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Biomedical subjects

D Maher

Publications and source records attributed to D Maher.

At least 19 recordsLinked to original sources
PubMed2001

Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa.

BACKGROUND: Tuberculosis is a leading cause worldwide of morbidity and mortality among HIV-infected people. The HIV era has seen a dramatic increase of the tuberculosis case fatality rate (CFR) in high HIV prevalence populations. Providing care for HIV-infected people must include measures to tackle this high tuberculosis CFR. AIMS: To analyse the extent of the increased tuberculosis CFR in high HIV prevalence populations in sub-Saharan Africa, the reasons for this increase and the causes of death, in order to identify possible ways of tackling this problem. METHODS: References were obtained by searching the MEDLINE on 'tuberculosis', 'HIV infection', and 'mortality' (MesH or textword). In addition, available data from National Tuberculosis Programme reports were reviewed. FINDINGS: Tuberculosis CFR is closely linked to HIV prevalence. Limited autopsy data suggest that death from HIV-related diseases other than tuberculosis is probably the main reason for the increased CFR in HIV-infected tuberculosis patients. Among HIV-infected tuberculosis patients, the higher tuberculosis CFR in sputum smear-negative and extrapulmonary than in sputum smear-positive tuberculosis cases can also be attributed to misdiagnosis of HIV-related diseases as tuberculosis. The adverse effect of the HIV/AIDS epidemic on general health service performance probably accounts for the higher tuberculosis CFR among HIV-negative tuberculosis patients in high prevalence populations than that in low HIV-prevalence populations. CONCLUSION: Tackling the problem of the increased tuberculosis CFR in high HIV prevalence populations requires collaboration between tuberculosis control and HIV/AIDS programmes in implementing measures such as improved health services, tuberculosis and HIV control services, preventive treatment for HIV-related diseases and anti-HIV treatment.

AIDS-Related Opportunistic Infections↗
PubMed2000

A randomized, double blind study in young healthy adults comparing cell mediated and humoral immune responses induced by influenza ISCOM vaccines and conventional vaccines.

Although current influenza vaccines have been shown to reduce influenza-related morbidity and mortality, there is a desire to develop more efficacious products. Vaccines which can induce CD8(+) cytotoxic T cell (CTL) responses in addition to strong antibody responses may be more effective in preventing disease since it has been demonstrated that CTL contribute to protective immunity, even against drift variants of influenza A viruses. The immunogenicity of two types of experimental influenza vaccines, which were based on immune stimulating complexes (ISCOM), were evaluated and compared with a conventional non-adjuvanted inactivated split virion vaccine, after immunization of human volunteers. In this randomized, double blind study, it was shown that the ISCOM vaccines altered the kinetics of the serum antibody response, resulting in more rapid titer rises against the vaccine strains. This accelerated antibody response coincided with enhanced in vitro proliferative T cell responses, which were observed shortly after vaccination. In addition, CTL responses were observed in a higher proportion of the vaccinees receiving an ISCOM vaccine, than in vaccinees receiving the conventional influenza vaccine.

Adjuvants, Immunologic↗
PubMed2000

N-[2-(4-methylphenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea as a potent inhibitor of NNRTI-resistant and multidrug-resistant human immunodeficiency virus type 1.

The composite non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket model was used to study a number of thiourea analogues with different substitutions at the 4-phenyl position including N-[2-(4-methylphenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-244), which inhibited recombinant RT better than trovirdine or compound HI-275 with an unsubstituted phenyl ring. HI-244 effectively inhibited the replication of HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells with an IC50 value of 0.007 microM, which is equal to the IC50 value of trovirdine. Notably, HI-244 was 20 times more effective than trovirdine against the multidrug-resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V, 41L and 215Y) and seven times more potent than trovirdine against the NNRTI-resistant HIV-1 strain A17 with a Y181C mutation.

Anti-HIV Agents↗
PubMed2000

Contribution of 'TB clubs' to tuberculosis control in a rural district in Ethiopia.

SETTING: A rural district (Estie) in South Gonder, Ethiopia. OBJECTIVE: To describe the contribution of 'TB clubs' (small support groups of patients based on where they live) to the performance of the tuberculosis control programme in Estie District. DESIGN: A descriptive study of the formation of 'TB clubs', their contribution to case-finding and the treatment outcomes before and after formation of the 'TB clubs'. RESULTS: The proportion of actual among expected attendances of tuberculosis patients for follow-up during treatment at health facilities significantly increased (P < 0.001) after the introduction of the TB clubs. Community elders, community health agents and local health workers helped TB clubs to refer tuberculosis suspects, promote treatment adherence and trace defaulters as an integral part of a district tuberculosis programme. The TB clubs referred 181 tuberculosis suspects in the community for investigation, of whom 65% subsequently had a diagnosis of tuberculosis. TB clubs identified 69% of all patients and 76% of new sputum smear-positive pulmonary patients diagnosed in the district. Treatment success rates in new sputum smear-positive, smear-negative and extra-pulmonary tuberculosis patients were 83%, 79% and 81%, respectively. CONCLUSION: The formation of TB clubs contributed to the effective implementation of a district tuberculosis programme. Further evaluation is needed to assess the sustainability and applicability of the approach in other settings.

Adult↗
PubMed2000

Community involvement in tuberculosis control: lessons from other health care programmes.

Decentralising tuberculosis control measures beyond health facilities by harnessing the contribution of the community could increase access to effective tuberculosis care. This review of community-based health care initiatives in developing countries gives examples of the lessons for community contribution to tuberculosis control learned from health care programmes. Sources of information were Medline and Popline databases and discussions with community health experts. Barriers to success in tuberculosis control stem from biomedical, social and political factors. Lessons are relevant to the issues of limited awareness of tuberculosis and the benefits of treatment, stigma, restricted access to drugs, case-finding and motivation to continue treatment. The experience of other programmes suggests potential for an expansion of both formal and informal community involvement in tuberculosis control. Informal community involvement includes delivery of messages to encourage tuberculosis suspects to come forward for treatment and established tuberculosis patients to continue treatment. A wide range of community members provide psychological and logistic support to patients to complete their treatment. Lessons from formal community involvement indicate that programmes should focus on ensuring that treatment is accessible. This activity could be combined with a variety of complementary activities: disseminating messages to increase awareness and promote adherence, tracing patients who interrupt treatment, recognising adverse effects, and case detection. Programmes should generally take heed of existing political and cultural structures in planning community-based tuberculosis control programmes. Political support, the support of health professionals and the community are vital, and planning must involve or stem from the patients themselves.

Communicable Disease Control↗
PubMed2000

Mortality rates and recurrent rates of tuberculosis in patients with smear-negative pulmonary tuberculosis and tuberculous pleural effusion who have completed treatment.

SETTING: Queen Elizabeth Central Hospital, Blantyre, and Zomba Central Hospital, Zomba, Malawi. OBJECTIVE: To follow-up human immunodeficiency virus (HIV) seropositive and HIV-seronegative patients with smear-negative pulmonary tuberculosis (PTB) and pleural TB who had completed treatment with two different regimens in Blantyre and Zomba, and to assess rates of mortality and recurrent TB. DESIGN: Patients with smear-negative and pleural TB who had completed 8 months ambulatory treatment in Blantyre or 12 months standard treatment in Zomba and who were smear and culture negative for acid-fast bacilli at the completion of treatment were actively followed every 4 months for a total of 20 months. RESULTS: Of 248 patients, 150 with smear-negative PTB and 98 with pleural TB, who completed treatment and were enrolled, 205 (83%) were HIV-positive. At 20 months, 145 (58%) patients were alive, 85 (34%) had died and 18 (7%) had transferred out of the district. The mortality rate was 25.7 per 100 person-years, with increased rates strongly associated with HIV infection and age >45 years. Forty-nine patients developed recurrent TB. The recurrence rate of TB was 16.1 per 100 person-years, with increased rates strongly associated with HIV infection, having smear-negative PTB and having received 'standard treatment'. CONCLUSION: High rates of mortality and recurrent TB were found in patients with smear-negative PTB and pleural effusion during 20 months of follow-up. TB programmes in sub-Saharan Africa must consider appropriate interventions, such as co-trimoxazole and secondary isoniazid prophylaxis, to reduce these adverse outcomes.

Adult↗
PubMed1999

N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1.

The thiophene-ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLV(IIIB). The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC50 value of 3.3 microM, whereas the IC50 values of trovirdine, nevirapine, and delavirdine were all >100 microM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1.

Anti-HIV Agents↗
PubMed1999

N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea and N'-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1.

We have replaced the pyridyl ring of trovirdine with an alicyclic cyclohexenyl, adamantyl or cis-myrtanyl ring. Only the cyclohexenyl-containing thiourea compound N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]- thiourea (HI-346) (as well as its chlorine-substituted derivative N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]- thiourea/HI-445) showed RT inhibitory activity. HI-346 and HI-445 effectively inhibited recombinant RT with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM). In accord with this data, both compounds inhibited the replication of the drug-sensitive HIV-1 strain HTLV(IIIB) with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cellular HIV-1 inhibition assays was: HI-445 = HI-346 (IC50 = 3 nM) > MKC-442 (IC50 = 4 nM) = AZT (IC50 = 4 nM) > trovirdine (IC50 = 7 nM) > delavirdine (IC50 = 9 nM) > nevirapine (IC50 = 34 nM). Surprisingly, the lead compounds HI-346 and HI-445 were 3-times more effective against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V,41L, and 215Y) than they were against HTLV(IIIB) with wild-type RT. HI-346 and HI-445 were 20-times more potent than trovirdine, 200-times more potent than AZT, 300-times more potent than MKC-442, 400-times more potent than delavirdine, and 5000-times more potent than nevirapine against the multidrug resistant HIV-1 strain RT-MDR. HI-445 was also tested against the RT Y181C mutant A17 strain of HIV-1 and found to be >7-fold more effective than trovirdine and >1,400-fold more effective than nevirapine or delavirdine. Similarly, both HI-346 and HI-445 were more effective than trovirdine, nevirapine, and delavirdine against the problematic NNI-resistant HIV-1 strain A17-variant with both Y181C and K103N mutations in RT, although their activity was markedly reduced against this strain. Neither compound exhibited significant cytotoxicity at effective concentrations (CC50 >100 microM). These findings establish the lead compounds HI-346 and HI-445 as potent inhibitors of drug-sensitive as well as multidrug-resistant stains of HIV-1.

Aminopyridines↗