Catalytic organometallic anticancer complexes.

Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a sigma-donor/pi-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich "piano-stool" ruthenium arene complexes [(eta(6)-arene)Ru(azpy)I](+) (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenyl- or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine Ru(II) complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential -0.2 to -0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.

Can current national surveillance systems in England and Wales monitor sexual transmission of hepatitis C among HIV-infected men who have sex with men?

BACKGROUND: Recent reports suggest an increase in sexually-transmitted hepatitis C infection among HIV-infected men who have sex with men (MSM) in European cities. We investigated whether current national surveillance systems in England and Wales (E&W) are able to monitor sexual transmission of hepatitis C infection among HIV-infected MSM. METHODS: Routine laboratory reports of hepatitis C diagnoses and data from sentinel hepatitis C testing surveillance were matched to HIV diagnosis reports to determine: (i) the number of MSM diagnosed with HIV and hepatitis C (1996-2003); (ii) the number of HIV-diagnosed MSM tested for hepatitis C and found to be positive at sentinel sites (2003). RESULTS: (i) Between 1996-2003, 38,027 hepatitis C diagnoses were reported; 25,938 (68%) were eligible for matching with HIV diagnoses. Thirty-one men (four in London) had both a HIV and hepatitis C diagnosis where the only risk was sex with another man. Numbers of "co-diagnosed" MSM increased from 0 in 1996 to 14 in 2003. The majority of MSM (22/31) tested hepatitis C positive after HIV diagnosis. (ii) Of 78,058 test results from sentinel hepatitis C testing sites in 2003, 67,712 (87%) were eligible for matching with HIV diagnoses. We identified 242 HIV-diagnosed MSM who did not inject drugs who tested for hepatitis C in 2003; 11 (4.5%) tested hepatitis C positive (95% CI: 2.3%-8.0%). Applying this percentage to all MSM seen for HIV-related care in E&W in 2003, an estimated 680 MSM living with diagnosed HIV would have tested positive for sexually-transmitted hepatitis C (95% CI: 346-1208). CONCLUSION: Matching routine laboratory reports of hepatitis C diagnoses with HIV diagnoses only identified 31 HIV infected MSM with sexually-transmitted hepatitis C infection. Clinical studies suggest that this is an underestimate. On the other hand, matching sentinel surveillance reports with HIV diagnoses revealed that in E&W in 2003 nearly 5% of HIV-diagnosed MSM tested hepatitis C positive where the only risk was sex with another man. Reports of sexually-transmitted hepatitis C infection were not confined to London. Enhanced surveillance is needed to monitor sexually-transmitted hepatitis C among HIV-infected MSM in E&W.

Sexually transmitted infections in Western Europe among HIV-positive men who have sex with men.

BACKGROUND: Since 1996, there has been a resurgence in sexually transmitted infections (STIs) among men who have sex with men (MSM) in Western Europe. This has coincided with a significant decrease in HIV-associated mortality following the introduction of highly active antiretroviral therapies (HAART) and a corresponding increase in the number of MSM living with HIV. Levels of unprotected anal intercourse have also increased. In this article, we use STI surveillance data from a number of Western European countries to better understand the contribution of HIV-positive MSM to the recent increase in STIs. METHODS: Published literature, surveillance reports, and ad hoc publications relating to HIV prevalence trends and STIs among HIV-positive MSM in Western Europe were reviewed. RESULTS: Post-HAART, HIV prevalence among community samples of MSM ranged from 5% to 18%. HIV prevalence among MSM diagnosed with an STI was substantially higher. On average, HIV prevalence among MSM diagnosed with syphilis in 11 countries was 42% (range 14%-59%). Most HIV-positive MSM with syphilis were aware of their HIV status. In England and Wales, 32% of MSM with gonorrhea were HIV-positive in 2004. Outbreaks of lymphogranuloma venereum have been documented in 9 countries; HIV-positive MSM accounted for 75% of cases on average (range 0%-92%). Cases of sexually transmitted hepatitis C have been predominantly identified among HIV-positive MSM in Rotterdam, Paris, Amsterdam, and the United Kingdom. CONCLUSIONS: In Western Europe, STIs have been disproportionately diagnosed among HIV-positive MSM post-HAART. Improved survival coupled with serosorting among HIV-positive MSM appears to explain the high prevalence of HIV among MSM with STIs. STI transmission among HIV-positive men will have contributed substantially to increasing STI trends seen among MSM in Western Europe, since 1996. These findings highlight the need for routine STI testing among HIV-positive MSM as well as safer sex messages highlighting the implications of STI coinfection.

Does the recent increase in HIV diagnoses among men who have sex with men in the UK reflect a rise in HIV incidence or increased uptake of HIV testing?

OBJECTIVES: To determine whether the increase in HIV diagnoses since 1997 among men who have sex with men (MSM) in the UK reflects a rise in HIV incidence or an increase in HIV testing. METHODS: Estimates of HIV incidence were derived using data from UK HIV surveillance systems (HIV diagnoses; CD4 surveillance; unlinked anonymous surveys) for 1997-2004. Data on HIV testing were provided by KC60 statutory returns, voluntary testing and unlinked anonymous surveys in sentinel genitourinary medicine (GUM) clinics. RESULTS: HIV diagnoses among MSM in the UK rose by 54% between 1997 and 2004 (from 1382 to 2124), with variation by age and geographical location. The number of HIV diagnoses among MSM <35 years of age in London showed no increase, but in all other groups it increased. Throughout the UK, uptake of HIV testing increased significantly among MSM attending GUM clinics between 1997 and 2004, including "at-risk" MSM (p<0.001). Direct incidence estimates (serological testing algorithm for recent HIV seroconversion assay) provided no evidence of a statistically significant increase or decrease in HIV incidence. Indirect estimates suggested that there may have been a rise in HIV incidence, but these estimates were influenced by the increased uptake of HIV testing. CONCLUSIONS: The number of HIV diagnoses increased among MSM in the UK between 1997 and 2004, except among younger MSM in London, in whom there was no change. The increase in HIV diagnoses among MSM in the UK since 1997 seems to reflect an increase in HIV testing rather than a rise in HIV incidence.

Phenylazo-pyridine and phenylazo-pyrazole chlorido ruthenium(II) arene complexes: arene loss, aquation, and cancer cell cytotoxicity.

Ru(II) eta6-arene complexes containing p-cymene (p-cym), tetrahydronaphthalene (thn), benzene (bz), or biphenyl (bip), as the arene, phenylazopyridine derivatives (C5H4NN:NC6H5R; R = H (azpy), OH (azpy-OH), NMe2 (azpy-NMe2)) or a phenylazopyrazole derivative (NHC3H2NN:NC6H5NMe2 (azpyz-NMe2)) as N,N-chelating ligands and chloride as a ligand have been synthesized (1-16). The complexes are all intensely colored due to metal-to-ligand charge-transfer Ru 4d6-pi* and intraligand pi -->pi* transitions (eta = 5000-63 700 M-1 cm-1) occurring in the visible region. In the crystal structures of [(eta6-p-cym)Ru(azpy)Cl]PF6 (1), [(eta6-p-cym)Ru(azpy-NMe2)Cl]PF6 (5), and [(eta6-bip)Ru(azpy)Cl]PF6 (4), the relatively long Ru-N(azo) and Ru-(arene-centroid) distances suggest that phenylazopyridine and arene ligands can act as competitive pi-acceptors toward Ru(II) 4d6 electrons. The pKa* values of the pyridine nitrogens of the ligands are low (azpy 2.47, azpy-OH 3.06 and azpy-NMe2 4.60), suggesting that they are weak sigma-donors. This, together with their pi-acceptor behavior, serves to increase the positive charge on ruthenium, and together with the pi-acidic eta6-arene, partially accounts for the slow decomposition of the complexes via hydrolysis and/or arene loss (t(1/2) = 9-21 h for azopyridine complexes, 310 K). The pKa* of the coordinated water in [(eta6-p-cym)Ru(azpyz-NMe2)OH2]2+ (13A) is 4.60, consistent with the increased acidity of the ruthenium center upon coordination to the azo ligand. None of the azpy complexes were cytotoxic toward A2780 human ovarian or A549 human lung cancer cells, but several of the azpy-NMe2, azpy-OH, and azpyz-NMe2 complexes were active (IC50 values 18-88 microM).

Past it? HIV and older people in England, Wales and Northern Ireland.

The majority of those infected and affected by HIV are younger adults. The ability of highly active antiretroviral therapies (HAART) to extend survival means that those infected when younger may reach older age, and future increases in numbers of older individuals living with HIV in England, Wales and Northern Ireland (E,W&NI) are expected. Evidence that older individuals engage in risky sexual behaviours suggests potential for HIV transmission. Data from national HIV/AIDS surveillance systems were reviewed (1997-2001). An older individual is defined as aged 45 years or over. Between 1997 and 2001, 2290 older individuals were diagnosed with HIV; 361 in 1997, rising to 648 in 2001. Heterosexual acquisition accounted for 1073 (47%) infections; 662 were male. Where reported, 666 (65%) older heterosexuals were probably infected in Africa, 144 (14%) in the United Kingdom and 113 (11%) in Asia. There were 1020 (45%) new diagnoses acquired homosexually; white (92%), infected in the United Kingdom (78%). Numbers of older individuals accessing HIV-related services more than doubled between 1997 (2488) and 2001 (5175). In 2001, 2270 (53%) were London residents. Between 1997 and 2001, among HIV-infected older individuals attending genitourinary medicine (GUM) clinics, the proportions previously undiagnosed were 60% and 82% in heterosexual males and females respectively, and for men who have sex with men (MSM), 42%. Numbers of older individuals newly diagnosed with HIV have increased in recent years. The increase in numbers of older individuals accessing HIV-related services were in excess of younger adults. A significant proportion of older HIV-infected female heterosexuals and MSM were undiagnosed. Awareness must be raised among clinicians, and an 'aged response' to HIV is required.