Quantitative relationship between the octanol/water partition coefficient and the diffusion limitation of the exchange between adipose and blood

Background  

The goal of physiologically based pharmacokinetics (PBPK) is to predict drug kinetics from an understanding of the organ/blood exchange. The standard approach is to assume that the organ is "flow limited" which means that the venous blood leaving the organ equilibrates with the well-stirred tissue compartment. Although this assumption is valid for most solutes, it has been shown to be incorrect for several very highly fat soluble compounds which appear to be "diffusion limited". This paper describes the physical basis of this adipose diffusion limitation and its quantitative dependence on the blood/water (K_bld-wat) and octanol/water (K_ow) partition coefficient.     

Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery

Background

The aim of this study was to provide a model-based analysis of the pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Methods

We studied nine patients aged 0.5 to 4 years who received a continuous remifentanil infusion via a computer-controlled infusion pump during cardiac surgery with mildly hypothermic CPB were studied. Arterial blood samples taken prior to, during and after CPB were analyzed for remifentanil concentrations using a validated gas-chromatographic mass-spectrophotometric assay. We used population mixed-effects modeling to characterize remifentanil pharmacokinetics. The final model was evaluated by its predictive performance.

Results

The pharmacokinetics of remifentanil was described by a 1-compartment model with adjustments for CPB. Population mean parameter estimates were 1.41 L for volume of distribution (V) and 0.244 L/min for clearance. V was increased during CPB and post-CPB to 2.41 times the pre-CPB value. The median prediction error and the median of individual median absolute prediction error were 2.44% and 21.6%, respectively.

Conclusion

Remifentanil dosage adjustments are required during and after CPB due to marked changes in the V of the drug. Simulations indicate that a targeted blood concentration of 14 ng/mL is achieved and maintained in 50% of typical patients by administration of an initial dose of 18 μg remifentanil followed by an infusion of 3.7 μg/min before, during and post-CPB, supplemented with a bolus dose of 25 μg given at the start of CPB.     

The unexpected importance of mosquito oviposition behaviour for malaria: non-productive larval habitats can be sources for malaria transmission

Background

Mosquitoes commute between blood-meal hosts and water. Thus, heterogeneity in human biting reflects underlying spatial heterogeneity in the distribution and suitability of larval habitat as well as inherent differences in the attractiveness, suitability and distribution of blood-meal hosts. One of the possible strategies of malaria control is to identify local vector species and then attack water bodies that contain their larvae.

Methods

Biting and host seeking, not oviposition, have been the focus of most previous studies of mosquitoes and malaria transmission. This study presents a mathematical model that incorporates mosquito oviposition behaviour.

Results

The model demonstrates that oviposition is one potential factor explaining heterogeneous biting and vector distribution in a landscape with a heterogeneous distribution of larval habitat. Adult female mosquitoes tend to aggregate around places where they oviposit, thereby increasing the risk of malaria, regardless of the suitability of the habitat for larval development. Thus, a water body may be unsuitable for adult mosquito emergence, but simultaneously, be a source for human malaria.

Conclusion

Larval density may be a misleading indicator of a habitat's importance for malaria control. Even if mosquitoes could be lured to oviposit in sprayed larval habitats, this would not necessarily mitigate – and might aggravate – the risk of malaria transmission. Forcing mosquitoes to fly away from humans in search of larval habitat may be a more efficient way to reduce the risk of malaria than killing larvae. Thus, draining, fouling, or filling standing water where mosquitoes oviposit can be more effective than applying larvicide.     

Community-aggregated plant traits interact with soil nutrient heterogeneity to determine ecosystem functioning

Background and aims

Spatial distribution of soil nutrients (soil heterogeneity) and availability have strong effects on above- and belowground plant functional traits. Although there is ample evidence on the tight links between functional traits and ecosystem functioning, the role played by soil heterogeneity and availability as modulators of such relationship is poorly known.

Methods

We conducted a factorial experiment in microcosms containing grasses, legumes and non-legume forbs communities differing in composition to evaluate how soil heterogeneity and availability (50 and 100 mg N) affect the links between traits and ecosystem functioning. Community-aggregated specific leaf area (SLA_agg) and specific root length (SRL_agg) were measured as both relevant response traits to soil heterogeneity and availability, and significant effect traits affecting ecosystem functioning (i.e., belowground biomass, β-glucosidase and acid phosphatase activities, and in situ N availability rate).

Results

SRL_agg was negatively and significantly associated to β-glucosidase, phosphatase and N availability rate in the high nutrient availability and heterogeneous distribution scenario. We found a significant negative relationship between SLA_agg and availability rate of mineral-N under low nutrient availability conditions.

Conclusions

Soil heterogeneity modulated the effects of both traits and nutrient availability on ecosystem functioning. Specific root length was the key trait associated with soil nutrient cycling and belowground biomass in contrasted heterogeneous soil conditions. The inclusion of soil heterogeneity into the trait-based response-effect framework may help to scale from plant communities to the ecosystem level.     

A novel method to measure regional muscle blood flow continuously using NIRS kinetics information

Background

This article introduces a novel method to continuously monitor regional muscle blood flow by using Near Infrared Spectroscopy (NIRS). We demonstrate the feasibility of the new method in two ways: (1) by applying this new method of determining blood flow to experimental NIRS data during exercise and ischemia; and, (2) by simulating muscle oxygenation and blood flow values using these newly developed equations during recovery from exercise and ischemia.

Methods

Deoxy (Hb) and oxyhemoglobin (HbO₂), located in the blood ofthe skeletal muscle, carry two internal relationships between blood flow and oxygen consumption. One is a mass transfer principle and the other describes a relationship between oxygen consumption and Hb kinetics in a two-compartment model. To monitor blood flow continuously, we transfer these two relationships into two equations and calculate the blood flow with the differential information of HbO₂ and Hb. In addition, these equations are used to simulate the relationship between blood flow and reoxygenation kinetics after cuff ischemia and a light exercise. Nine healthy subjects volunteered for the cuff ischemia, light arm exercise and arm exercise with cuff ischemia for the experimental study.

Results

Analysis of experimental data of both cuff ischemia and light exercise using the new equations show greater blood flow (four to six times more than resting values) during recovery, agreeing with previous findings. Further, the simulation and experimental studies of cuff ischemia and light exercise agree with each other.

Conclusion

We demonstrate the accuracy of this new method by showing that the blood flow obtained from the method agrees with previous data as well as with simulated data. We conclude that this novel continuous blood flow monitoring method can provide blood flow information non-invasively with NIRS.

     

Neuroaxial anesthesia in a patient with progressive systemic sclerosis : case presentation and review of the literature on systemic sclerosis

Background

Systemic sclerosis (SSc), a progressive disease characterized by excessive accumulation of connective tissue components. Although most patients have long survival, some of them progress rapidly to death. Pulmonary system involvement and pulmonary hypertension are the most frequent cause of death. When the patient with SSc is to be operated, the anesthetic procedure could be a serious problem. In this article, we report a combined spinal – epidural technique in a patient with progressive SSc and the anesthetic considerations that could be recommended for these patients.

Case presentation

A 68-year-old woman who had a history of progressive systemic sclerosis, pulmonary fibrosis, kyphoscoliosis and decreased oral apertura underwent total hip arthroplasty. This operation was performed successfully under combined spinal epidural anesthesia.

Conclusion

Systemic sclerosis is a complex disease that involves multiple organ systems. Every aspects of anesthetic care may be altered or hindered by the pathogenesis of disease. Although the choice of regional or general anesthesia is unclear, to choose combined spinal epidural anesthesia may be useful.     

Predicting effects of blood flow rate and size of vessels in a vasculature on hyperthermia treatments using computer simulation

Background

Pennes Bio Heat Transfer Equation (PBHTE) has been widely used to approximate the overall temperature distribution in tissue using a perfusion parameter term in the equation during hyperthermia treatment. In the similar modeling, effective thermal conductivity (K_eff) model uses thermal conductivity as a parameter to predict temperatures. However the equations do not describe the thermal contribution of blood vessels. A countercurrent vascular network model which represents a more fundamental approach to modeling temperatures in tissue than do the generally used approximate equations such as the Pennes BHTE or effective thermal conductivity equations was presented in 1996. This type of model is capable of calculating the blood temperature in vessels and describing a vasculature in the tissue regions.

Methods

In this paper, a countercurrent blood vessel network (CBVN) model for calculating tissue temperatures has been developed for studying hyperthermia cancer treatment. We use a systematic approach to reveal the impact of a vasculature of blood vessels against a single vessel which most studies have presented. A vasculature illustrates branching vessels at the periphery of the tumor volume. The general trends present in this vascular model are similar to those shown for physiological systems in Green and Whitmore. The 3-D temperature distributions are obtained by solving the conduction equation in the tissue and the convective energy equation with specified Nusselt number in the vessels.

Results

This paper investigates effects of size of blood vessels in the CBVN model on total absorbed power in the treated region and blood flow rates (or perfusion rate) in the CBVN on temperature distributions during hyperthermia cancer treatment. Also, the same optimized power distribution during hyperthermia treatment is used to illustrate the differences between PBHTE and CBVN models. K_eff (effective thermal conductivity model) delivers the same difference as compared to the CBVN model. The optimization used here is adjusting power based on the local temperature in the treated region in an attempt to reach the ideal therapeutic temperature of 43°C. The scheme can be used (or adapted) in a non-invasive power supply application such as high-intensity focused ultrasound (HIFU). Results show that, for low perfusion rates in CBVN model vessels, impacts on tissue temperature becomes insignificant. Uniform temperature in the treated region is obtained.

Conclusion

Therefore, any method that could decrease or prevent blood flow rates into the tumorous region is recommended as a pre-process to hyperthermia cancer treatment. Second, the size of vessels in vasculatures does not significantly affect on total power consumption during hyperthermia therapy when the total blood flow rate is constant. It is about 0.8% decreasing in total optimized absorbed power in the heated region as γ (the ratio of diameters of successive vessel generations) increases from 0.6 to 0.7, or from 0.7 to 0.8, or from 0.8 to 0.9. Last, in hyperthermia treatments, when the heated region consists of thermally significant vessels, much of absorbed power is required to heat the region and (provided that finer spatial power deposition exists) to heat vessels which could lead to higher blood temperatures than tissue temperatures when modeled them using PBHTE.     

PKQuest: measurement of intestinal absorption and first pass metabolism – application to human ethanol pharmacokinetics

Background

PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose – PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption.

Methods

PKQuest was applied to previously published ethanol pharmacokinetic data.

Results

The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small.

Conclusions

The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at http://www.pkquest.com.     

Prise en charge du priapisme à Dakar

Objective

Evaluate the management of patients with priapism.

Patients and methods

This is a retrospective study over 4 years from August 1, 2002 to July 31, 2006, on 35 patients. The frames of the study were three major services of urology of Senegal which are located in Dakar. The following parameters were studied: age, time evolution of priapism, anamnestic information, the type of hemodynamic priapism, the results of paraclinical data, the surgical treatment (the surgical technique, the anesthetic technique), the duration of hospitalization, the treatment associated, the per- and postoperative complications, immediate and long term results.

Results

The average age of patients was 21.2 years. The age group most represented was that of 20 to 30 years. The majority of patients (43%) had known history of sickle-cell disease. Most patients were (65%) supported within 24 hours of evolution (65%). In all patients, priapism was low bandwidth. In 50% of cases, patients with sickle cell disease had a SS form. In about half the cases (62%), the anesthetic technique chosen was the penile block. The puncture of the corpora cavernosa was the most widely used means of therapy (63%). No major postoperative complication was deplored in the care of patients in our series. In almost all patients (95%), a durable detumescence was noted the day of the beginning of treatment or the next day.

Conclusion

Priapism, although rare in Africa, is characterized by the predominance of sickle cell disease as etiology and the particularly long period before treatment.     

The pharmacokinetics of the interstitial space in humans

Background  

The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes.     

PKQuest: volatile solutes - application to enflurane,nitrous oxide,halothane, methoxyflurane and toluene pharmacokinetics

BACKGROUND: The application of physiologically based pharmacokinetic models (PBPK) to human studies has been limited by the lack of the detailed organ information that is required for this analysis. PKQuest is a new generic PBPK that is designed to avoid this problem by using a set of "standard human" default parameters that are applicable to most solutes. RESULTS: PKQuest is used to model the human pharmacokinetics of the volatile solutes. A "standard human" value for the lipid content of the blood and each organ (klip) was chosen. This set of klip and the oil/water partition coefficient then specifies the organ/blood partition for each organ. Using this approach, the pharmacokinetics of inert volatile solute is completely specified by just 2 parameters: the water/air and oil/water partition coefficients. The model predictions of PKQuest were in good agreement with the experimental data for the inert solutes enflurane and nitrous oxide and the metabolized solutes halothane and toluene. METHODS: The experimental data that was modeled was taken from previous publications. CONCLUSIONS: This approach greatly increases the predictive power of the PBPK. For inert volatile solutes the pharmacokinetics are determined just from the water/air and oil/water partition coefficient. Methoxyflurane cannot be modeled by this PBPK because the arterial and end tidal partial pressures are not equal (as assumed in the PBPK). This inequality results from the "washin-washout" artifact in the large airways that is established for solutes with large water/air partition coefficients.PKQuest and the worked examples are available on the web www.pkquest.com.     

Foraging responses of clonal plants to multi-patch environmental heterogeneity: spatial preference and temporal reversibility

Background and aims

Plant root placement is highly plastic in order to acquire patchily distributed nutrients and to ensure their survival, growth and reproduction. Considering the spatial extension of clonal organs, we selected two clonal plants (Leymus chinensis (Trin.) Tzvel. and Hierochloe glabra Trin.) to determine the spatio-temporal effects of environmental heterogeneity on belowground organs and newly-born ramets.

Methods

Small-scale and multi-patch heterogeneous environments were manipulated by creating four patches filled with different types of soil in a same pot. The four patches were composed of sandy soil, sandy loam, loam soil and humus soil, respectively. Ramet number, bud number, mean spacer length, rhizome length, and biomass allocation within each patch were measured to identify plant foraging responses.

Results

The preferential patch of L. chinensis was humus soil patch which was the highest in nutrient availability, whereas H. glabra preferred to place ramets in sandy loam and loam soil patches. When growing in homogeneous environments, both species randomly rooted their offspring ramets in the four compartments. In heterogeneous environments, foraging responses were detected in ramet placement, aboveground biomass and total rhizome length. However, there were no differences in bud number or belowground biomass among four types of patches in heterogeneous environments, which might suggest that there would be no inter-patch differences in seedling establishment in the next year.

Conclusions

Plants show selective allocation of offspring ramets to preferential patches in the presence of multi-patch environmental heterogeneity. Responses of H. glabra to multi-patch heterogeneity were faster than those of L. chinensis, demonstrating that the foraging patterns are species-specific. Clonal plants can rapidly respond to environmental heterogeneity, whereas foraging responses are potentially reversible over a longer temporal scale.     

The relationship between perceived sense of control and visceral adipose tissue - the North Texas Healthy Heart Study

Background

The purpose of this study was to assess the relationship between one's sense of control and visceral adipose tissue.

Methods

This cross-sectional study recruited 571 subjects (45 years and older) who were asymptomatic of CHD from Fort Worth, Texas from 2006 to 2008. Subjects completed a questionnaire, body measurements, a multi-slice computed tomography scan to assess for visceral adipose tissue (VAT) centered at the L4L5 spinal interspace, and serum chemistries. The natural log of L4L5 VAT (lnVAT) was used in all analyses to achieve normality of the data with final analyses including 506 participants. Linear regression was used to estimate unadjusted and adjusted beta-coefficients and standard errors for the association between sense of control and lnVAT.

Results

A total of 506 participants were used in the data after adjusting for normality of the data. An increase in sense of control was associated with a decrease in lnVAT in the unadjusted (p < 0.001) and adjusted (p = 0.03) models. Other factors significantly associated with lnVAT in the adjusted model include age, BMI, male gender, non-Hispanic African American, and diet.

Conclusions

Sense of control remained as an independent factor associated with visceral adiposity despite adjusting for traditional cardiovascular risk factors, including BMI. Future studies should focus on establishing a causal relationship between sense of control and visceral adiposity.     

Response of Populus tremula to heterogeneous B distributions in soil

Background

Poplars accumulate inordinate amounts of B in their leaves and are candidate plants for the remediation of B contaminated soil. We aimed to determine the effect of heterogeneous B distribution in soil by comparing the growth and B accumulation of young Populus tremula trees growing in soil with heterogeneous and homogeneous B distributions.

Methods

The first of two experiments focused on the tolerance and B accumulation of P. tremula under heterogeneous soil B distributions, while the second was designed to study fine root growth under such conditions in detail.

Results

Growth and B accumulation of P. tremula were unaffected by the spatial distribution of B. Root and shoot growth were both reduced simultaneously when leaf B concentrations increased above 800 mg kg^?1. In the heterogeneous soil B treatments, root growth was more reduced in spiked soil portions with B concentrations >20 mg kg^?1. Fine root length growth was stronger inhibited by B stress than secondary growth.

Conclusions

The root growth responses of P. tremula to B are primarily a systemic effect induced by shoot B toxicity and local toxicity effects on roots become dominant only at rather high soil B concentrations. Local heterogeneity in soil B should have little influence on the phytoremediation of contaminated sites.     

Automatic noninvasive measurement of systolic blood pressure using photoplethysmography

Background

Systolic blood flow has been simulated in the abdominal aorta and the superior mesenteric artery. The simulations were carried out using two different computational hemodynamic methods: the finite element method to solve the Navier Stokes equations and the lattice Boltzmann method.

Results

We have validated the lattice Boltzmann method for systolic flows by comparing the veloCity and pressure profiles of simulated blood flow between methods. We have also analyzed flow-specific characteristics such as the formation of a vortex at curvatures and traces of flow.

Conclusion

The lattice Boltzmann Method is as accurate as a Navier Stokes solver for computing complex blood flows. As such it is a good alternative for computational hemodynamics, certainly in situation where coupling to other models is required.     

Inhaled corticosteroid use is associated with increased circulating T regulatory cells in children with asthma

Background

T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use.

Methods

Peripheral blood mononuclear cells from healthy control subjects (N?=?93) and asthmatic children of varying disease severity (N?=?66) were characterized by multi-parameter flow cytometry.

Results

Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma.

Conclusion

We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.     

Cerebral blood flow during cardiopulmonary bypass in pediatric cardiac surgery: the role of transcranial Doppler – a systematic review of the literature

Background

Transcranial Doppler Ultrasound (TCD) is a sensitive, real time tool for monitoring cerebral blood flow velocity (CBFV). This technique is fast, accurate, reproducible and noninvasive. In the setting of congenital heart surgery, TCD finds application in the evaluation of cerebral blood flow variations during cardiopulmonary bypass (CPB).

Methodology

We performed a search on human studies published on the MEDLINE using the keyword "trans cranial Doppler" crossed with "pediatric cardiac surgery" AND "cardio pulmonary by pass", OR deep hypothermic cardiac arrest", OR "neurological monitoring".

Discussion

Current scientific evidence suggests a good correlation between changes in cbral blood flow and mean cerebral artery (MCA) blood flow velocity. The introduction of Doppler technology has allowed an accurate monitorization of cerebral blood flow (CBF) during circulatory arrest and low-flow CPB. TCD has also been utilized in detecting cerebral emboli, improper cannulation or cross clamping of aortic arch vessels. Limitations of TCD routine utilization are represented by the need of a learning curve and some experience by the operators, as well as the need of implementing CBF informations with, for example, data on brain tissue oxygen delivery and consumption.

Conclusion

In this light, TCD plays an essential role in multimodal neurological monitorization during CPB (Near Infrared Spectroscopy, TCD, processed electro encephalography) that, according to recent studies, can help to significantly improve neurological outcome after cardiac surgery in neonates and pediatric patients.     

Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study

Background

Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV).

Hypothesis

Systemic inflammation and glycemia influence circadian blood pressure variability.

Methods

Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD (high-glycemic-index, high-fat) simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat) mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP) and heart rate (HR) were recorded by telemetry every 5 minutes during both sleep (day) and active (night) periods. Pulse pressure (PP) was calculated (PP = SBP-DBP).

Results

[mean(SEM)]: The AD fed group displayed significant increase in body weight (after 90 days; p < 0.01). Fasting glucose, adipokine (leptin and adiponectin) concentrations significantly increased (at 90 and 172 days; all p < 0.05), along with a trend for increased concentrations of systemic pro-inflammatory cytokines (MCP-1 and TNF-α) on day 90. The AD fed group, with significantly higher FG, also exhibited significantly elevated circadian (24-hour) overall mean SBP, DBP, PP and HR (all p < 0.05).

Conclusion

These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system) which generate abnormal CBPV.     

Does the Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

Background

Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D) polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease.

Methods

Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives) responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality.

Results

Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes.

Conclusion

Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers.