A Dominguez-Gil

Universidad Austral de Chile, Ciudad de Valdivía, Los Ríos, Chile

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Publications (198)355.45 Total impact

  • XI congreso de la Sociedad Española de Farmacia Industrial y Galénica (SEFIG), Alicante, Spain; 02/2013
  • V Congreso Internacional de Educación Superior en Ciencias Farmacéuticas (EDUSFARM), http://www.edusfarm2012.ull.es/contenido/autores/Martin_A.html; 06/2012
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    ABSTRACT: Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C → T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 - 0.00279 · GGT) · 0.602(CYP2B6*6 [G/T]) · 0.354(CYP2B6*6 [T/T]) · 0.793(MRP4 1497C → T), where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C → T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.
    Antimicrobial Agents and Chemotherapy 09/2011; 55(11):5314-24. · 4.57 Impact Factor
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    ABSTRACT: Evaluation of the performance of a modified Enzyme Multiplied Immunoassay Technique for therapeutic drug monitoring of plasma free mycophenolic acid (fMPA) concentrations. A fMPA assay was developed on a Viva-E analyzer. A study of prior ultrafiltration conditions and analytical validation of the EMIT assay were performed. The method was reliable and reproducible. fMPA levels can be monitored using this EMIT assay with the advantage of being an automated method.
    Clinical biochemistry 10/2010; 44(2-3):260-3. · 2.02 Impact Factor
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    ABSTRACT: Analytical interferences in digoxin immunoassays constitute a well-known problem, with repercussions for therapeutic drug monitoring. Clinically effective doses of spironolactone and potassium canrenoate cross-react in several digoxin immunoassays, producing falsely elevated or lowered concentrations. This study evaluates the interferences caused by these drugs in the microparticle enzyme immunoassay (MEIA III) in comparison with another 3 immunoassays used for digoxin therapeutic drug monitoring: MEIA II, fluorescence polarization immunoassay, and enzyme multiplied immunoassay. The potential clinical implications of assay discrepancies in patient care are also assessed. To evaluate assay performance, in vitro specimens and real patient samples were measured using the 4 assays. Five serum pools were spiked with digoxin to achieve concentrations of 1 and 2.25 ng/mL digoxin and measured with the immunoassays before and after supplementation. Real samples from patients receiving digoxin (n = 39), digoxin and spironolactone (n = 35), or digoxin and potassium canrenoate (n = 4) were also quantified. The influence of ultrafiltration was evaluated in 3 pools from 29 additional patients. The implications of assay discrepancies for dose recommendations were also evaluated. In general, the results obtained for the in vitro and in vivo approaches coincided, confirming statistically significant differences in the assays regardless of the type of sample. MEIA III showed positive interference against the well-known negative interference attributed to MEIA II. According to Bland-Altman analysis, it is not possible to assume the interchangeability of the immunoassays evaluated. Thus, individual patients must be monitored with the same technique even in the absence of potential interferences. Discordant digoxin dose recommendations were estimated in 31% of patients not treated with interfering drugs and in 43% of cotreated patients. From a clinical perspective, analytical interferences in digoxin immunoassays are a real and frequent problem, which seems even more important in view of the lower therapeutic range now recommended.
    Therapeutic drug monitoring 03/2010; 32(2):169-76. · 2.43 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the reliability for dosage individualization and Bayesian adaptive control of several literature-retrieved amikacin population pharmacokinetic models in patients who were critically ill. Four population pharmacokinetic models, three of them customized for critically-ill patients, were applied using pharmacokinetic software to fifty-one adult patients on conventional amikacin therapy admitted to the intensive care unit. An estimation of patient-specific pharmacokinetic parameters for each model was obtained by retrospective analysis of the amikacin serum concentrations measured (n = 162) and different clinical covariates. The model performance for a priori estimation of the area under the serum concentration-time curve (AUC) and maximum serum drug concentration (C(max)) targets was obtained. Our results provided valuable confirmation of the clinical importance of the choice of population pharmacokinetic models when selecting amikacin dosages for patients who are critically ill. Significant differences in model performance were especially evident when only information concerning clinical covariates was used for dosage individualization and over the two most critical determinants of clinical efficacy of amikacin i.e. the AUC and C(max) values. Only a single amikacin serum level seemed necessary to diminish the influence of population model on dosage individualization.
    Journal of Pharmacy and Pharmacology 07/2009; 61(6):759-66. · 2.03 Impact Factor
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    ABSTRACT: A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n = 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.
    Antimicrobial Agents and Chemotherapy 06/2009; 53(7):2791-8. · 4.57 Impact Factor
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    ABSTRACT: Hyperhidrosis may be an adverse drug event (ADE) induced by the effect on any of the components of human thermoregulation. Some of our efavirenz (EFV)-treated patients have reported excessive nocturnal sweating that resolved after dose reduction. A representative clinical case of a male patient being treated with a night-time 600-mg dose of EFV who reported severe nocturnal sweating is reported here. His EFV plasma concentrations were always above normal and he was homozygous for a deficient function-allele of CYP2D6; for this reason, his EFV dose was reduced to 400mg=d. Simultaneous with this reduction, the patient described a progressive decrease in nocturnal sweating until its complete disappearance 15-20 days after this new drug dosage. The mechanism explaining sweating could be similar to the one suggested for hyperhidrosis related to serotonin uptake inhibitors, because this hyperhidrosis is episodic, nocturnal, and dose dependent. Hyperhidrosis could correspond to a dose-dependent ADE induced by EFV, therefore, a reduction of EFV from 600 to 400mg/d seems to control it. EFV crosses the hematoencephalic barrier and reaches a mean concentration in the cerebroespinal fluid equivalent to 0.69% of the plasma concentration. The ability of EFV to accessing the central nervous system (CNS) could explain an effect on thermoregulation. Hyperhydrosis is not easily discovered through a routine anamnesis because it is not noted on the EFV package insert, so its incidence may be higher than expected. Additionally, hyperhidrosis may be an indicator of elevated EFV plasma concentrations and hence may be controlled through a reduction of dose.
    AIDS patient care and STDs 03/2009; 23(3):143-5. · 2.68 Impact Factor
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    ABSTRACT: The use of vancomycin against Staphylococcus aureus is currently debated because of the increasing resistance developed by this pathogen. Nevertheless, antibacterial effectiveness is a limited resource that must be protected and restored. Novel dosage strategies based on pharmacokinetic/pharmacodynamic analyses are needed to retain effectiveness that could improve drug exposure in patients infected with such pathogens. The aim of this study was to assess whether standard or higher vancomycin dosages are required to increase the probability of attaining a target pharmacokinetic/pharmacodynamic index for several staphylococcal strains and thus to estimate the minimum vancomycin daily dose related to a high probability of effective treatment in patients with malignant haematological disease. Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR) for different vancomycin daily dosages, using a population pharmacokinetic model previously defined in patients with malignant haematological disease and the minimum inhibitory concentration (MIC) distribution for vancomycin against several staphylococcal species (vancomycin-susceptible S. aureus and vancomycin-intermediate S. aureus [VISA], S. epidermidis, S. haemolyticus and coagulase-negative Staphylococcus [CNS] species) obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in order to predict the dose that would achieve the pharmacokinetic/pharmacodynamic index value associated with efficacy (the area under the concentration-time curve from 0 to 24 hours divided by the MIC [AUC(24)/MIC >/=400]). CFR values showed dependence on the renal function of the patient and the causative pathogen. Only in patients with a creatinine clearance (CL(CR)) <60 mL/min did the standard vancomycin dosage (2000 mg/day) induce CFRs >60% for all staphylococci, except the VISA strains. CFRs for S. aureus of 90.6%, 47.3% and 31.2% for CL(CR) values of <60, 60-120 and >120 mL/min, respectively, were obtained, whereas for the VISA strains, the corresponding values were only 14.0%, 0.3% and 0%. The impact of potential pathogens on CFRs is also significant. According to our pharmacokinetic/pharmacodynamic analysis, in patients with normal renal function (CL(CR) between 60 and 120 mL/min) vancomycin 2000 mg/day leads to a risk of not achieving the recommended AUC(24)/MIC breakpoint of 52.7%, 70.4%, 74.9% and 80.3% for S. aureus, S. haemolyticus, CNS and S. epidermidis, respectively. Application of our results to clinical practice graphically allows us to obtain the recommended dose for any a priori-selected probability of attaining the AUC(24)/MIC ratio of >/=400 and to evaluate the CFRs for any dosing regimen used in this population group, depending on the patients' renal function. Application of pharmacokinetic/pharmacodynamic analysis based on Monte Carlo simulation offers an excellent tool for selecting the therapeutic option with the highest probability of clinical success in patients with malignant haematological disease. Thus, for vancomycin-susceptible S. aureus, if a CFR >/=80 is assumed as clinically acceptable, vancomycin doses of 1500, 3000 and 4000 mg/day for a CL(CR) of <60, 60-120 and >120 mL/min, respectively, will be required.
    Clinical Pharmacokinetics 01/2009; 48(4):273-80. · 5.49 Impact Factor
  • AIDS (London, England) 12/2008; 22(18):2549-51. · 4.91 Impact Factor
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    ABSTRACT: Abstract In an attempt to obtain the basic data necessary in research into the possible use of papaverine in sustained action formulas in the form of complexes with Montmorillonite, the “in vitro” adsorption and desorption of the drug as a function of different factor was studied. The study of the interaction and adsorption mechanisms was carried out by adsorption isotherms, X-ray diffraction and I.R. spectroscopy. The adsorption of papaverine by Montmorillonite increases with the rise in pH of the solution, within the pH range studied (2-4) in agreement with the solubility of the compound. According to the isotherms, adsorption increases with the concentration of the solution up to 79.16 mEq/100 g (very close to the exchange capacity of the clay). The data fulfill Langmuir's equation, implying a chemical adsorption mechanism. The results of the X-ray diffraction and I.R. spectroscopy studies confirm the intercalation of the organic cation into the interlayer space of montmorillonite, forming a complex of defined spacing (17.66 Å (DL = 8.06 Å)). The studies revealed that cation exchange is the mechanism responsible for this interaction. The “in vitro” desorption studies showed that the amount of papaverine desorbed from the complex depends on the pH of the solution, on its ionic strength, on the presence of free drug and on the elimination rate of the desorbed complex; in all cases, desorption was seen to be very low. In general, release of the drug follows a single first order kinetic process with a rapid initial desorption of the drug.
    10/2008; 11(11):1909-1930.
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    ABSTRACT: Abstract The interaction between oxprenolol hydrochloride and montmorillonite was studied by adsorption isotherms, x-ray diffraction and i.r. spectroscopy. The adsorption isotherm fits Langmuir's equation and the maximum amount of oxprenolol adsorbed by the clay is 70 mEq/100 g of clay. The results of x-ray diffraction studies and i.r. spectroscopy reveal that the oxprenolol molecule is adsorbed into the interlayer space of the clay and that the mechanism of adsorption is cation exchange.
    10/2008; 9(6):1019-1029.
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    ABSTRACT: This study develops a population pharmacokinetic model for lamotrigine (LTG) in Spanish and German patients diagnosed with epilepsy. LTG steady-state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 600 patients, with a total of 1699 plasma drug concentrations. The data were analyzed according to a one-compartment model using the nonlinear mixed effect modelling program. The influences of origin (Germany or Spain), sex, age, total body weight, and comedication with valproic acid (VPA), levetiracetam, and enzyme-inducing antiepileptic drugs (phenobarbital [PB], phenytoin [PHT], primidone [PRM], and carbamazepine [CBZ]) were investigated using step-wise generalized additive modelling. The final regression model for LTG clearance (CL) was as follows: CL(L/h) = 0.028*total body weight*e(-0.713*VPA)*e0.663*PHT*e0.588*(PB or PRM)*e0.467*CBZ*e0.864*IND, where IND refers to two or more inducers added to LTG treatment; this factor as well as VPA, PHT, PB, PRM, and CBZ take a value of zero or one according to their absence or presence, respectively. The administration of inducers led to a significant increase in mean LTG CL (values of 0.045-0.070 L/h/kg vs. 0.028 L/h/kg being reached in monotherapy), whereas VPA led to a significant decrease in CL (0.014 L/h/kg). Thus, comedication with these analyzed drugs can partly explain the interindividual variability in population LTG CL, which decreased from the basic model by more than 40%. The proposed model may be very useful for clinicians in establishing initial LTG dosage guidelines. However, the interindividual variability remaining in the final model (clearance coefficient of variation close to 30%) make these a priori dosage predictions imprecise and justifies the need for LTG plasma level monitoring to optimize dosage regimens. Thus, this final model allows easy implementation in clinical pharmacokinetic software and its application in dosage individualization using the Bayesian approach.
    Therapeutic Drug Monitoring 08/2008; 30(4):483-9. · 2.23 Impact Factor
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    ABSTRACT: The population kinetics of gentamicin and amikacin were studied comparatively in newborn patients with a similar range of gestation age (37.9 ± 2.9 and 36.7 ± 3.6 weeks), postnatal age (13.8 ± 7.4 and 16.7 ± 7 days) and weight (2.85 ± 0.57 and 2.72 ± 0.75 kg), undergoing routine therapeutic monitoring of their serum levels. Individual kinetic analysis of serum drug levels was done using a single-compartment model. The population model employed assumes the existence of residual variability in the serum concentrations and interindividual variability in the pharmacokinetic parameters. The clearance and the apparent distribution volume were calculated for each patient using a two-stage method. Statistically significant differences were obtained in the distribution parameters (0.54 ± 0.17 and 0.43 ± 0.13 1/kg) of both drugs (P<0.05), but not in serum clearance. The interindividual variability in the pharmacokinetic parameters was similar. These results help to improve the forecasting quality of the ‘a priori’ methods for the initial dosing of aminoglycoside antibiotics in this type of patient.
    Journal of Clinical Pharmacy and Therapeutics 06/2008; 18(6):411 - 413. · 2.10 Impact Factor
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    Santiago Grau, Francisco Alvarez-Lerma, Alfonso Domínguez-Gil
    Expert Review of Anticancer Therapy 01/2008; 5(6):913-6. · 3.22 Impact Factor
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    ABSTRACT: To identify the variables affecting vancomycin pharmacokinetics in medical ICU patients and to evaluate the potential efficacy of dosage schedules by PK/PD analysis. A retrospective pharmacokinetic analysis of serum levels obtained in routine vancomycin monitoring was performed. A 12-bed general ICU of a university teaching hospital. Forty-six vancomycin-treated ICU patients fitting the following criteria: over 18 years old; more than three concentration data per patient; absence of renal replacement support, cardiac surgery and neoplastic disorders. Clinical information was collected from the patients' medical records. Details of vancomycin therapy, dosage and blood sampling times were obtained from pharmacokinetic reports. Population analysis were made by the standard two-stage approach. Vancomycin clearance and distribution volume were estimated individually assuming a one-compartment pharmacokinetic model. PK/PD analysis was performed by Monte Carlo simulation. In the ICU patients, higher Vd (nearly twice the quoted value of 0.72 l/kg) and different vancomycin clearance-creatinine clearance relationship were found. Renal function, the APACHE score, age and serum albumin accounted for more than 65% of drug clearance variability. Vancomycin standard dosages led to a 33% risk of not achieving the recommended AUC(24h)/MIC breakpoint for Staphylococcus aureus. The population kinetics and PK/PD analyses based on Monte Carlo simulation procedures offer an excellent tool for selecting the therapeutic option with the highest probability of clinical success in ICU patients.
    Intensive Care Medicine 03/2007; 33(2):279-85. · 5.54 Impact Factor
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    ABSTRACT: This study determines vancomycin (VAN) population pharmacokinetics (PK) in adult patients with hematological malignancies. VAN serum concentration data (n = 1,004) from therapeutic drug monitoring were collected retrospectively from 215 patients. A one-compartment PK model was selected. VAN pharmacokinetics population parameters were generated using the NONMEM program. A graphic approach and stepwise generalized additive modeling were used to elucidate the preliminary relationships between PK parameters and clinical covariates analyzed. Covariate selection revealed that total body weight (TBW) affected V, whereas renal function, estimated by creatinine clearance, and a diagnosis of acute myeloblastic leukemia (AML) influenced VAN clearance. We propose one general and two AML-specific models. The former was defined by CL (liters/h) = 1.08 x CL(CR(Cockcroft and Gault)) (liters/h); CV(CL) = 28.16% and V (liters) = 0.98 x TBW; CV(V) =37.15%. AML models confirmed this structure but with a higher clearance coefficient (1.17). The a priori performance of the models was evaluated in another 59 patients, and clinical suitability was confirmed. The models were fairly accurate, with more than 33% of the measured concentrations being within +/-20% of the predicted value. This therapeutic precision is twofold higher than that of a non-customized population model (16.1%). The corresponding standardized prediction errors included zero and a standard deviation close to unity. The models could be used to estimate appropriate VAN dosage guidelines, which are not clearly defined for this high-risk population. Their simple structure should allow easy implementation in clinical software and application in dosage individualization using the Bayesian approach.
    Antimicrobial Agents and Chemotherapy 01/2006; 49(12):4934-41. · 4.57 Impact Factor
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    ABSTRACT: A prospective pharmacokinetic study was performed in Caucasian patients from an intensive care unit with respiratory support to evaluate the influence of this circumstance on the pharmacokinetic behaviour of levofloxacin. A standard dosage regimen of 500 mg/day was administered to nine Caucasian patients included in the study, irrespective of their demographic characteristics. The experimental data on plasma concentrations were analysed by independent-modelling techniques to estimate the following pharmacokinetic parameters: area under the plasma concentration-time curve (AUC), volume of distribution at steady state (V(ss)), plasma clearance (CL), maximum plasma concentration at steady state (C(max)(,)(ss)) and elimination half-life (t((1/2))(beta)). Multiple regression analysis was applied to establish the type of correlation between the pharmacokinetic parameters and patient characteristics; the Monte Carlo simulation technique was implemented for the pharmacokinetic/pharmacodynamic analysis based on the probability distribution of the values of AUC/minimum inhibitory concentration (MIC) and C(max)(,)(ss)/MIC observed in this group of patients. The results show that for AUC the simplest linear model with creatinine clearance as the only independent variable fits the data at a 99% confidence level, explaining more than 85% of the observed variability in this parameter. The volume of distribution, however, showed a statistical correlation with the severity of the illness (Simplified Acute Physiology Score II), although total bodyweight also explains a high percentage of variability of these parameters. Since the group of patients included in the study was small and also included obese individuals, it is difficult to estimate with precision the contribution of each circumstance (overweight or illness severity) to the pharmacokinetic behaviour of levofloxacin.
    Clinical Pharmacokinetics 02/2005; 44(6):627-35. · 5.49 Impact Factor
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    ABSTRACT: To analyse the pharmacokinetic basis for the use of extended-interval dosage regimens of gentamicin in neonates using population pharmacokinetics. The population pharmacokinetics of gentamicin was studied retrospectively in a population of 113 neonates divided into two groups: one for computing the population model (n=97) and another for validation (n=36). A one-compartment pharmacokinetic model and non-linear mixed-effects modelling were used to assess the population pharmacokinetic model. Weight (W) and postnatal age (PA) were the covariates that influenced the pharmacokinetic parameters of gentamicin. The final population model obtained was: distribution volume, V (L)=0.636 x W (kg)0.852; clearance, Cl (L/h)=0.032 x W (kg)1.482+0.0024 x PA (days). The predictive performance of the model in the population validation was adequate for clinical purposes. The optimized population model allowed us to simulate gentamicin serum levels and their variability, in this kind of patient, when extended-interval dosage administration regimens were implemented. According to our pharmacokinetic population model, initial doses of gentamicin of 10 mg/kg, and dosage intervals between 36-48 h, appear to be appropriate to achieve target peak and trough serum levels of 15-20 and <0.5 mg/L, respectively, when extended-interval dosage regimens are implemented in newborns. The half-life of gentamicin in premature babies of very low weight and gestational age <31 weeks is long. Thus, to achieve serum concentrations in the 1-10 mg/L range, the use of dosage regimens of 5 mg/kg at 36-48 h dosage intervals seems suitable.
    Journal of Antimicrobial Chemotherapy 08/2004; 54(1):193-8. · 5.34 Impact Factor
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    ABSTRACT: The conversion of novel therapeutics into medicines is frequently delayed by the lack of parallel investment in the ‘enabling’ field of drug delivery. During the past few years, a large number of new drug delivery technologies have been optimized to guide the potential drug specifically to the target where it is needed and to deliver it at an effective concentration and at the correct time, with safety and reproducibility. In this article, the use of micro- and nanosystems, pulsatile drug delivery systems, macromolecular conjugation and microfabricated systems together with their application in preclinical or clinical investigation will be discussed.
    Trends in Pharmacological Sciences 08/2004; 25(7):382-7. · 9.25 Impact Factor

Publication Stats

996 Citations
355.45 Total Impact Points

Institutions

  • 2009–2011
    • Universidad Austral de Chile
      Ciudad de Valdivía, Los Ríos, Chile
  • 1990–2011
    • Hospital Universitario de Salamanca
      Helmantica, Castille and León, Spain
  • 1978–2008
    • Universidad de Salamanca
      • • Departamento de Farmacia y Tecnología Farmacéutica
      • • Facultad de Farmacia
      Salamanca, Castile and Leon, Spain
  • 1997
    • University of Coimbra
      • Faculdade de Farmácia
      Coimbra, Distrito de Coimbra, Portugal
  • 1994–1997
    • Universidad del País Vasco / Euskal Herriko Unibertsitatea
      • Faculty of Pharmacy
      Bilbao, Basque Country, Spain