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Pyridoclax is an original oligopyridine lead, very promising in treatment of chemoresistant cancers. However, from solubility measurement and permeability evaluation, it appeared that this compound can be considered as a BCS II drug, with a poor water solubility. To overcome this unfavorable property, two strategies were proposed and compared: pyridoclax di-hydrochloride salt synthesis and formulation of pyridoclax-loaded nanoemulsions (PNEs) efficiently performed by transposing the spontaneous emulsification process previously developed by our team. Whereas the salt improved the thermodynamic solubility of the drug by a factor 4, the apparent solubility of the encapsulated pyridoclax was 1000-fold higher. Their stability was assessed upon dilution in various complex biomimetic media relevant for oral administration (SGF, FaSSIF-V2, FeSSIF-V2) or for the intravenous route (PBS). The solubility of the salt was affected by the nature of the medium, indicating that it could precipitate after administration, negatively impacting its bioavailability and its efficiency in vivo. On the contrary, in all media, PNEs remained stable in terms of granulometric properties (determined by DLS), ζ-potential and encapsulation efficiency (measured by HPLC). Thus, such nanomedicines appear as a valuable option to perform preclinical studies on the promising pyridoclax.

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Kisspeptin, the product derived from KiSS-1, and its cognate receptor, GPR54, both exert a role in the neuroendocrine control of reproduction by regulating gonadotrophin-releasing hormone (GnRH) secretion. In the present study, we demonstrate, using dual immunofluorescence with specific antibodies, that the KiSS-1 and GPR54 genes are both expressed in rat gonadotrophs. All luteinising hormone beta-immunoreactive (LH beta-ir) cells were stained by the KiSS-1 antibody but some kisspeptin-ir cells were not LH beta positive; thus, we cannot exclude the possibility that kisspeptins are expressed in other pituitary cells. All GPR54-ir are co-localised with LH beta cells, but only a subset of LH beta cells are stained with the GPR54 antibody. Using the real-time reverse transcription-polymerase chain reaction (RT-PCR), we found that the expression of KiSS-1 and GPR54 is differentially regulated by steroids. In the female, KiSS-1 mRNA levels dramatically decreased following ovariectomy (OVX), and this decrease was prevented by administration of 17beta-oestradiol (E(2)), but not by administration of GnRH antagonist or agonist. Administration of E(2) in OVX rats receiving either GnRH antagonist or agonist clearly shows that E(2) acts directly on the pituitary to positively control KiSS-1 expression. In OVX rats, administration of the selective oestrogen receptor (ER)alpha ligand propylpyrazoletriol, but not the selective ER beta ligand diarylpropionitrile, mimics this effect. By contrast, our study shows that GPR54 expression is positively regulated by GnRH and negatively controlled by chronic exposure to E(2). In summary, our data document for the first time that, in the female rat pituitary, KiSS-1 expression is up-regulated by oestradiol, similarly to that seen in the anteroventral periventricular nucleus of the hypothalamus. Conversely, GPR54 is up-regulated by GnRH, which exclusively targets gonadotrophs.

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Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

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The objective of this work was to precisely analyse the reduction of the antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after 1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle, selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after starting STN electrical stimulation. The levodopa mean daily dose was reduced by 57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%, respectively, at 1 month and to 77 and 40% at 1 year. At 12 months postoperatively, one third of the patients no longer received any antiparkinsonian drugs and the others were on monotherapy of either levodopa or dopamine agonists or received a combined treatment of a dopaminergic agonist and levodopa. In conclusion, STN stimulation allows a major reduction and simplification of antiparkinsonian treatment which can usually be achieved during the early postoperative period.

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OBJECTIVE: Pharmacokinetic (PK) interindividual variability in amikacin has been shown to be wide in neonates. This study evaluated the evolution of this variability with gestational age (GA) at birth in relation to renal maturation. METHODS: Population PK values of amikacin were studied in 131 newborns (postnatal age 1 day, GA 24-41 weeks) divided into 16 groups, defined by GA, from 24 to 41 weeks (with a mean of 8.2 infants per group). PK variables were Kel/Vol, Ks/Vs, Cl/Vol. Cls/ where: Kel = Kslope x GA + Kintercept, Cl = Clslope x GA + Clintercept, and Vol = Vs x body weight. Ki and Cli were held as constants. The nonparametric distribution of the probability density function (PDF) was obtained, as were mean, median, and SD values of each PK variable for each GA group. RESULTS: Amikacin elimination increased linearly with GA, showing that GA is a good covariate of renal elimination. Amikacin volume of distribution increased with body weight up to a GA of about 38 weeks and then decreased for highest GA values. However, the PDF for the individual GA groups showed a multimodal PK distribution. Kel, Vol, Vs, Cl, and Cl, standard deviations increased linearly with GA, showing differential renal maturation. The higher the GA, the more interindividual PK variability increased. CONCLUSIONS: These results show that amikacin elimination and the volume of distribution are dependent upon GA, and that differential renal maturation in neonates is responsible for the wider PK interindividual variability with high GA. Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA. Bayesian adaptive control of therapeutics might be particularly indicated to obtain efficacy for each neonate as early as the first dose.

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Ageing generates an important inter- and intra-individual variability in drug pharmacokinetics. The increasing frequency of ofloxacin adverse effects in elderly patients results from increased ofloxacin plasma levels about two or threefold over normal concentrations. A retrospective study of ofloxacin population pharmacokinetics in 17 elderly patients (83.6 +/- 6.8 years) shows the existence of three subgroups according to ofloxacin total clearance [group 1: 1.44 l/h, group 2: 4.37 l/h and group 3: 15.08 l/h] reflecting the important inter-individual variability. No correlation between this clearance and creatinine clearance, nor between this clearance and age, could be established, showing the limits of traditional drug monitoring in the elderly. Ofloxacin pharmacokinetic parameters estimated by the non-parametric software NPEM2 in the 17 elderly patients (absorption rate constant, Ka: 2.668 +/- 1.256 h-1; apparent volume of distribution related to weight, Vs: 1.272 +/- 0.778 l/kg; elimination rate constant, Ks: 0.265 +/- 0.247 10(-3) min/ml/h) are clearly different from those estimated in young adults. These results show the limits of classic drug monitoring in the elderly, and also the interest of adaptive control of a drug regimen.

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Various suggestions have been made for empirical pharmacodynamic indices of antibiotic effectiveness, such as areas under the drug concentration-time curve in serum (AUC), AUC > MIC, AUC/MIC, area under the inhibitory curve (AUIC), AUC above MIC, and time above MIC (T > MIC). In addition, bacterial growth and killing models, such as the Zhi model, have been developed. The goal of the present study was to compare the empirical behavior of the Zhi model of bacterial growth and killing with the other empirical pharmacodynamic indices described above by using simulated clinical data analyzed with the USC*PACK PC clinical programs for adaptive control of drug therapy, with one model describing a concentration-dependent antibiotic (tobramycin) and another describing a concentration-independent antibiotic (ticarcillin). The computed relative number of CFU was plotted against each pharmacodynamic index, with each axis parameterized over time. We assumed that a good pharmacodynamic index should present a clear and continuous relationship between the time course of its values and the time course of the bacterial killing as seen with the Zhi model. Preliminary work showed that some pharmacodynamic indices were very similar. A good sensitivity to the change in the values of the MIC was shown for AUC/MIC and also for T > MIC. In addition, the time courses of some other pharmacodynamic indices were very similar. Since AUC/MIC is easily calculated and shows more sensitivity, it appeared to be the best of the indices mentioned above for the concentration-dependent drug, because it incorporated and used the MIC the best. T > MIC appeared to be the best index for a concentration-independent drug. We also propose a new composite index, weighted AUC (WAUC), which appears to be useful for both concentration-dependent and concentration-independent drugs.

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To establish a reference for MAP Bayesian adaptive control of amikacin therapy in non-insulin-dependent diabetic patients, 30 patients (age: 63.5 +/- 10.1 years) were studied. Weight (84.2 +/- 15.4 kg) and body mass index (28.0 +/- 4.3 kg/m2 for males and 30.5 +/- 6.4 kg/m2 for females) were stable during treatment. Creatinine clearance (CCr) was 70.3 +/- 27.2 ml/min/1.73 m2 before treatment and 69.6 +/- 24.3 ml/min/1.73 m2 (NS) at the end of treatment (2 to 15 days). 129 serum concentrations were drawn (4.8 +/- 2.6 levels per patient). The one-compartment model was parameterized as having Vs (l.kg-1) and Kslope (min/ml.h) for each unit of CCr (Kel = Kintercept + Kslope x CCr). The non-renal Kintercept was fixed at 0.00693 h-1. The NPEM computes the joint probability densities. The mean, median, and SD were respectively: Vs = 0.3574, 0.3654, 0.0825 l.kg-1; Kslope = 0.0026, 0.0027, 0.0007 min/ml.h. For the a priori first doses determination, precision is higher with the new population. No difference in adaptive control was observed. In additive, the full joint density probability should be used to develop stochastic multiple model linear quadratic (MMLQ) adaptive control strategies.

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