Biomedical subjects

C H Nguyen

Publications and source records attributed to C H Nguyen.

At least 19 recordsLinked to original sources

PubMed2001

De novo establishment and cost-effectiveness of Papanicolaou cytology screening services in the Socialist Republic of Vietnam.

BACKGROUND: Cervical carcinoma is the leading cause of cancer-related death among women in the developing world. The absence of cervical screening in Vietnam and other developing countries is due in large part to the perceived expense of implementing Papanicolaou cytology screening services, although, to the authors' knowledge, the cost-effectiveness of establishing such services has never been studied in a developing country. METHODS: Using decision analytic methods, the authors assessed cost-effectiveness of Pap screening from a societal perspective in Vietnam, the world's 9th most populous developing country (estimated 1999 population, 79 million). Outcomes measured included life expectancy, cervical carcinoma incidence, cost per woman, and cost-effectiveness. RESULTS: Total costs to establish a nationwide 5-year interval Pap screening program in Vietnam will average less than $148,400 annually during the 10-year time period assumed necessary to develop the program and may be considerably lower if only high risk geographic areas are targeted. Maintenance costs will average less than $0.092 annually per woman in the target screening population. Assuming 70% program participation, cervical carcinoma incidence will decrease from 26 in 100,000 to 14.8 in 100,000, and cost-effectiveness will be $725 per discounted life-year. Several assumptions used in this analysis constitute biases against the effectiveness of Pap screening, which in reality may be significantly more cost-effective than reported here. CONCLUSIONS: Contrary to widespread belief, Pap screening in developing countries such as Vietnam is extraordinarily inexpensive and appears to be cost-effective. Because prospects are uncertain regarding useful alternatives to the Pap test, the evidence-based argument for establishing conventional Pap screening services in developing countries such as Vietnam is compelling. Population-based conventional Pap screening services have been established de novo in Vietnam and are now operational.

Adult↗

PubMed2001

Antiviral activity of 4-benzyl pyridinone derivatives as HIV-1 reverse transcriptase inhibitors.

In this overview, the antiviral properties of the Curie-pyridinone compounds, a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) developed as anti-HIV agents, are described. These compounds are hybrids between hydroxyethoxymethyl-phenylthiothymine (HEPT) and Merck pyridinones. Several structure-activity relationships (SAR) studies between HIV-1 reverse transcriptase (RT) and the Curie-pyridinones are described. The Curie-pyridinones are potent inhibitors of both HIV-1 replication in cell culture and of HIV-1 RT activity in vitro. They are specific to HIV-1 and do not inhibit the replication of HIV-2. The mechanism of inhibition is non-competitive with respect to the natural substrate dGTP. For these reasons, the Curie-pyridinones can be considered as non-nucleoside inhibitors of HIV-1 RT. Moreover, they have the unusual ability to reach the reverse transcription complex inside the extracellular virions and may therefore be useful as retrovirucides. This might lead to the design and synthesis of new drugs able to interact with the retroviral enzyme inside the viral core.

Journal Article↗

PubMed2000

Synthesis and antiviral activity of 4-benzyl pyridinone derivatives as potent and selective non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors.

Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde derivatives. Biological studies revealed that some of the new 4-benzylpyridinones show potent HIV-1 specific reverse transcriptase inhibitory properties. Compounds 14, 19, and 27, which inhibit the replication of HIV-1 in CEM-SS cells, with IC(50) values ranging from 0.2 to 6 nM are the most active compounds in this series. Biochemical studies showed that compound 27 strongly inhibited the activity of a recombinant HIV-1 RT. Moreover, the infectivity of isolated HIV-1 particles was severely decreased after exposure to compound 27. Although cross resistance is frequently observed between non-nucleoside reverse transcriptase inhibitors, compound 27 was capable of inhibiting a virus resistant to nevirapine with an IC(50) of 40 nM.

Anti-HIV Agents↗

PubMed2000

Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase.

To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. In marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC(50) = 0.45 microM) against HIV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was observed for these bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respective sites. Interestingly, however, the results indicate that the AZT-HEPT conjugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the former compounds interact preferentially with the hydrophobic pocket in RT, whereas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.

Anti-HIV Agents↗

PubMed2000

A new family of sequence-specific DNA-cleaving agents directed by triple-helical structures: benzopyridoindole-EDTA conjugates.

Sequence-specific DNA recognition can be achieved by oligonucleotides that bind to the major groove of oligopyrimidine x oligopurine sequences. These intermolecular structures could be used to modulate gene expression and to create new tools for molecular biology. Here we report the synthesis and biochemical characterization of triple helix-specific DNA cleaving reagents. It is based on the previously reported triplex-specific ligands, benzo[e]pyridoindole (BePI) and benzo[g]pyridoindole (BgPI), covalently attached to ethylenediaminotetraacetic acid (EDTA). In the presence of iron, a reducing agent and molecular oxygen, BgPI-EDTA x FeII but not BePI-EDTA x FeII induced a double-stranded cut in a plasmid DNA at the single site where a triplex-forming oligonucleotide binds. At single nucleotide resolution, it was found that upon triplex formation BePI-EDTA x FeII led to cleavage of the pyrimidine strand and protection of the purine strand. BgPI-EDTA x FeII cleaved both strands with similar efficiency. The difference in cleavage efficiency between the two conjugates was rationalized by the location of the EDTA x FeII moiety with respect to the grooves of DNA (major groove: BePI-EDTA x FeII, minor groove: BgPI-EDTA x FeII). This work paves the way to the development of a new class of triple helix directed DNA cleaving reagents. Such molecules will be of interest for sequence-specific DNA cleavage and for investigating triple-helical structures, such as H-DNA, which could play an important role in the control of gene expression in vivo.

DNA↗

PubMed2000

Incidence of childhood cancer in Ho Chi Minh City, Vietnam, 1995-97.

Incidence rates of childhood cancer for the city of Ho Chi Minh are presented for the first time. For the 3-year period 1995-97, a total of 302 cancer cases were registered in children under 15 years of age, with a male to female ratio of 1.1. The overall crude rate was 78.8 and the age-standardised incidence rate was 88.4 per million person-years, which was low in comparison with other countries in eastern Asia and with the predominantly white population of Australia. Leukaemia (principally acute lymphocytic), brain tumours and lymphomas were the most common childhood neoplasms, which is consistent with the pattern observed in other registries of the region. The rate of retinoblastoma was higher than in the other regional registries. On the other hand, no cases of hepatocellular carcinoma were registered.

Adolescent↗

PubMed2000

Outcomes of contact investigations of infectious tuberculosis patients.

The objective of this study was to describe outcomes of tuberculosis (TB) contact investigations, factors correlated with those outcomes, and current successes and ways to improve TB contact investigations. We abstracted clinic records of a representative U.S. urban sample of 1,080 pulmonary, sputum-smear(+) TB patients reported to CDC July 1996 through June 1997 and the cohort of their 6,225 close contacts. We found a median of four close contacts per patient. Fewer contacts were identified for homeless patients. A visit to the patient's residence resulted in two additional (especially child) contacts identified. Eighty-eight percent of eligible contacts received tuberculin skin tests (TSTs). Recording the last exposure date to the infectious patient facilitated follow-up TST provision. Thirty-six percent of contacts were TST(+). Household contacts and contacts to highly smear(+) or cavitary TB patients were most likely to be TST(+). Seventy-four percent of TST(+) contacts started treatment for latent TB infection (LTBI), of whom 56% completed. Sites using public health nurses (PHNs) started more high-risk TST(-) contacts on presumptive treatment for LTBI. Using directly observed treatment (DOT) increased the likelihood of treatment completion. We documented outcomes of contact investigation efforts by urban TB programs. We identified several successful practices, as well as suggestions for improvements, that will help TB programs target policies and procedures to enhance contact investigation effectiveness.

Adolescent↗

PubMed1999

Effect of nucleoside analogs and non-nucleoside inhibitors of HIV-1 reverse transcriptase on cell-free virions.

Reverse transcription takes place in the cytoplasm of infected cells, although it has been demonstrated that retroviruses can also initiate reverse transcription prior to infection of target cells. In addition to partial reverse transcripts, full-length proviral molecules have been detected in the plasma and seminal fluid of HIV-1 seropositive patients. Intravirion endogenous reverse transcription appears to be directly correlated with an increased level of infectivity. Therefore, the ability of an inhibitor to reach and inhibit the replication complex in the core of the free-virion may constitute an important part of its capacity to suppress viral infection. In this work we tested the ability of some reverse transcriptase inhibitors to decrease viral infectivity in pretreated highly purified virions. Our results showed that Curie pyridinone [Dollé et al. (1995), J Med Chem 38: 4,679-4,686], a non nucleoside RT inhibitor, strongly inhibited the infectivity of extracellular HIV-1 particles. Other non nucleoside inhibitors (TIBO R82913, HEPT, nevirapine) tested in these conditions were unable to do so. Our data indicate that the effect of Curie pyridinone on intact virions may be related to its capacity to tightly bind the target RT. This approach may lead to the design and synthesis of new drugs able to interact with the retroviral enzyme inside the viral core.

Anti-HIV Agents↗

PubMed1999

Design of a triple-helix-specific cleaving reagent.

BACKGROUND: Double-helical DNA can be recognized sequence specifically by oligonucleotides that bind in the major groove, forming a local triple helix. Triplex-forming oligonucleotides are new tools in molecular and cellular biology and their development as gene-targeting drugs is under intensive study. Intramolecular triple-helical structures (H-DNA) are expected to play an important role in the control of gene expression. There are currently no good probes available for investigating triple-helical structures. We previously reported that a pentacyclic benzoquinoquinoxaline derivative (BQQ) can strongly stabilize triple helices. RESULTS: We have designed and synthesized the first triple-helix-specific DNA cleaving reagent by covalently attaching BQQ to ethylenediaminetetraacetic acid (EDTA). The intercalative binding of BQQ should position EDTA in the minor groove of the triple helix. In the presence of Fe(2+) and a reducing agent, the BQQ-EDTA conjugate can selectively cleave an 80 base pair (bp) DNA fragment at the site where an oligonucleotide binds to form a local triple helix. The selectivity of the BQQ-EDTA conjugate for a triplex structure was sufficiently high to induce oligonucleotide-directed DNA cleavage at a single site on a 2718 bp plasmid DNA. CONCLUSIONS: This new class of structure-directed DNA cleaving reagents could be useful for cleaving DNA at specific sequences in the presence of a site-specific, triple-helix-forming oligonucleotide and also for investigating triple-helical structures, such as H-DNA, which could play an important role in the control of gene expression in vivo.

Base Pairing↗

PubMed1998

Cancer incidence in Ho Chi Minh City, Viet Nam, 1995-1996.

The results from the population-based cancer registry for the city of Ho Chi Minh in 1995-1996 represent the first information on the incidence of cancer in southern Viet Nam. A total of 4,080 cancer cases in males and 4,338 in females were registered, corresponding to age-standardized incidence rates (ASRs) of 130.9 per 100,000 in men and 100.7 per 100,000 in women. As elsewhere in South East Asia, the principal cancer of men was liver cancer (ASR 25.3), with moderately high rates of lung cancer (ASR 24.6) and stomach cancer (ASR 16.5); cancer of the penis, reportedly very common in early case series from Viet Nam, is now rarely seen. In women, cervical cancer was the dominant malignancy (ASR 26.0) followed by breast cancer (ASR 12.2) and stomach cancer (ASR 7.5). Although there may be some under-registration in these early years of operation, the recorded rates of cervical cancer and liver cancer are already high and suggest that southern Viet Nam would benefit from an effective cervical cancer screening programme, as well as efforts to interrupt the transmission of hepatitis B virus to reduce liver cancer incidence and effective anti-smoking programs.

Adolescent↗

PubMed1998

Triple helices formed at oligopyrimidine*oligopurine sequences with base pair inversions: effect of a triplex-specific ligand on stability and selectivity.

Oligonucleotide-directed triple helix formation is mostly restricted to oligopyrimidine*oligopurine sequences of double helical DNA. An interruption of one or two pyrimidines in the oligopurine target strand leads to a strong triplex destabilisation. We have investigated the effect of nucleotide analogues introduced in the third strand at the site opposite the base pair inversion(s). We show that a 3-nitropyrrole derivative (M) discriminates G*C from C*G, A*T and T*A in the presence of a triplex-specific ligand (a benzo[e]pyridoindole derivative, BePI). N6-methoxy-2,6-diaminopurine (K) binds to an A*T base pair better than a T*A, G*C or C*G base pair. Some discrimination is still observed in the presence of BePI and triplex stability is markedly increased. These findings should help in designing BePI-oligonucleotide conjugates to extend the range of DNA sequences available for triplex formation.

Chromosome Inversion↗

PubMed1998

Rational design of a triple helix-specific intercalating ligand.

DNA triple helices offer new perspectives toward oligonucleotide-directed gene regulation. However, the poor stability of some of these structures might limit their use under physiological conditions. Specific ligands can intercalate into DNA triple helices and stabilize them. Molecular modeling and thermal denaturation experiments suggest that benzo[f]pyrido[3, 4-b]quinoxaline derivatives intercalate into triple helices by stacking preferentially with the Hoogsteen-paired bases. Based on this model, it was predicted that a benzo[f]quino[3,4-b]quinoxaline derivative, which possesses an additional aromatic ring, could engage additional stacking interactions with the pyrimidine strand of the Watson-Crick double helix upon binding of this pentacyclic ligand to a triplex structure. This compound was synthesized. Thermal denaturation experiments and inhibition of restriction enzyme cleavage show that this new compound can indeed stabilize triple helices with great efficiency and specificity and/or induce triple helix formation under physiological conditions.

Animals↗

PubMed1998

A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria.

To investigate the pharmacokinetic and pharmacodynamic properties of artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) in Plasmodium vivax infections, 12 male Vietnamese adults with slide-positive vivax malaria received either intravenous ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2) with the alternative preparation given 8 hr later in a randomized, open, cross-over study. Following intravenous injection, ARTS had a peak plasma drug concentration (Cmax) of 35.6 microM (13.7 mg/L), an elimination half-life (t1/2) of 2.2 min, a clearance (CL) of 3.0 L/hr/kg, and a volume of distribution (V) of 0.16 L/kg. Dihydroartemisinin had a Cmax of 7.7 microM (2.2 mg/L), a tmax of 8 min, a t1/2 of 37 min, an apparent CL of 1.1 L/hr/kg, and an apparent V of 0.9 L/kg. Following oral ARTS, the mean relative bioavailability of DHA was 85%, the Cmax was 3.0 microM (0.85 mg/L), the tmax was 75 min, and t1/2 was 40 min. The mean time to 50% reduction in the parasite count (PCT50) and median fever clearance time were 3 hr and 16 hr, respectively. Following intravenous ARTS (group 1), the PCT50 for total parasites, rings, trophozoites, and gametocytes was 3.3 hr, 3.2 hr, 4.0 hr, and 3.6 hr, respectively. This study confirms that ARTS is effective against P. vivax, with rapid clearance of sexual and asexual forms of the parasite. Artesunate is a suitable initial treatment for vivax malaria, or when the plasmodial species cannot be reliably identified.

Administration, Oral↗

PubMed1998

1-Amino-substituted 8-hydroxy-4,5-dimethyl-5H-pyrido[4,3-b]indoles with propyl- or methyl substituents at the 9-, and 7,9-positions: synthesis and biological evaluation.

The title compounds were synthesized in 9-10 steps in order to compare their cytotoxic properties to that for 1-(3-dimethylaminopropyl)-amino-4,5-dimethyl- 8-hydroxy-5H-pyrido[4,3-b]indole. Whereas the latter is a potent cytotoxic agent, displaying significant antitumour activity, the corresponding 9-propyl (and 7,9-dimethyl) derivatives were found to be > 10-fold less cytotoxic.

Animals↗

PubMed1998

Synthesis, properties and biological evaluation of substituted furo[3,2-e] and pyrano[3,2-e]pyrido[4,3-b]indoles.

Furo[3,2-e]- and pyrano[3,2-e]pyrido[4,3-b] indoles were synthesized from 1,4,5-trisubstituted 8-hydroxy-5H-pyrido[4,3-b]indoles. The intermediates, 10-chloro-6H-furo[3,2-e]pyrido[4,3-b]indole (11), 10-chloro-2,6-dihydro-1H-furo[3,2-e]pyrido-[4,3-b]indole (10) and 11-chloro-2,3-dihydro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (15), were substituted by diamines under thermal conditions (180 degrees C). In contrast, 11-chloro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (14), 9-allyl-1-chloro-4,5-dimethyl-5H-pyrido[4,3-b]indole (9a) and 8-propargyloxy-4,5-dimethyl-5H-pyrido[4,3-b]indole (8) led mainly to 1-aminosubstituted 8-hydroxy-5H-pyrido[4,3-b]indole derivatives resulting from an unexpected C3 unit elimination. When examined in three tumour cell lines (L1210 leukaemia, the B16 melanoma and the MCF7 breast adenocarcinoma) the new amino substituted furo[3,2-e]-, dihydrofuro[3,2-e]- and dihydropyrano[3,2-e]-pyrido[4,3-b]indole derivatives revealed cytotoxic properties, especially important for the 2,6-dihydro-1H-furo[3,2-e]pyrido[4,3-b]indole series. The most active compound (12b) significantly inhibits both DNA topoisomerases I and II, and is as potent as Adriamycin at inhibiting cell proliferation and inducing a massive accumulation of L1210 cells in the G2 + M phase of the cell cycle. However, 12b was less active than Adriamycin when tested in vivo against P388 leukaemia or the B16 melanoma tumour models.

Animals↗

PubMed1997

Complementary advantages of fluorescence and SIMS microscopies in the study of cellular localization of two new antitumor drugs.

Low light level fluorescence microscopy studies have been carried out on MCF7-P human mammary tumor cells to localize the intracellular distribution of two new anticancer drugs, Pazelliptine and Intoplicine, which are currently under clinical evaluation. These two molecules are thought to act at the nuclear level, through DNA topoisomerase interactions. Because fluorescence of these compounds appears strongly quenched by intercalation in double strand DNA, secondary ion mass spectrometry (SIMS) imaging was used to check the presence of the drugs in the nuclear compartment. In spite of chemical structure similitudes, pazelliptine and intoplicine appear to be distributed in quite different ways within the cells. Incubation for 1 and 24 hours also allowed us to bring to light strong differences in the distribution kinetics. Pazelliptine quickly enters into the nucleoli but is no longer present in the nucleus after 24 hours incubation. Intoplicine was not detected by fluorescence in the nucleus, however SIMS microscopy allowed us to show its accumulation within this cellular compartment as a function of time of exposure. This study shows the complementarity of fluorescence and SIMS microscopies.

Antineoplastic Agents↗

PubMed1996

Ligand-induced formation of triple helices with antiparallel third strands containing G and T.

We have examined the effects of benzopyridoindole derivatives on triple helices with antiparallel third strands. Absorption spectroscopy, footprinting, and gel retardation experiments demonstrate that a benzopyridoindole derivative (BePI) is able to induce formation of a triple helix with an antiparallel (G, T)-containing third strand, which does not form in the absence of this ligand. This triple-helical complex is very stable with a half-dissociation temperature as high as 51 degrees C, and its formation is pH independent. Antiparallel oligonucleotides containing thymine and guanine bind strongly to double-helical DNA under physiological conditions in the presence of only 0.5 microM BePI. Formation of a BePI-stabilized triple helix strongly inhibits cleavage of the target duplex by DNase I.

Base Sequence↗

PubMed1996

Stabilization of triple helical DNA by a benzopyridoquinoxaline intercalator.

Biophysical, footprinting, and chemical probing experiments are described which characterize the triple helix-stabilizing effects of a benzo[f]pyridoquinoxaline derivative BfPQ-4,3 structurally related to the previously reported benzo[f]pyridoindole compound BePI [Mergny et al. (1992) Science 256, 1681-1684]. Two parallel triple helix model systems have been investigated; one in which the third strand matched perfectly a 27 base pair purine-pyrimidine motif in target DNA and another in which the third strand was one nucleotide longer, i.e., a 28-mer. In the latter system, the pairing of the (Y)28 third strand to the (Y.R)27 target induces the formation of a bulge containing at least one unpaired base, which can be evidenced by chemical probing experiments with osmium tetroxide. BPQ, which uinwinds a duplex DNA by 17 degrees as judged by viscometric experiments and otherwise behaves as a typical nonspecific intercalculating drug, promotes the formation of Y.R.Y parallel triple helix containing both T.A.T and C.G.C+ triplets. Both DNase I and MPE.FeII footprinting experiments concur that triplex formation with the target (Y.R)27 sequence can be detected in the presence of BPQ at about 10-fold lower oligonucleotide concentrations than are required to produce an equivalent footprint in the absence of the drug. In addition, BPQ will promote binding to the polypurine-polypyrimidine target sequence by the longer mismatched oligonucleotide, providing significant stabilization of the parallel bulge-containing(Y.R)27,(Y)28 triplex with nearly the same efficiency as the bulge-free (Y.R)27.(Y)28 triplex. Thus in vivo BPQ might enhance the formation of both undesired and desired DNA triplexes. By performing an MPE*FeII probing reaction with a 5'-32 P-labeled oligonucleotide third strand, we have obtained evidence that BPQ is actually bound to the triplex region and may distort in a sequence-specific fashion.

Base Sequence↗