Have we improved use of medicines in developing and transitional countries and do we know how to? Two decades of evidence.

OBJECTIVE: To assess progress in improving use of medicines in developing and transitional countries by reviewing empirical evidence, 1990-2009, concerning patterns of primary care medicine use and intervention effects. METHODS: We extracted data on medicines use, study setting, methodology and interventions from published and unpublished studies on primary care medicine use. We calculated the medians of six medicines use indicators by study year, country income level, geographic region, facility ownership and prescriber type. To estimate intervention impacts, we calculated greatest positive (GES) and median effect sizes (MES) from studies meeting accepted design criteria. RESULTS: Our review comprises 900 studies conducted in 104 countries, reporting data on 1033 study groups from public (62%), and private (mostly for profit) facilities (26%), and households. The proportion of treatment according to standard treatment guidelines was 40% in public and <30% in private-for-profit sector facilities. Most indicators showed suboptimal use and little progress over time: Average number of medicines prescribed per patient increased from 2.1 to 2.8 and the percentage of patients receiving antibiotics from 45% to 54%. Of 405 (39%) studies reporting on interventions, 110 (27%) used adequate study design and were further analysed. Multicomponent interventions had larger effects than single component ones. Median GES was 40% for provider and consumer education with supervision, 17% for provider education alone and 8% for distribution of printed education materials alone. Median MES showed more modest improvements. CONCLUSIONS: Inappropriate medicine use remains a serious global problem.

Amyloid-beta-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation.

Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer's disease (AD). A leaky blood-brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid beta (Abeta) peptides of 1-40 and 1-42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of Abeta 1-40, the Abeta variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Abeta 1-40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC-dextran when compared with cells incubated with the scrambled Abeta 1-40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin-5 and ZO-1 were unaffected. JNK and p38MAPK inhibition prevented both Abeta 1-40-mediated down-regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD.

The effects of different kinds of user fee on prescribing costs in rural Nepal.

OBJECTIVES: (1) To estimate the cost of irrational prescribing, and (2) to compare the effect of three different kinds of user fee on prescribing costs, in rural Nepal. METHODS: A controlled before-after study was conducted in 33 government primary health care facilities in rural eastern Nepal during 1992-95. A fee per prescription (covering all drugs in whatever amounts) was regarded as the control against which two types of fee per drug item (covering a full course of treatment for each item) were compared. The average total cost to the patient for two drug items was the same in all fee systems. Total cost, expected cost (according to standard treatment guidelines) and wastage costs (total minus expected cost) per prescription were calculated from an average of 400 prescribing episodes per facility per year. The proportion of prescriptions conforming to standard treatment guidelines was calculated from 30 prescriptions per facility per year. RESULTS: 20-52% of total drug costs were due to inappropriate drug prescription. A fee per drug item, as compared with a fee per prescription, was associated with (1) significantly fewer drug items prescribed per patient, (2) significantly lower drug costs per prescription, (3) significantly lower wastage due to inappropriate drug prescription, and (4) a significantly greater proportion of prescriptions conforming to standard treatment guidelines. Average drug cost per prescription (which was 24-33 Nepali rupees [NRs] across districts and time) was 5.7 NRs (95% confidence interval 1.0 to 10.4) and 9.3 NRs (95% confidence interval 4.8 to 13.8) less with the two different item fees, respectively, than with the fee per prescription. CONCLUSION: The economic consequences of irrational prescribing are severe, particularly in association with charging a fee per prescription. Item fees in the public sector reduce irrational prescribing and associated costs.

The effects of different kinds of user fees on prescribing quality in rural Nepal.

This study evaluated the effects of three different kinds of user fee on the quality of prescribing in rural Nepal. Using data from 33 public health facilities, we performed a controlled before-and-after study, comparing a fee per prescription (covering all drugs in whatever amounts) against one- and two-band fees per drug item (covering a full course of treatment for each item). With the one-band item fee, each item incurred the same fee; with the two-band item fee, more expensive items incurred a higher fee and cheaper ones a lower fee. Thirteen indicators of prescribing quality were evaluated based on an average of 400 prescribing episodes per facility per year. The percentage of prescriptions conforming to standard treatment guidelines was 12% (95% confidence interval [CI] 3% to 21%) and 15% (95% CI 6% to 24%) greater with the one- and two-band item fees, respectively, than with the fee per prescription. Prescribing quality improved through a reduction in the number of unnecessary, but not necessary, drug items prescribed per patient. Item-based fees are associated with significantly better prescribing quality than a fee per prescription; therefore, item-based fees are preferred over a fee per prescription when considering methods of cost recovery.

Consequences of over-prescribing on the dispensing process in rural Nepal.

OBJECTIVE: To investigate the effect of increasing numbers of drugs prescribed on the dispensing process in rural Nepal. DESIGN: Cross-sectional survey, on average 25 exiting patients per facility in 33 government health facilities. OUTCOME MEASURES: Percentage of cases where there was a dispensing error, and where the patient knew the dosing schedules of the dispensed drugs. RESULTS: A greater number of drug items prescribed and dispensed per patient was significantly associated with a greater percentage of cases where there was a dispensing error (P=0.00000), and where the patient did not know the dosing schedules of the dispensed drugs (P=0.00000). CONCLUSION: The prescribing (and dispensing) of more drugs per patient, an indication of over-prescription, is associated with significantly poorer dispensing.

Modulation of signal-transduction pathways by chemopreventive agents.

For a disease such as cancer, where a number of alterations to normal cell function accumulate over time, there are several opportunities to inhibit, slow down or even reverse the process. Many of the changes which drive the disease process occur in cell-signalling pathways that regulate proliferation and apoptosis. As our knowledge of these complicated signalling networks improves, it is becoming clear that many molecules, both drugs and naturally occurring dietary constituents, can interact beneficially with deregulated pathways. Aspirin and other non-steroidal anti-inflammatory drugs, as well as natural compounds present in plants such as green vegetables and tea, can modulate signalling by affecting kinase activity and therefore phosphorylation of key molecules. Examples of pathways which can be modulated by these agents include activation of the transcription factor nuclear factor kappaB by tumour promoters or cytokines, signalling by growth factors through the growth-factor receptor/extracellular-regulated protein kinase pathways and by a number of other molecules through the stress-activated c-Jun N-terminal kinase and p38 pathways. These mitogen-activated protein kinase pathways regulate a number of transcription factors including c-Fos and c-Jun. Evidence exists, at least from in vitro experiments, that by targeting such pathways, certain dietary compounds may be able to restore abnormal rates of apoptosis and proliferation to more normal levels.

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.