidence for the cardioprotective effect of estrogen.

Animals↗
PubMed1999

Docetaxel (Taxotere) in combination with vinorelbine in non-small cell lung cancer.

Following encouraging preclinical evidence suggesting anticancer synergy when docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and vinorelbine are administered together, a clinical trial was designed to determine the maximum tolerated dose of the combination when given with granulocyte colony-stimulating factor support to 27 patients with advanced non-small cell lung cancer. Doses were escalated in stages to a maximum of 45 mg/m2 vinorelbine and 60 mg/m2 docetaxel, both administered on day 1 of a 2-week cycle. Hematologic toxicity was mild, with febrile neutropenia complicating only four of the 209 cycles delivered. Clinically significant fluid retention and peripheral neuropathy were also uncommon. Major response was seen in 37% of patients. The median survival was 9 months and 1-year survival was approximately 35%. The combination of 45 mg/m2 vinorelbine and 60 mg/m2 docetaxel has now moved into a phase II trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Mega-HAART: preliminary results and correlation with baseline resistance.

This is a brief report of preliminary results of the assessment of the correlation between baseline viral drug susceptibility and virological response in patients receiving mega-HAART. A total of 37 patients received > or = 6 drugs with a median follow-up of 8 months. There was evidence of extensive loss of viral drug susceptibility at baseline among the 24 patients analysed. Results showed that the magnitude and duration of virological response was associated with phenotypic viral drug resistance, although resistance did not lead to virological failure in all cases, and susceptibility did not lead to response in all cases.

Antiretroviral Therapy, Highly Active↗
PubMed1998

Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group.

BACKGROUND: The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens. METHODS: We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998. FINDINGS: By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23.3 deaths per 100 person-years of follow-up (95% CI 20.6-26.0), and fell to 4.1 per 100 person-years of follow-up (2.3-5.9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65.4 per 100 person-years of follow-up for those on no treatment, 7.5 per 100 person-years of follow-up for patients on dual therapy, and 3.4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0.16 (0.08-0.32), which rose to 0.90 (0.50-1.64) after adjustment for treatment. INTERPRETATION: Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.

Adult↗
PubMed1998

The M184V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT inhibitors.

OBJECTIVE: To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patients. DESIGN AND METHODS: A total of 255 samples from patients treated with lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and stavudine using a recombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold compared with wild-type (high-level resistance, > 10-fold). A genotypic analysis of plasma-derived reverse transcriptase coding regions was carried out in samples with cross-resistance. RESULTS: The majority of samples displayed wild-type or greater than wild-type sensitivity to zalcitabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in samples with high ZDV resistance. There was no obvious correlation between cross-resistance and genotype; all but two samples were mutant at codon 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n=27) were four- to eightfold less sensitive to abacavir. There were no other genotypic changes in addition to M184V known to be associated with abacavir resistance. CONCLUSIONS: Cross-resistance was not commonly observed in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavudine or combinations containing abacavir.

Anti-HIV Agents↗
PubMed1998

Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions.

BACKGROUND: Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy. METHODS AND RESULT: The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use. CONCLUSIONS: Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.

Aged↗
PubMed1998

Tirapazamine-cisplatin: the synergy.

Tirapazamine is a novel bioreductive agent with selective cytotoxicity against hypoxic tumour cells. Synergy with cisplatin and other chemotherapeutic agents has been shown in preclinical trials. Pharmacokinetic studies of tirapazamine have revealed that exposure increases with dose over the range of 18-450 mg m(-2) for a single dose and of 9-390 mg m(-2) for multiple doses. Plasma clearance is high. Tirapazamine has been clinically tested in combination with cisplatin at escalating doses in a phase I trial and at therapeutic doses in three separate phase II trials in patients with advanced non-small-cell lung cancer (NSCLC) in 11 study centres. Limiting toxicity for tirapazamine at an intravenous dose of 390 mg m(-2) was acute, reversible hearing loss. Other frequently observed side-effects included muscle cramping and gastrointestinal symptoms. Tirapazamine did not cause myelosuppression, and no toxic deaths were reported in these trials. The anti-tumour efficacy against previously untreated, advanced NSCLC was evaluated by cumulative intent-to-treat analysis of 132 patients. The objective response rate (confirmed by two independent measurements) was 25% [confidence interval (CI) 17.8-33.33], with a median survival of 38.9 weeks (CI 29.4-49.9). The efficacy of tirapazamine plus cisplatin shown in these trials was better than that of historical controls with cisplatin monotherapy. Two large-scale international trials have been conducted, involving more than 70 centres, to confirm these results. The CATAPULT I trial compares tirapazamine plus cisplatin with cisplatin and has finished accrual with 446 patients. The CATAPULT II trial, which is comparing tirapazamine plus cisplatin with etoposide plus cisplatin, had enrolled 550 patients by June 1997. Follow-up is ongoing. Tirapazamine is the promising first drug from a new class of cytotoxic agents with a novel mechanism of action. It can be effectively combined with cisplatin, and possibly with other agents, because of its safety profile and lack of overlapping dose-limiting toxicity, such as myelosuppression. The combination of tirapazamine and cisplatin appears to be safe and effective in the treatment of NSCLC.

Antineoplastic Agents↗
PubMed1998

Dual resistance to zidovudine and lamivudine in patients treated with zidovudine-lamivudine combination therapy: association with therapy failure.

Human immunodeficiency virus type 1 (HIV-1) strains dually resistant to zidovudine and lamivudine (3TC) may arise during zidovudine-3TC combination therapy. The objective of this cross-sectional study (n = 43 patients) was to test the association between therapy response (clinical and immunologic) to zidovudine-3TC and the level of phenotypic zidovudine resistance and zidovudine resistance-associated genotype of 3TC-resistant isolates. Other variables included were baseline CD4+ cell count, baseline Centers for Disease Control and Prevention (CDC) classification, virus load, and time receiving zidovudine. Phenotypic resistance was assessed using a recombinant virus assay. Genotypic analysis was based on population sequencing of plasma HIV-1. In a univariate analysis using a logistic regression model, it was found that therapy response was significantly associated with phenotypic and genotypic zidovudine resistance, baseline CD4+ cell count, and virus load. After adjustment for all variables, phenotypic resistance to zidovudine remained the only significantly associated factor, independent of baseline CD4+ cell count, baseline CDC classification, and virus load.

Anti-HIV Agents↗
PubMed1998

Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride.

Human immunodeficiency virus type 1 (HIV-1) strains resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) may easily be selected for in vitro and in vivo under a suboptimal therapy regimen. Although cross-resistance is extensive within this class of compounds, newer NNRTIs were reported to retain activity against laboratory strains containing defined resistance-associated mutations. We have characterized HIV-1 resistance to loviride and the extent of cross-resistance to nevirapine, delavirdine, efavirenz, HBY-097, and tivirapine in a set of 24 clinical samples from patients treated with long-term loviride monotherapy by using a recombinant virus assay. Genotypic changes associated with resistance were analyzed by population sequencing. Overall, phenotypic resistance to loviride ranged from 0.04 to 3.47 log10-fold. Resistance was observed in samples from patients who had discontinued loviride for up to 27 months. Cross-resistance to the other compounds was extensive; however, fold resistance to efavirenz was significantly lower than fold resistance to nevirapine. No genotypic changes were detected in three samples; these were sensitive to all of the NNRTIs tested. The most common genotypic change was the K103N substitution. The range of phenotypic resistance in samples containing the K103N substitution could not be predicted from a genotypic analysis of known NNRTI resistance-associated mutations. The Y181C substitution was detected in one isolate which was resistant to loviride and delavirdine but sensitive to efavirenz, HBY-097, and tivirapine. Our data indicate that the available newer NNRTIs which retain activity against some HIV-1 strains selected by other compounds of this class in vitro may have compromised clinical efficacy in some patients pretreated with NNRTI.

Acetamides↗
PubMed1998

A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs.

Combination therapy with protease (PR) and reverse transcriptase (RT) inhibitors can efficiently suppress human immunodeficiency virus (HIV) replication, but the emergence of drug-resistant variants correlates strongly with therapeutic failure. Here we describe a new method for high-throughput analysis of clinical samples that permits the simultaneous detection of HIV type 1 (HIV-1) phenotypic resistance to both RT and PR inhibitors by means of recombinant virus assay technology. HIV-1 RNA is extracted from plasma samples, and a 2.2-kb fragment containing the entire HIV-1 PR- and RT-coding sequence is amplified by nested reverse transcription-PCR. The pool of PR-RT-coding sequences is then cotransfected into CD4+ T lymphocytes (MT4) with the pGEMT3deltaPRT plasmid from which most of the PR (codons 10 to 99) and RT (codons 1 to 482) sequences are deleted. Homologous recombination leads to the generation of chimeric viruses containing PR- and RT-coding sequences derived from HIV-1 RNA in plasma. The susceptibilities of the chimeric viruses to all currently available RT and/or PR inhibitors is determined by an MT4 cell-3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based cell viability assay in an automated system that allows high sample throughput. The profile of resistance to all RT and PR inhibitors is displayed graphically in a single PR-RT-Antivirogram. This assay system facilitates the rapid large-scale phenotypic resistance determinations for all RT and PR inhibitors in one standardized assay.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy.

Gemcitabine is a nucleoside analog that is useful in the treatment of solid tumors. Its use has been postulated to produce lung injury by causing a capillary leak syndrome. We describe a gemcitabine-treated female patient who developed severe dyspnea, diffuse pulmonary infiltrates, and hypoxia, with evidence of interstitial disease on pulmonary function tests. Following the administration of oral corticosteroids, she had complete resolution of all signs and symptoms of gemcitabine toxicity. Physicians should be aware of this treatable complication of gemcitabine therapy.

Adenocarcinoma↗
PubMed1998

Nevirapine/didanosine/lamivudine once daily in HIV-1-infected intravenous drug users.

Human immunodeficiency virus (HIV)-infected, active intravenous drug users received once-daily therapy consisting of a combination of didanosine (2',3'-dideoxyinosine or DDI), lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine or 3TC] and nevirapine. Preliminary results for the first 24 weeks show that the regimen provides potent immunological and antiviral effects.

Adult↗
PubMed1998

[Comparison of adjuvant chemotherapy in breast carcinoma with a combination of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and AC (doxorubicin, cyclophosphamide). Initial results of a national cooperative study].

The aim of this multicentric, prospective randomized trial is to evaluate and to compare, effects and toxicities of two chemotherapeutic combinations (AC and CMF) in adjuvant treatment of breast cancer. Both combinations were given in equitoxic doses and number of cycles was only four. There are 106 women treated for breast cancer T1c-3a, N0-1, M0 in the study. After surgery the patients were randomized, 54 for AC combination and 52 for CMF. We evaluate toxicity of this treatment in all patients in the study. Hematological and nonhematological side effects were comparable in both groups except alopecia (in the group AC was 100%). The study is not finished yet. Preliminary analysis does not show any difference between these two groups.

Antineoplastic Combined Chemotherapy Protocols↗