Spectrum of cholangitis

Of 402 patients admitted with biliary disease over the last three years, cholangitis has been diagnosed in 36. This represents an 8.8 per cent overall incidence and a 33.8 per cent incidence among patients who have undergone operation or manipulation involving the common duct. Based on this experience, a program of prophylaxis and treatment of cholangitis has been devised with special emphasis on the management of elderly patients in the initial postoperative period.     

Metiamide: more than an H2-receptor antagonist.

The effect of metiamide on acid secretion and calcium uptake by the frog gastric mucosa was tested alone and in combination with histamine, pentagastrin, aminophylline, and dibutyrl cyclic AMP (db cAMP). Metiamide inhibited all stimulants including db cAMP which presumably acts intracellularly beyond the H2 receptor. Metiamide, therefore, actively inhibits at a point within the cell beyond the adenylated cyclase membrane receptor complexes. Metiamide also increases calcium influx into the parietal cell, suggesting yet another possible mechanism of inhibition.     

Comparison of the uptake of retinoids 13-cis-retinoic acid and Ro 13-6298 delivered to HL-60 cells by serum albumin or low-density lipoprotein

Retinoids, a class of polyisoprenoids including retinol and retinoic acid, regulate and control diverse physiological functions via their cell-differentiating and morphogenic potential. In the present study we showed that the extracellular concentration of retinoid-binding proteins such as albumin limits the amount of retinoid entering the human promyelocytic leukemia cell line HL-60. These cells accumulate 5?–?10 times more retinoid when delivered free in solution than when bound to either albumin or low-density lipoprotein (LDL). Moreover, the effect of protein binding is concentration-dependent, with a higher concentration of binding protein corresponding to a lower level of cellular uptake. Furthermore, the uptake of the ester derivative is higher than that of the acidic retinoid. These observations suggest that (a) the cellular uptake of both retinoids occurs via the free form of the ligand in solution, with the free concentration of ligand decreasing as the carrier-protein concentration increases, and (b) according to a passive mechanism, the ester derivative, unionized and lipophilic, enters the cells more easily than does the acidic derivative.     

Pharmacologie des catécholamines chez l’enfant

A safe use of catecholamine drugs in children with shock could improve the prognosis. In addition to the specific molecule, dosing regimen determines the effect. A good knowledge of properties of the four main catecholamine drugs (dopamine, dobutamine, epinephrine, and norepinephrine) is essential for the right choice of drug and dosing regimen. However, dose–effect relationships are nonlinear and variable between subjects. Given growth and maturation phenomena, this variability is greater in children. Pharmacokinetic–pharmacodynamic studies may explain this variability. Numerous studies on dopamine and dobutamine reported between subject variabilities, but failed to estimate it. Recent population studies on epinephrine and norepinephrine in children were able to quantify between subject variabilities and explain it by identifying covariates, namely weight, age, and severity of illness, that influence some pharmacologic parameters. The smaller the child, the higher dosing regimen should be employed. Dosing of catecholamine drugs in children should not be a linear extrapolation from adult recommendations.     

Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC_0–24]) were higher in SP than in BP (median AUC_0–24, 38.04 and 12.95 mg · liter⁻¹ · h, respectively). The median (range) SP-to-BP AUC_0–24 ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC_0–24 ratios were lower than 1. The impact of FTC SP AUC_0–24 or FTC SP-to-BP AUC_0–24 ratio on spVL detection was not significant (P = 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.     

Tubular transporters OAT1 and MRP2 and clearance of adefovir

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.     

Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide

Background Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols.Methods Mice and dogs received IV IPM daily for 3 days. Single-day dosing—oral and IV—to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.Results For mice, the LD₁₀ for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87–134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T_1/2 was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T_1/2 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T_1/2 was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation.Conclusions Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m² with a clearance of 39.5 l/h, and a T_1/2 of 1 h 45 min for a 70-kg patient.     

Prospective assessment and histological analysis of adherent perinephric fat in partial nephrectomies

Objectives

The complexity of partial nephrectomy (PN) is partly anticipated by morphometric tumor-based scores that do not consider patient-related issues such as adherent perinephric fat (APF). Also, the objective is to prospectively assess the predictive factors of APF during PN, its effect on complications, and to correlate it to the histological reality.

Proton magnetic resonance spectroscopy of brain metabolic shifts induced by acute administration of 2‐deoxy‐d‐glucose and lipopolysaccharides

In vivo proton magnetic resonance spectroscopy (¹H MRS) of outbred stock ICR male mice (originating from the Institute of Cancer Research) was used to study the brain (hippocampus) metabolic response to the pro‐inflammatory stimulus and to the acute deficiency of the available energy, which was confirmed by measuring the maximum oxygen consumption. Inhibition of glycolysis by means of an injection with 2‐deoxy‐d ‐glucose (2DG) reduced the levels of gamma‐aminobutyric acid (GABA, p < 0.05, in comparison with control, least significant difference (LSD) test), N‐acetylaspartate (NAA, p < 0.05, LSD test) and choline compounds, and at the same time increased the levels of glutamate and glutamine. An opposite effect was found after injection with bacterial lipopolysaccharide (LPS) – a very common pro‐inflammatory inducer. An increase in the amounts of GABA, NAA and choline compounds in the brain occurred in mice treated with LPS. Different metabolic responses to the energy deficiency and the pro‐inflammatory stimuli can explain the contradictory results of the brain ¹H MRS studies under neurodegenerative pathology, which is accompanied by both mitochondrial dysfunction and inflammation. The prevalence of the excitatory metabolites such as glutamate and glutamine in 2DG treated mice is in good agreement with excitation observed during temporary reduction of the available energy under acute hypoxia or starvation. In turn, LPS, as an inducer of the sickness behavior, which was manifested as depression, sleepiness, loss of appetite etc., shifts the brain metabolic pattern toward the prevalence of the inhibitory neurotransmitter GABA. Copyright © 2014 John Wiley & Sons, Ltd.