Community participation in a multisectoral intervention to address health determinants in an inner-city community in central Havana

It is increasingly acknowledged that the process of community involvement is critical to the successful implementation of community-based health interventions. Between 1995 and 1999, a multisectoral intervention called Plan Cayo Hueso was launched in the inner-city community of Cayo Hueso in Havana, Cuba, to address a variety of health determinants. To provide a better understanding of the political structures and processes involved, the Cuban context is described briefly. The interventions included improvements in housing, municipal infrastructure, and social and cultural activities. A qualitative study, consisting of interviews of key informants as well as community members, was conducted to evaluate the community participatory process. Questions from an extensive household survey pre- and postintervention that had been conducted in Cayo Hueso and a comparison community to assess the effectiveness of the intervention also informed the analysis of community participation, as did three community workshops held to choose indicators for evaluating effectiveness and to discuss findings. It was found that formal leaders led the interventions, providing the institutional driving force behind the plan. However, extensive community involvement occurred as the project took advantage of the existing community-based organizations, which played an active role in mobilizing community members and enhanced linkage systems critical to the project's success. Women played fairly traditional roles in interventions outside their households, but had equivalent roles to men in interventions within their household units. Most impressive about this project was the extent of mobilization to participate and the multidimensional ecosystem approach adopted. Indeed, Plan Cayo Hueso involved a massive mobilization of international, national, and community resources to address the needs of this community. This, as well as the involvement of community residents in the evaluation process, was seen as resulting in improved social interactions and community well-being and enhanced capacity for future action. While Cuba is unique in many respects, the lessons learned about enhancing community participation in urban health intervention projects, as well as in their evaluation, are applicable worldwide.     

Cardiovascular reactivity and cardiovascular risk factors in normotensive individuals of less than 40 years of age

BACKGROUND: Cardiovascular hyperactivity has been found to be related to cardiovascular risk factors among the population as a whole. Knowing whether these factors are also related to the population of individuals under age 40 could be important for modifying lifestyles and for taking action to prevent cardiovascular diseases. METHODS: A representative comparative study was made out of 249 individuals with normal blood pressure, of both sexes, within the 18-40 age range. These individuals were divided into two groups based on the results of the hand-held weight test (HHWT), this test take into account the use of an isometric exercise to achieve cardiovascular reactivity. One of the groups was composed of individuals with cardiovascular hyperreactivity (n = 62), with blood pressure (BP) values of equal or higher 90/140 mmHg following the hand-held weight test, the other group was composed of individuals with normal cardiovascular reactivity (n = 187), with blood pressure values less 90/140 mmHg. Using a logic regression model, the relationship was determined by age, sex, family history of FH of HBP), physical activity (PhysAct), cigarette-smoking (CS), alcoholic beverage intake (ABI), salt intake (SI) and race with the condition of cardiovascular hyperreactivity. RESULTS: The risk of having cardiovascular hyperreactivity was double for those individuals who had a family history of high blood pressure (OR = 2.88 IC 95%: 1.54-5.36). For every year of age, the risk of hyperreactivity increased 1.08 times, having increased up to 1.14 times. On the other hand, the body mass index revealed a significant relationship independent of the condition of vascular hyperreactivity (OR = 1.11 IC 95%: 1.01-1.21). None of the other variables studies showed any relationship to the condition of cardiovascular hyperreactivity. CONCLUSIONS: Individuals within the 18-40 age range who have normal blood pressure, have a higher risk of cardiovascular reactivity if they have a family history of high blood pressure, if their body mass index increases and with the age increment.     

The drug efflux-metabolism alliance: biochemical aspects

The considerable overlap in the substrate selectivity and tissue localization of CYP3A and P-glycoprotein has led to the hypothesis that this transporter and enzyme pair act as a coordinated absorption barrier against xenobiotics. A historical perspective on the investigation of this interactive alliance is given, starting from the understanding of the role of intestinal metabolism in explaining cyclosporine clinical data. Several animal studies using mdr1a-/- knockout mice have demonstrated P-glycoprotein's importance in limiting drug absorption and decreasing bioavailability. Human clinical studies investigating the importance of intestinal CYP3A and P-glycoprotein through inhibition or induction of these proteins have provided further evidence of this interaction. Recent in vitro studies using CYP3A4-expressing Caco-2 cells are reported. These studies reveal that the role of P-glycoprotein in the intestine extends beyond simply limiting parent drug absorption but also includes increasing the access of drug to metabolism by CYP3A through repeated cycles of absorption and efflux.     

Characterizing the Expression of CYP3A4 and Efflux Transporters (P-gp,MRP1, and MRP2) in CYP3A4-Transfected Caco-2 Cells After Induction with Sodium Butyrate and the Phorbol Ester 12-O-Tetradecanoylphorbol-13-Acetate

Purpose. To examine the changes in expression levels of CYP3A4 and efflux transporters in CYP3A4-transfected Caco-2 (colon carcinoma) cells in the presence of the inducers sodium butyrate (NaB) and 12-O-tetradecanoylphorbol-13-acetate (TPA). To characterize the transport of [³H]-digoxin and the metabolism of midazolam in the cells under different inducing conditions. Methods. CYP3A4-Caco-2 cells were seeded onto cell culture inserts and were grown for 13-14 days. Transport and metabolism studies were performed on cells induced with NaB and/or TPA for 24 h. The expression and localization of P-gp, MRP1, MRP2, and CYP3A4 were examined by Western blot and confocal microscopy. Results. In the presence of both inducers, CYP3A4 protein levels were increased 40-fold over uninduced cells, MRP2 expression was decreased by 90%, and P-gp and MRP1 expression were unchanged. Midazolam 1-OH formation exhibited a rank order correlation with increased CYP3A4 protein, whereas [³H]-digoxin transport (a measure of P-gp activity) was unchanged with induction. P-gp and MRP2 were found on the apical membrane, whereas MRP1 was found peri-nuclear within the cell. CYP3A4 displayed a punctate pattern of expression consistent with endoplasmic reticulum localization and exhibited preferential polarization towards the apical side of the cell. Conclusions. The present study characterized CYP3A4-Caco-2 cell monolayers when induced for 24 h in the presence of both NaB and TPA. These conditions provide intact cells with significant CYP3A4 and P-gp expression suitable for the concurrent study of transport and metabolism.     

Grapefruit Juice Activates P-Glycoprotein-Mediated Drug Transport

Purpose. Grapefruit juice (GJ) is known to increase the oral bioavailability of many CYP3A-substrates by inhibiting intestinal phase-I metabolism. However, the magnitude of AUC increase is often insignificant and highly variable. Since we earlier suggested that CYP3A and P-glycoprotein (P-gp) form a concerted barrier to drug absorption, we investigated the role of P-gp in GJ-drug interactions. Methods. The transcellular bidirectional flux of drugs that are (i) CYP3A-and/or P-gp substrates (Vinblastine, Cyclosporine, Digoxin, Fexofenadine, Losartan) or that are (ii) primary CYP3A-substrates (Felodipine, Nifedipine) was evaluated across MDCK-MDR1 cell monolayers with or without GJ, verifying monolayer integrity at all times. Results. While both apical-to-basal (A-B) and basal-to-apical (B-A) fluxes of all CYP3A/P-gp substrates tested were increased in the presence of GJ, the resulting net efflux (B-A/A-B) was in all cases significantly greater with GJ than control (Vin, 28.0 vs. 5.1; CsA, 9.9 vs. 2.8; Dig, 22. 9 vs. 14.7, Fex, 22.3 vs. 11.1, Los, 39.6 vs. 26). In contrast, no such GJ flux effect was observed with Pel and Nif, substrates of CYP3A only (2 vs. 1.7 and 1.2 vs. 1.3). Conclusions. GJ significantly activates P-gp-mediated efflux of drugs that are substrates of P-gp, potentially partially counteracting the CYP3A-inhibitory effects of GJ.     

Recommendations for bioequivalence testing of cyclosporine generics revisited

The immunosuppressant cyclosporine is generally considered a critical-dose drug. The validity of standard criteria to establish bioequivalence between cyclosporine formulations has recently been challenged. Recommendations included establishment of individual bioequivalence rather than average bioequivalence, establishment of bioequivalence in transplant patients and in subgroups known to be poor absorbers, as well as long-term efficacy and safety studies in transplant patients. However, at the moment individual bioequivalence is a theoretical concept, the practical benefits of which have not statistically been proven. The proposed patient pharmacodynamic studies can be expected to require an unrealistically high number of subjects to achieve sufficient statistical power. It is well established that the common practice of blood-concentration-guided dosing of cyclosporine efficiently compensates for interindividual and intraindividual variability and allows for safely switching cyclosporine formulations as bioinequivalent as Sandimmune and Neoral. Recent studies comparing the generic cyclosporine formulation SangCya with Neoral, including individual bioequivalence, bioequivalence in transplant patients, and long-term safety after switching from Sandimmune to SangCya, confirmed that it was valid to conclude bioequivalence of both cyclosporine formulations based on standard average bioequivalence criteria. Present FDA guidelines for approving bioequivalence can be considered adequate and sufficient for generic cyclosporine formulations.     

The novel immunosuppressant SDZ-RAD protects rat brain slices from cyclosporine-induced reduction of high-energy phosphates

1. SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side-effect of cyclosporine. 2. We studied the effect of SDZ-RAD and its combination with cyclosporine on high-energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using 31P-magnetic resonance spectroscopy (MRS). 3. Cyclosporine significantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 micrograms l-1: 93 +/- 3% of control (NTP), 91 +/- 3% (PCr); 500 micrograms l-1: 84 +/- 2% (NTP), 73 +/- 2 (PCr); 5000 micrograms l-1: 68 +/- 3% (NTP), 55 +/- 5% (PCr); n = 6; P < 0.02). 4. In contrast, after perfusion for 2 h, SDZ-RAD (500 micrograms l-1 and 5000 micrograms l-1) significantly increased high-energy phosphate concentrations in the brain slices (P < 0.02). Even at the lowest concentration, SDZ-RAD protected brain energy metabolism against cyclosporine toxicity: 100 micrograms l-1 SDZ-RAD + 5000 micrograms l-1 cyclosporine: 86 +/- 3% (NTP), 83 +/- 7% (PCr), n = 3, P < 0.03 compared to cyclosporine alone. 5. As evaluated using an algorithm based on Loewe isobolograms, the effects of SDZ-RAD/cyclosporine combinations on brain energy reduction were antagonistic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. 6. We conclude that cyclosporine inhibits mitochondrial high-energy phosphate metabolism, which can be antagonized by SDZ-RAD.     

Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies

Pharmaceutical Research - Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here. Using recently published...     

Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats

Kidney disease is generally thought to affect all segments of a nephron equally. Bricker and co-workers first proposed this as the Intact Nephron hypothesis in 1971, and evidence to date has usually supported this hypothesis. However, most supporting studies have involved severe renal failure, which may not be suitable to differentiate effects on functional sites or to test the hypothesis. The work included here examines the effects of limited renal failure on two separate functions of the nephron: glomerular filtration, as measured by inulin clearance and proximal tubular organic anion secretory function, as measured by p-aminohippuric acid (PAH) clearance. Renal failure was induced in rats by intravenous administration of uranyl nitrate, a nephrotoxin. Doses used were 0.3, 1.0, and 3.0 mg/kg rat body weight. Five days later, rats were given an intravenous infusion of PAH and inulin. Renal clearance of each compound was calculated. Results obtained in these experiments show that, at the lowest uranyl nitrate dose, PAH clearance was significantly decreased but inulin clearance was not. The ratio of CL_PAH/CL_IN was decreased from 2.55 in control rats to 1.21 in rats given the low dose of nephrotoxin. At higher uranyl nitrate doses, both clearance rates were significantly decreased and the ratio of CL_PAH/CL_IN remained close to 1.0. These results indicate that the active transport functions of the nephron can be differentiated from passive transport functions. Caution should be exercised in extrapolating renal disease changes in active renal secretion to changes in passive renal elimination and the reverse.This work was supported in part by NIH grants GM 26691 and GM 36633. C.A.G. was supported in part by a fellowship from the American Foundation for Pharmaceutical Education.