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PubMed2006

Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy.

We investigated, in patients tested between 1991 and 2004, the patterns of mutually exclusive human immunodeficiency virus-1 thymidine-analogue mutations (TAMs) in 4039 reverse-transcriptase sequences with > or = 1 TAM. TAM pattern 1, which included M41L and L210W and excluded K70R and is coupled with more-extensive cross-resistance to drugs, became the most frequent pattern after 1996. In 1465 genotypes from 684 patients in whom highly active antiretroviral therapy (HAART) was unsuccessful, predictors of this pattern were the number of previous HAART regimens undergone (adjusted odds ratio [OR], 1.09 [95% confidence interval {CI}, 1.02-1.16]), use of stavudine/lamivudine (adjusted OR, 1.42 [95% CI, 1.05-1.99]), use of nevirapine (adjusted OR, 1.60 [95% CI, 1.14-2.24]), use of efavirenz (adjusted OR, 1.56 [95% CI, 1.08-2.27]), and use of ritonavir (adjusted OR, 1.35 [95% CI, 1.04-1.75]).

Anti-HIV Agents↗
PubMed2006

Rate of virologic failure and selection of drug resistance mutations using different triple nucleos(t)ide analogue combinations in HIV-infected patients.

Virologic failure seems to occur more frequently in HIV-infected patients treated with triple nucleoside analogue (NA) combinations than with regimens including nonnucleoside reverse transcriptase inhibitors or protease inhibitors. However, the rate of failure and resistance profiles may differ with distinct triple NA combinations. A retrospective review of all HIV-infected individuals who received triple NA combinations at our institution was conducted. Virologic failure was defined as lack of achievement of plasma HIV-RNA<50 copies/ml at week 16 following initiation of antiretroviral therapy or as viral rebound in subjects with prior undetectable viremia. Genotypic analyses were performed at the time of first virological failure. Of the 261 patients identified, 13 were drug naive, 126 had underwent simplification, and 122 were antiretroviral-experienced patients with detectable viral load. Virologic failure was recorded in 95 (36.4%) after an average follow-up of 19 months. Rates were 0.67 in drug-naive, 0.55 in simplification, and 2.38 in rescue interventions for 100 persons-month follow-up. Factors associated with virologic failure in the multivariate Cox regression analysis were rescue vs naive or simplification strategies (OR 2.6; 95% CI 1.6-4.2) and using tenofovir as part of the combination (OR 2.04; 95% CI 1.3-3.2). In contrast, the use of AZT prevented virologic failure (OR 0.52; 95% CI 0.3-0.8). M184V was the most frequent resistance mutation (75.4%), followed by T215Y (52.5%) and K65R (14.8%). Of note, K65R did not develop in patients taking AZT nor in those with prior thymidine-associated mutations (TAMs). Conversely, subjects who developed K65R did not accumulate TAMs. Virologic failure is relatively frequent in patients treated only with triple NA regimens, particularly in the setting of rescue therapy. The use of TDF might be associated with a higher risk of virologic failure and, conversely, AZT might be protective. The presence of TAMs precluded the selection of K65R in patients treated with TDF. Resistance pathways for TDF and thymidine analogues seem to be divergent and could be the basis to explore a synergism between these drugs.

Adenine↗
PubMed1995

Interferon-beta, retinoids, and tamoxifen in the treatment of metastatic breast cancer: a phase II study.

Based on the additive or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines and on preclinical and clinical data on retinoids alone and in combination with antiestrogen or interferon, we designed a pilot phase II study to test the toxicity of simultaneous administration of interferon-beta (IFN-beta), retinoids (R), and tamoxifen (TAM) and the efficacy of this combination as salvage therapy in a group of patients with metastatic breast cancer (MBC). A total of 49 stage IV breast cancer patients, 11 pretreated with hormones, 26 with chemotherapy, and 12 with both, received 30 mg TAM and two dose levels of IFN-beta and retinyl palmitate. Among 49 evaluable patients, 27 achieved a clinical response (55%; 95% CI 41-69%), 10 had stable disease (20%), and in 12 (25%) the disease progressed. Toxicity with both dose levels was moderate and mainly hepatic. Median response duration, not statistically different in estrogen receptor-positive and negative patients, was 31.4 months (range 4.9-67). Median overall survival was 19.2 months (range 2-69). We have shown that long-term administration of TAM, IFN-beta, and retinyl palmitate is feasible with moderate toxicity. We have also demonstrated that this regimen is active in pretreated MBC patients and that responses are not influenced by receptor status.

Adult↗
PubMed2007

PP2B-mediated dephosphorylation of c-Jun C terminus regulates phorbol ester-induced c-Jun/Sp1 interaction in A431 cells.

The c-Jun/Sp1 interaction is essential for growth factor- and phorbol 12-myristate 13-acetate (PMA)-induced genes expression, including human 12(S)-lipoxygenase, keratin 16, cytosolic phospholipase A2, p21(WAF1/CIP1), and neuronal nicotinic acetylcholine receptor beta4. Here, we examined the mechanism underlying the PMA-induced regulation on the interaction between c-Jun and Sp1. We found that treatment of cells with PMA induced a dephosphorylation at the C terminus of c-Jun at Ser-243 and a concomitant inhibition of PP2B by using PP2B small interfering RNA, resulting in reduction of PMA-induced gene expression as well as the c-Jun/Sp1 interaction. The c-Jun mutant TAM-67-3A, which contains three substitute alanines at Thr-231, Ser-243, and Ser-249 compared with TAM-67, binds more efficaciously with Sp1 and is about twice as efficacious as TAM-67 in inhibiting the PMA-induced activation of the 12(S)-lipoxygenase promoter. Importantly, PP2B not only dephosphorylates the c-Jun at Ser-243 but also interacts with c-Jun in PMA-treated cells. PMA stimulates the association of the PP2B/c-Jun/Sp1 complex with the promoter. These findings indicate the dephosphorylation of c-Jun C terminus is required for the c-Jun/Sp1 interaction and reveal that PP2B plays an important role in regulating c-Jun/Sp1 interaction in PMA-induced gene expression.

Calcineurin↗
PubMed2006

Modeling for cost-effective-adjuvant aromatase inhibitor strategies for postmenopausal women with breast cancer.

BACKGROUND: To determine cost-effective (CE) strategies comparing adjuvant upfront aromatase inhibitor (AI) with sequential tamoxifen (TAM) AI in postmenopausal (PM) women with breast cancer (BC). DESIGN: A Markov model was constructed to calculate cumulative costs and quality-adjusted life year (QALY) gains for upfront AI and TAM-AI in a hypothetical cohort of 60-year-old PM women with BC. Costs, utilities and probabilities were derived from the literature. The hazard ratios (HRs) of AI strategies were applied to a baseline cancer recurrence risk (RR) to determine CE strategies at the $50,000/QALY gain threshold. A direct payer perspective is utilized, and costs and benefits were discounted at 3%. RESULTS: Two-way sensitivity analyses are presented to determine CE strategies across a wide range of HRs and in different clinical scenarios including varying RRs (low, average, high and very high). TAM-AI is the preferred CE strategy at low and average RR, while upfront AI is CE at very high RR. The CE strategy in patients with high RR was dependent on the scenario examined. CONCLUSIONS: This model may help health care providers select CE-adjuvant AI strategies in PM women with BC, until further direct evidence is available from randomized clinical trials.

Anastrozole↗
PubMed2006

From adjuvant to preventive breast cancer treatment: bridging the gap over troubled waters.

Recently, chemoprevention trials have demonstrated the efficacy of preventive medical treatment (PMT) in reducing breast cancer (BC) detection rates in at-risk affected and unaffected women selected according to clinical and/or familial risk criteria, particularly with the use of tamoxifen (TAM). Major concerns limiting the routine use of TAM are the questionable benefit/risk ratio and poor patient compliance, which justify the studies undertaken to determine the efficacy of aromatase inhibitors (AIs) with respect to TAM. Issues such as therapy duration, impact on survival, incidence of side-effects and which subsets benefit most from treatment, still remain unsolved. Therefore, only ER+ BC patients are routinely subjected to PMT, independently of their BRCA1/2 status, using adjuvant hormonal therapy. More attention must be focused towards BRCA1/2 carriers as they are probably the women at highest risk of developing BC, in which available data remain controversial and in which hormone-therapy might be important. Hence, at-risk women (affected patients or unaffected women) should be carefully evaluated for inclusion into highly selected preventive clinical trials aimed at evaluating PMT independently of, or according to, BC predisposition status (unknown, positive or negative BRCA1/BRCA2 status) and with respect to menopausal status. BC patients, harboring a BRCA1/2 predisposition, may represent the best subset for extended adjuvant treatment, useful as PMT, simultaneously. Only the evolving differentiation of categories of at-risk women will allow physicians to discriminate PMT in a highly selective manner.

Breast Neoplasms↗
PubMed1998

Prevention of estrogen carcinogenesis in the hamster kidney by ethinylestradiol: some unique properties of a synthetic estrogen.

Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.

Animals↗
PubMed1999

A dominant-negative mutant of c-Jun inhibits cell cycle progression during the transition of CD4(-)CD8(-) to CD4(+)CD8(+) thymocytes.

While Jun/Fos-containing transcription factors are known to be necessary for many TCR-mediated events in mature T cells, relatively little is known about their roles in thymocyte development. We have generated transgenic mice that express a trans-dominant-negative mutant of c-Jun (TAM-67) specifically in thymocytes. Expression of TAM-67 inhibited the up-regulation of AP-1-responsive genes such as c-jun and IL-2 in stimulated thymocytes from transgenic mice. In addition, altered thymocyte development in TAM-67-expressing mice was revealed by a decrease in thymic cellularity ( approximately 50%) which could be accounted for primarily by a reduction in the number of CD4(+)CD8(+) thymocytes, a large percentage of which retained CD25. The decrease in the number of CD4(+)CD8(+) thymocytes did not appear to be due to an enhanced rate of apoptosis but rather to a decrease in the number of CD4(-)CD8(-)CD25(-) cells in the S + G(2)/M stages of the cell cycle. These results indicate that Jun/Fos-containing transcription factors promote the proliferative burst that accompanies the transition from the CD4(-)CD8(-) to the CD4(+)CD8(+) stage of thymocyte development.

Animals↗
PubMed2003

Thymidine analogue mutations in antiretroviral-naive HIV-1 patients on triple therapy including either zidovudine or stavudine.

AIMS: The aims of this study were to: (i) determine the incidence of thymidine-associated mutations (TAMs) in an observational clinical cohort of naive HIV-1 patients who stopped first-line therapy including either zidovudine or stavudine; and (ii) assess the immunological and virological responses to subsequent second-line therapy in patients who switched from zidovudine to stavudine or conversely. PATIENTS AND METHODS: Plasma samples from 165 patients who stopped first-line antiretroviral therapy containing either zidovudine or stavudine were examined for the presence of drug-resistant genotypes. Subsequent second-line immunological and virological follow-up was performed in 136 patients who switched from zidovudine to stavudine and conversely. RESULTS: Among the 93 patients who stopped first-line therapy including zidovudine and the 72 who stopped first-line therapy including stavudine, genotypic resistance testing was available for 67 (72%) and 54 (75%), respectively. The presence of TAMs was significantly more frequent in the zidovudine than the stavudine group (23.8% versus 5.5; P = 0.006). The short- and long-term immunological and virological responses to second-line therapy were comparable in the zidovudine and stavudine groups, despite different baseline profiles of viral resistance (median increase in CD4 cells/mm3 at 1 year of therapy, 118 versus 119; viral load <400 copies/mL, 47% versus 47%). CONCLUSIONS: These results suggest that TAMs occur in more patients on antiretroviral regimens including zidovudine than on regimens including stavudine. Although the results from observational studies should be interpreted cautiously, these findings may be useful in determining the optimal sequencing of zidovudine and stavudine for the treatment of naive HIV-1-infected patients.

Adolescent↗
PubMed2003

Long-term virological outcome and resistance mutations at virological rebound in HIV-infected adults on protease inhibitor-sparing highly active antiretroviral therapy.

OBJECTIVE: To assess the durability of the undetectability of HIV plasma viraemia (pV) and to determine the factors associated with virological rebound (VR) in HIV-infected adults on protease inhibitor (PI)-sparing highly active antiretroviral therapy (HAART). The development of resistance mutations during virologically successful therapy and VR was also analysed. MATERIALS AND METHODS: One hundred and twenty-six HIV-infected adults on PI-sparing HAART were prospectively followed from April 1998 to December 2002: Group 1, naive for antiretroviral drugs (n = 26); Group 2, previously PI-HAART-exposed patients (n = 19); Group 3, previously exposed to suboptimal therapy (n = 81). Genotypic resistance tests on peripheral blood mononuclear cells or on plasma RNA (when feasible) were carried out when undetectable HIV pV was demonstrated for at least 48 weeks. Additionally, patients showing a therapy adherence >95% developing VR were also tested at rebound, at simplification and during previous suboptimal therapy exposure. RESULTS: The median follow-up time was 630 [329-903] days. VR was considered as two consecutive pV levels >50 copies/mL. Twenty-two (17.5%) patients developed VR. Only therapy adherence <95% was independently associated with VR (adjusted hazard ratio: 8.42; 95% CI: 3.33-21.27). Twenty (40%) of the 50 patients with pV < 50 copies/mL for at least 48 weeks showed at least one thymidine-associated mutation (TAM) but none had NNRTI-resistance mutations. Ten (83.3%) of 12 available adherent patients showing VR harboured NNRTI-resistance-associated mutations; 50% of them were considered as wild-type strains at simplification time. However, the TAM number and resistance mutations profile found on suboptimal exposure were very similar to those found at VR on simplification therapy. CONCLUSIONS: PI-sparing HAART allows maintenance of successful long-term control of HIV replication, adherence to therapy being the main factor associated with VR. However, a small proportion of patients on simplification regimen may develop VR regardless of therapy compliance. VR on PI-sparing HAART is characterized by the emergence of NNRTI cross-resistance mutations. Finally, TAMs 'archived' during previous suboptimal exposures are partially involved in subsequent VR on simplification HAART.

Adult↗
PubMed2002

Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy.

BACKGROUND: Human sulfotransferase 1A1 (SULT1A1) catalyzes the sulfation of a variety of phenolic and estrogenic compounds, including 4-hydroxytamoxifen (4-OH TAM), the active metabolite of tamoxifen. A functional polymorphism in exon 7 of the SULT1A1 gene (SULT1A1*2) has been described that generates an enzyme that has approximately twofold lower activity and is less thermostable than that of the common allele SULT1A1*1. We investigated the hypothesis that that high sulfation activity would increase the elimination of 4-OH TAM by examining whether the presence of this polymorphism affects the efficacy of tamoxifen therapy. METHODS: We examined the relationship between the SULT1A1*2 allele and survival in a cohort of 337 women with breast cancer who received tamoxifen (n = 160) or who did not (n = 177). SULT1A1 genotype was determined by restriction fragment polymorphism analysis. Patient survival was evaluated according to SULT1A1 genotype using Kaplan-Meier survival functions. Hazard ratios (HRs) were calculated from adjusted Cox proportional hazards modeling. All statistical tests were two-sided. RESULTS: Among tamoxifen-treated patients, those who were homozygous for the SULT1A1*2 low-activity allele had approximately three times the risk of death (HR = 2.9, 95% confidence interval [CI] = 1.1 to 7.6) as those who were homozygous for the common allele or those who were heterozygous (SULT1A1*1/*2). Among patients who did not receive tamoxifen, there was no association between survival and SULT1A1 genotype (HR = 0.7, 95% CI = 0.3 to 1.5). CONCLUSIONS: Sulfation of 4-OH TAM provides a previously unanticipated benefit, possibly due to alterations in the bioavailability of the active metabolite or to undefined estrogen receptor-mediated events. These data alternatively suggest that variability in the metabolism of tamoxifen may affect its efficacy.

Adult↗
PubMed1993

Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer.

BACKGROUND: The antioestrogen tamoxifen and progestins act via different receptors and may therefore have complementary effects against human breast cancer. This possibility was tested in a randomized study which compared the effects of tamoxifen, standard-dose megestrol acetate, and these two agents in combination, in patients with metastatic breast cancer. PATIENTS AND METHODS: 184 post-menopausal patients with metastatic breast cancer were randomized to initial treatment with either tamoxifen (TAM) 40 mg daily, megestrol acetate (MA) 160 mgm daily, or the combination of the two administered simultaneously. Patients crossed over to the alternative single agent on relapse or disease progression. Patients were evaluated for response, time to initial and ultimate treatment failure, and survival. RESULTS: There were no significant differences between the three groups with respect to response rates, nor the other parameters. Patient survival was significantly associated with age > 60 years, ER positive status, and the absence of visceral metastases. CONCLUSIONS: TAM and MA are both equally effective in response induction as initial treatments and the combination has no advantage. Sequential treatment is still optimal, TAM being the preferred initial agent in view of the reported side effects with MA.

Aged↗
PubMed1991

Japanese early phase II study of droloxifene in the treatment of advanced breast cancer. Preliminary dose-finding study.

Droloxifene, a new tamoxifen (TAM)-derived compound, has excellent antiestrogenic activity. This compound exhibits less endogenously estrogenic but higher antiestrogenic activity, with better tolerability than TAM in experimental models. Two phase II studies of droloxifene were performed in 47 Japanese institutions to assess the optimal dose. The first was a randomized comparative study using 20, 40, and 80 mg, respectively, once a day. The other was a pilot study using 120 mg once a day. The subjects of both studies were women with primary or recurrent advanced breast cancer, regardless of estrogen receptor status and menopausal status. Of 94 patients enrolled in the comparative study, 22, 26, and 23 were evaluable in the 20-, 40-, and 80-mg groups, respectively. Of the 71 evaluable patients, 14 (19.7%) were negative for estrogen receptor, and 36 (50.7%) had a previous history of TAM therapy. The response rate complete response + partial response (CR + PR) was 13.6% for 20 mg, 15.4% for 40 mg, and 17.4% for 80 mg. The rate of no change (NC) was 31.9%, 46.1%, and 47.8%, and that of progressive disease (PD) was 54.5%, 38.5% and 34.8%, respectively, in the 20-, 40-, and 80-mg groups. In the other study, 16 patients were enrolled in the pilot study with 120 mg of droloxifene, of whom 14 were evaluable. The response rate was slightly higher: four responders (28.6%) were assessed as CR + PR, six (42.9%) as NC, and four (28.6%) as PD. These results suggest that the response rate may be dose-dependent and that PD rates seem lower in the higher doses. No serious side effects were encountered, and droloxifene was well tolerated even in the higher doses. At present, a final randomized dose-finding study with 80 mg/day and 120 mg/day is being carried out.

Adult↗
PubMed1993

Chemohormonal therapy of unresectable hepatocellular carcinoma.

This article reports a prospective randomized controlled study to investigate the effect of sex hormone therapy combined with intra-arterial chemotherapy for hepatocellular carcinoma (HCC). Thirty patients with unresectable HCC were randomly divided into two groups. A catheter was inserted into the hepatic artery of all patients. The first group (group A) was administered 60 mg/m2 of cisplatin (CDDP) on day 15 and 13 mg/m2 of Adriamycin (ADM) on day 1 and 8 postoperatively via the hepatic artery cannula; in addition, a daily dose of 150 mg 5-fluorouracil (5-FU) was administered orally. Tamoxifen (TAM) 25 mg/m2 daily and medroxyprogesterone acetate (MPA) 400 mg/m2 daily were also administered orally. TAM and MPA administration were alternated every 4 weeks. For the second group (group B) the same protocol of anticancer drugs administration, without the hormonal agents, was given. At least three courses of the treatments were carried out. Twelve patients in group A and 14 in group B were evaluated. Partial response of the hepatic tumor to the treatments was observed in 33.3% of group A patients and 21.4% of group B patients, a difference that was not statistically significant. The 1-year survival rate was 44.5% in group A and 33.0% in group B. The performance status of 25% of the patients in group A was significantly improved compared with 14.3% in group B (p < 0.05). TAM- and MPA-combined chemotherapy may not prolong the survival of patients with HCC, although it improves their quality of life.

Administration, Oral↗
PubMed2004

MIV-310 reduces HIV viral load in patients failing multiple antiretroviral therapy: results from a 4-week phase II study.

BACKGROUND: Drug resistance is an increasing problem in the treatment of HIV infection. MIV-310 (alovudine), a nucleoside reverse transcriptase inhibitor, potently inhibits the replication of highly mutated strains of HIV in vitro. We examined the efficacy of MIV-310 in highly pretreated patients. METHODS: In a phase II pilot study, 15 patients failing a current antiretroviral therapy with at least two thymidine-associated mutations (TAM) were given MIV-310 7.5 mg once daily for 4 weeks, in addition to their ongoing treatment. The primary endpoint was the plasma viral load reduction at week 4. RESULTS: At baseline, the median viral load was 3.93 log10 copies/ml and the median CD4 cell count was 360 cells/mm3. After 4 weeks of MIV-310 administration, the median decrease in viral load was -1.13 log10. Interestingly, the median reduction was only -0.57 log10 in the four patients on stavudine, contrasting with a median reduction of -1.88 log10 in the 11 patients not receiving concomitant stavudine. The viral load fell by a median of -1.60 log10 in patients with two to three TAM (n = 7), and by -1.88 log10 in patients with four or five TAM (n = 8). The viral load rebounded in all patients after MIV-310 cessation. No mutations were found in the reverse transcriptase coding region during MIV-310 treatment. MIV-310 was well tolerated, with no serious adverse events and no treatment withdrawals. CONCLUSION: MIV-310 7.5 mg/day efficiently reduced the HIV viral load in patients failing a multiple-drug regimen. Further studies with different dosages and longer administration times are urgently needed.

Adult↗
PubMed1997

Effect of tamoxifen on the pharmacokinetics of doxorubicin in patients with non-Hodgkin's lymphoma.

The authors examined the effect of tamoxifen (TAM), a multiple-drug resistance modulator, on the pharmacokinetics of doxorubicin (DOX) in patients with non-Hodgkin's lymphoma treated according to the CHOP-protocol which included DOX, cyclophosphamide, vincristine, and prednisone. The dose of DOX was 50 mg/m2, but was reduced 25% if the patient was older than 60 years. Of these, 10 randomly-selected patients received a daily dose of 480 mg of TAM (Group-1) and 10 others did not (Group-2). Blood samples were collected at different time intervals, and DOX was measured in plasma by liquid chromatography. The concentration-time data of DOX exhibited the characteristics of the two-compartment open model well. The mean (SEM) values of alpha, beta, k12, k21, k10, Vc, Vss, AUC, total clearance, and mean residence time observed in Group-1 were 4.06 (0.96) hr(-1), 0.0395 (0.0068) hr(-1), 3.13 (0.79) hr(-1), 0.264 (0.052) hr(-1), 0.708 (0.19) hr(-1), 525 (156) l/m2, 1060 (163) l/m2, 1145 (234) microg x hr/l, 49.3 (8.5) l/hr x m2, and 26.8 (6.6) hours, respectively. Those in Group-2 were 4.99 (1.13) hr(-1), 0.0432 (0.0073) hr(-1), 2.46 (0.63) hr(-1), 0.111 (0.026) hr(-1), 2.46 (0.86) hr(-1), 231 (53) l/m2, 812 (149) l/m2, 1690 (276) microg x hr/l, 30.3 (4.1) l/hr x m2, and 29.7 (5.1) hours, respectively. Of these parameters, the difference between the two groups was significant (p < or = 0.0169) only in k21. Thus, the coadministration of TAM at the earlier-mentioned dose appears generally to have no significant influence on the pharmacokinetics of doxorubicin when used in the CHOP-protocol.

Adult↗
PubMed2006

Differential impact of thymidine analogue mutations on emtricitabine and lamivudine susceptibility.

The impact of drug resistance-associated mutations on subsequent antiretroviral therapy is an important consideration in managing treatment-experienced, HIV-1-infected patients. Lamivudine (3TC) and emtricitabine (FTC) are structurally related nucleoside reverse transcriptase inhibitors (NRTIs) approved for use in HIV-1-infected individuals. To evaluate whether susceptibility differences exist between lamivudine and emtricitabine, the phenotypic impact of common NRTI resistance-associated mutations was compared in HIV-1 from patient samples with paired FTC and 3TC susceptibility results. FTC phenotypic susceptibility was more greatly impacted than 3TC susceptibility in the presence of thymidine analogue mutations (TAMs), as the mean fold-change values were higher for FTC than for 3TC in groups of samples containing TAMs (P < 0.001 for 6 of 7 groups). For samples with K65R, L74I/V, or Q151M mutations, the phenotypic impact was similar, as the mean fold-change was not significantly different between drugs. Although the long-term clinical significance of these differences is unclear, they may suggest differential efficacy in some patients with prior NRTI experience, especially those with HIV harboring TAMs.

Anti-HIV Agents↗
PubMed1996

The Drosophila tamou gene, a component of the activating pathway of extramacrochaetae expression, encodes a protein homologous to mammalian cell-cell junction-associated protein ZO-1.

In Drosophila sensory organ development, the balance of activities between proneural genes and repressor genes defines a proneural cluster as a population of competent cells for neural development. In this study, we report the isolation and analysis of the tamou (tam) gene that encodes a cell-cell junction-associated protein, which is homologous to mammalian ZO-1, a member of the membrane-associated guanylate kinase homolog family. The tam mutation reduces the transcription of a repressor gene, extramacrochaetae, and causes enlargement of a proneural cluster where supernumerary precursor cells emerge, resulting in extra mechanosensory organs in the fly. These results suggest that the membrane-associated Tam protein is involved in the signaling pathway that activates emc expression.

Amino Acid Sequence↗