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This paper describes an LC-MS/MS method to determine the concentration of spironolactone and its metabolites 7-alpha-methylthiospironolactone and canrenone in blood plasma samples. The resulting assay is simple (using protein precipitation for sample preparation) and sensitive (the lower limit of quantification is close to 0.5 ng/ml) while requiring only 50 μl of plasma, making it especially suitable for analyzing samples obtained from pediatric and neonatal patients where sample sizes are limited. The sensitivity is achieved by using ammonium fluoride as an eluent additive, which in our case amplifies the signal from our analytes in the plasma solution on average about 70 times. The method is fully validated according to the European Medicines Agency’s guideline and used for the measurement of pediatric patients’ samples in clinical trials for evaluating oral spironolactone’s and its metabolites’ pharmacokinetics in children up to 2 years of age.

Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)—the first-line anthelminthic drug for medical treatment of CE—is metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = −0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 μg/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 μg/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 μg/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts (β = −17.2 μg/L/cm; 95th CI, −35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis. Electronic supplementary material The online version of this article (doi:10.1007/s00436-016-5054-x) contains supplementary material, which is available to authorized users.

Objectives Morphine is the drug of choice for severe pain. There is a four-fold variation in the recommended dose of intravenous morphine. We decided to determine the extent of inter-individual variation in clearance of morphine in children. Methods A systematic literature review was performed to identify papers describing the clearance of morphine in children. The following databases were searched: Medline (1946 to May 2013), Embase (1974 to May 2013), International Pharmaceutical Abstracts (1974 to May 2013), CINAHL (1937 to May 2013) and Cochrane library. From the papers the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. Results Twenty eight articles were identified. Only 12 studies gave clearance values for individual patients. The majority of the studies were in critically ill patients. Inter-individual variability of morphine clearance was observed in all age groups. The CV was 16–97% in preterm neonates, 24–150% in term neonates, 4.5–140% in infants, 14–55% in children and 14–74% in adolescents. The variation ratios of clearance were 2–13 fold (185 preterm neonates), 2–23 fold (72 term neonates), 2–10 fold (120 infants) 1.3–3 fold (17 children) and 2–2.6 fold (8 adolescents). The mean clearance was higher in children (21.5 to 80.5 ml/min/kg) than in neonates (2.2 to 20.2 ml/min/kg). Conclusions Large inter-individual variation was seen in morphine clearance values in critically ill neonates and infants. The variation in clearance is far greater than the variation in recommended doses. The dose of morphine should be titrated according to need after adequate pain assessment.

Abstract Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease. Objective This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response. Methods This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days). Results Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment. Conclusions Our results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer’s disease (AD).

Background Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic variation in drug exposure. This paper aimed to evaluate the effect of ethnicity on the bioavailability and clearance of oral and intravenous vinorelbine. Methods Oral and intravenous vinorelbine pharmacokinetics data in Asian patients were pooled from two-phase II studies of patients with non-small-cell lung cancer or advanced breast cancer in China. Blood vinorelbine and its active metabolite, 4′-O-deacetylvinorelbine, were quantified using liquid chromatography–tandem mass spectrometry. Bayesian pharmacokinetic parameters were calculated and vinorelbine monotherapy results (intravenous 25 mg/m2; oral 60 mg/m2) of the Asian data set were compared to a reference European data set (intravenous 30 mg/m2; oral 80 mg/m2). Subsequently, a population pharmacokinetics analysis was conducted in a combined cohort (Asian data set + historical vinorelbine pharmacokinetics database) to investigate for a potential effect of ethnicity. Results Pharmacokinetics data from the Asian data set (oral: n = 47; intravenous: n = 34) was compared to the European reference data set (oral: n = 48; intravenous: n = 48). Mean apparent clearance of oral vinorelbine and mean absolute clearance of intravenous vinorelbine was comparable between the Asian and reference European data set. A population pharmacokinetic analysis (oral: n = 222; intravenous: n = 111) demonstrated no influence of ethnicity on oral and intravenous vinorelbine bioavailability and clearance. Conclusion Vinorelbine pharmacokinetics were found to be comparable between Asian and European patients. No relevant influence of ethnicity on vinorelbine bioavailability and clearance for oral and intravenous routes of administration was observed.

This paper presents a data-driven approach for modeling the temporal profile of pharmacological magnetic resonance imaging (phMRI) data, in which the blood oxygen level-dependent (BOLD) response to an acute drug challenge is measured. To date, this type of data have typically been analysed using general linear models applied to each voxel individually, an approach that requires a pre-defined model of the expected response to the pharmacological stimulus. Previous approaches have defined this model using pharmacokinetic profiles, phMRI data from pilot studies, cognitive or physiological variables that have been acquired during the experiment or a simple pre-post boxcar profile. In contrast, the approach presented here is data-driven; a basis function is fitted to the data in a Bayesian framework using Gaussian processes. This method outperforms two previous multivariate approaches to fMRI analysis while also providing information about the shape of the BOLD response and hence, increasing the model interpretability.

This paper presents the application of nonlinear predictive control to drug dosing during anesthesia in prospective patients for undergoing surgery. A single-input (propofol) single output (Bispectral index (BIS)) patient model has been employed. The pharmacokinetic-pharmacodynamic model, which is in fact a Wiener-type model, has been used for prediction. A set of 12 patient models were studied while controlling BIS at 50 by applying our in-house nonlinear extended-prediction self-adaptive control strategy (NEPSAC). The results of this simulation study show that NEPSAC outperforms EPSAC, using a nominal patient model for prediction.

Dynamic-Contrast Enhanced MRI(DCE-MRI) is a method to analyze the perfusion dynamics in the tissues. The contrast agent concentration along the time, after the bolus injection, depends on the type of tissue observed, namely on its vascularization density and metabolic activity. The number of acquired volumes in this type of exam is usually very small, typically < 10, and the volumes are misaligned due to respiratory and cardiac activities. In this paper an algorithm to automatically characterize the malignancy of the tumor is presented based on the perfusion curves on each voxel of the tumor, obtained from DCE-MRI. A non-rigid registration procedure based on Mutual Information(MI) criterion is used to align the small volumes representing the region of interest(ROI) containing the tumor along the time. A pharmacokinetic(PK) third order linear model is estimated from the observations and its parameters are used to classify the malignancy of tumor.

This paper assesses the estimation of kinetic parameters from dynamic contrast-enhanced magnetic resonance imaging (DCEMRI). Asymptotic results from likelihood-based nonlinear regression are compared with results derived from the posterior distribution using Bayesian estimation, along with the output from an established software package (MRIW). By using the estimated error from kinetic parameters, it is possible to produce more accurate clinical statistics, such as tumor size, for patients with breast tumors. Further analysis has also shown that Bayesian methods are more accurate and do not suffer from convergence problems, but at a higher computational cost.

Quinolones have proven to be valuable drugs with interesting microbiological, pharmacokinetic, and therapeutic properties. The aim of this article is to give an overview of the toxicological profile of this class of compounds. Based on current knowledge, it appears that the pattern of preclinical adverse reactions is comparable for all quinolones, although there are some differences in both the incidence and the type of reaction induced by certain compounds. The published toxicological profile for the quinolones (Table 1) includes arthropathy, Achilles tendinitis and rupture, nephropathy, effects on the central nervous system (CNS), ocular toxicity, impairment of spermatogenesis, cardiovascular effects, possible mutagenic and carcinogenic effects, phototoxicity, photocarcinogenicity, photomutagenicity, drug interactions, and metabolic and nutritional events. The aim of this paper is to review and discuss the data derived from animal toxicology studies of the effects of quinolones at these target sites.

Etoposide has been introduced into cancer chemotherapy 15 years ago. A considerable amount of knowledge about the pharmacokinetics has accumulated since then, several reviews have been published recently, for a more detailed discussion of earlier studies in this field these publications should be consulted [1,2]. This paper will predominantly deal with pharmacokinetic aspects of schedules other than the “standard dose” IV treatments, e.g., locoregional application, dose reduction with impaired organ function, high dose treatment.

Many drugs acting on the central nervous system produce characteristic changes on the electroencephalogram (EEG). As early as the third decade of this century, Berger described in several papers that morphine, cocaine, barbiturates, and scopolamine altered the EEG [1,2]. In the last 10 years, drug-induced EEG changes have been described in detail for many intravenous drugs used in anesthesia. It has now generally been established that drugs acting on the central nervous system cause EEG changes that are specific, continuous, measurable, objective, sensitive, and reproducible. These properties made the EEG a powerful tool to measure drug effects. However, the correlation between EEG drug effects and clinical drug effects such as analgesia, hypnosis, and sedation has not yet been unraveled and remains to be definitively established. Therefore, the EEG must be considered as a “surrogate” effect measurement. A surrogate measure of effect can be defined as a secondary, drug-induced, measurable change in body physiology.

Relationships between pharmacokinetics (PK) and pharmacodynamics (PD) are now widely investigated for many drugs with the aim of improving the amount and the rate of drug delivery so as to control the duration and intensity of the pharmacological effect (Levy 1966; Holford 1981). Such relationships have not yet been investigated for toxic effects of drugs as occurs after acute self-poisoning. The establishment of relationships between kinetics of drugs at toxic doses (Toxicokinetics) and those of their pharmacological effects (Toxicodynamics) can be of interest in clinical toxicology. The aim would be to predict the occurrence and the intensity of toxic effects as a function of the ingested dose and the first plasma concentrations on admission of the patient to improve management. In this paper, we describe the different techniques of kinetic-effect modelling actually available, their applications in the case of acute digitalis poisoning and the limits of such techniques in clinical toxicology.

Nephrotoxicity is the major adverse effect of the valuable immunosuppressive drug cyclosporine. The pharmacology and pharmacokinetic behavior of cyclosporine is complex; clinically relevant considerations, including drug interactions, are covered in this paper. In addition, the major clinical syndromes associated with cyclosporine nephrotoxicity are discussed. These include initial oligoanuria after renal transplant, acute reversible episodes of renal dysfunction, chronic nephrotoxicity with tubulointerstitial fibrosis, hemolytic-uremic syndrome, hypertension, and electrolyte disturbances. An algorithm for distinguishing renal dysfunction due to allograft rejection from acute cyclosporine nephrotoxicity is proposed, since this distinction continues to be a difficult problem for nephrologists. Although therapeutic drug monitoring using blood or plasma cyclosporine levels has not fulfilled its promise, practical guidelines for the use of these studies are presented.

Up to 30% of patients resuscitated after an out-of-hospital cardiac arrest suffer from neurological damage [5]. Experimental data indicate that neurological damage goes on even after the restoration of spontaneous circulation. and that calcium may play a crucial role therein. Indeed, there is calcium influx into vascular smooth muscle cells, leading to cerebral vasoconstriction and hypoperfusion of the brain and calcium overflow into the neuronal cells. Following reports of a cerebroprotective action of the calcium entry blocker nimodipine in animal models of cerebral ischemia [4], there has been interest in the use of nimodipine in patients resuscitated after out-of-hospital cardiac arrest [8]. In the present paper we discuss some of the possible alterations in the pharmacokinetic properties of nimodipine in resuscitated patients and the kinetic data we obtained in such patients.

Life-threatening digitalis overdose can now be safely and rapidly reversed by administration of specific anti-digoxin Fab fragments (Antman et al 1990). The aim of the therapy is to lower the intravascular free drug concentration by changing the equilibrium of the free drug between the intravascular and intracellular body water compartments (Hursting et al 1987). Thus, a toxin concentration gradient from intracellular to intravascular space is created (Scherrmann et al 1989). Fab fragment administration has been shown to alter digoxin disposition (Schaumann et al 1986). To monitor the efficacy of Fab fragments, both free and total digoxin concentrations have to be determined. This paper reports the pharmacokinetics of free and total digoxin concentrations in five patients poisoned by digoxin and of Fab fragments for two of them.

First of all this paper discusses some present clinically relevant data on the pharmacokinetics of in particular, retarded forms of insulin. The influence of galenic preparations are then discussed in detail with regard to species specificity, incon-stancy of absorption, and the dependency of the absorption rate on the dose of insulin.

Propafenone is an antiarrhythmic drug that has been shown to be clinically effective in the treatment of supraventricular and ventricular premature beats (see Hochrein et al. 1977, Luderitz 1978, 1981, Neuss and Buss 1978, Theisen 1978, Petri and Rudolph 1979, Schmitz 1980, Seipel and Breithardt 1980, Scholz 1981). In this paper I shall briefly summarize the pharmacologic properties of propafenone as determined in animal experiments in vitro and in vivo. The pharmacokinetic properties of the drug and the results of toxicologic studies are also presented.

The present knowledge of pharmacokinetics and metabolism of digitoxin in man, derived from single dose (Caldwell et al., 1971;Doherty, 1968; Kramer et al., 1970; Lahrtz et al., 1969; Okita et al., 1953,1955; Vohringer and Rietbrock, 1974; Weissler et al., 1966) as well as from multiple dose studies (Jelliffe, 1967; Lukas, 1971,1973; Peters et al., 1975; Solomon et al., 1971; Storstein, 1974; Wirth et al., 1976) using different methods, can be characterized as follows: 1. The elimination of digitoxin with a half-life of 6–8 days in plasma and urine is very slow. 2. The metabolism of digitoxin in man is assumed to occur with a cleavage of digitoxose side chains, with a β-hydroxylation of digitoxin to digoxin, and with a formation of polar Compounds. However, there is controversy in the literature as to exactly how far digitoxin is quantitatively metabolized. There-fore, in this paper new data on digitoxin kinetics are presented during maintenance therapy.

Since introduction of s-adrenergic antagonists, there has been a burst of research works on the mechanism of their hypotensive effects, and the effectiveness of these drugs for the treatment of glaucoma is now well established. Not only the knowledge of the mechanism of their action, but also of pharmacokinetics is of value for designing logical therapeutic regimen. Therefore, the recent findings on the latter aspects of the s-adrenergic drugs are summarized in this paper.

This paper does not aim to give a complete overview of the pharmacokinetics of isosorbide dinitrate (ISDN) or other organic nitrates. I would rather concentrate on discussing some preliminary results that we obtained with ISDN in patients with chronic heart failure.

The use of phthalocyanines as photosensitizers in the photodynamic therapy (PDT) of tumours is raising the interest of several research and clinical groups because of the large potential advantages of these dyes. In particular, phthalocyanines are better tumour-photosensitizers than many porphyrins (1). We are using Zn(II)-phthalocyanine (Zn-Pc), which has a high degree of purity and can be readily incorporated into small unilamellarliposomes of dipalmitoyl-phosphatidylcholine (DPPC) (2). Preliminary PDT studies performed by injecting Balb/c mice bearing a transplanted MS-2 fibrosarcoma with 0.5 mg/kg Zn-Pc showed that an extensive necrosis of the tumour tissue can be obtained by irradiation with ca. 660 nm-light (total 2 2 light dose: 300 J/cm2; dose-rate: 270–370 mW/cm2). Therefore, it appears of interest to investigate the detailed aspects of the mechanisms by which Zn-Pc is accumulated and retained by tumours and, once photoactivated, causes the necrosis of the tumour tissue. In this paper, we report some pharmacokinetic and ultrastructural studies with Zn-Pc in vivo.

Carbamazepine which is the active substance of the anti-epileptic drug Tegretol® has the chemical structure of 5-carbamyl-5H-dibenzo[b, f]azepine. Recently several papers relating to the biotransformation of the drug have been published but our present knowledge still appears insufficient.

The effects of the impaired function of the excretory organs on the pharmacodynamics of muscle relaxants have been demonstrated and discussed for liver diseases by Duvaldestin et al. [13] and for alterations of renal parenchyma by Buzello u. Noldge [5]. We shall analyze whether the normal consequences of the aging process on the function of the excretory organs significantly alters the effects of neuromuscular blocking agents. In fact, the pharmacokinetics and certain dose-effect relationships for numerous drugs used in anesthetic practice (i.e., barbiturates, benzodiazepines, and narcotics) differ markedly for elderly patients as compared with younger subjects [3, 6, 16]. In this paper, we define a series of practical precautionary measures to take when using muscle relaxants in geriatric patients by addressing the following question: does aging modify the loading dose, the latency, and the duration of action of commonly used neuromuscular blocking agents for normal geriatric patients?

When a drug has been absorbed into the blood stream a series of processes take place which are mostly interrelated: dispositions in tissues and organs, excretion, metabolism. Most interesting is the permeation towards the target organ, in the case of narcotic analgesics, towards the brain. This paper will mainly deal with the kinetics of this permeation and other problems shall be treated only in so far as they are helpful to understand this particular process.

In modern therapeutic research it is a generally accepted that the knowledge of the qualitative and quantitative effects of a new drug is not sufficient for its characterization, but that as much as possible should be known about its fate in the body — i. e. absorption, blood levels, distribution, elimination, and biotransformation. In the case of Crasnitin 1 this is of special importance because therapy with enzymes is a rather new field of modern medicine, and the experience gained with other drugs may well be worthless with respect to asparaginase (Asnase) therapy. For this reason we made some efforts — like several other investigators [2, 3, 6, 7, 8] — to explore the fate of Asnase in the body, and I shall show in this paper that in our experiments Asnase has indeed some pharmacokinetic properties by which it differs considerably from other drugs.