Paul Dorveau (July 21, 1851 - January 7 1938), a librarian of the Ecole supérieure de pharmacie de Paris and cofounder of the Société d'histoire de la pharmacie

Paul Dorveaux was appointed librarian of the Ecole supérieure de pharmacie de Paris in 1884. He was associated to the foundation of the Société d' histoire de la pharmacie in 1913 because of his numerous national and international relations. This physician scholar devoted his life to the study of the medical and pharmaceutical history. Born in Lorraine he published studies on Metz pharmacy history. We owe him publications on the statutes of apothecary communities, pharmacy shops and libraries inventories, apothecaries biographies, new editions of ancient pharmacy books and a host of medical sciences studies. Paul Dorveauz published about 300 books and articles.     

Comparison of the intestinal absorption and bioavailability of γ-tocotrienol and α-tocopherol: in vitro, in situ and in vivo studies

The aim of this work was to compare the intestinal absorption kinetics and the bioavailability of γ-tocotrienol (γ-T3) and α-tocopherol (α-Tph) administered separately as oil solutions to rats in vivo. Also, to explain the significant difference in the oral bioavailability of the compounds: (1) the release profiles using the dynamic in vitro lipolysis model, (2) the intestinal permeability and (3) carrier-mediated uptake by Niemann-Pick C1-like 1 (NPC1L1) transporter were examined. Absolute bioavailability studies were conducted after oral administration of γ-T3 or α-Tph prepared in corn oil to rats. In situ rat intestinal perfusion with ezetimibe (a NPC1L1 inhibitor) was performed to compare intestinal permeability. The in vitro interaction kinetics with NPC1L1 was examined in NPC1L1 transfected cells. While the in vitro release studies demonstrated a significantly higher release rate of γ-T3 in the aqueous phase, the oral bioavailability of α-Tph (36%) was significantly higher than γ-T3 (9%). Consequent in situ studies revealed significantly higher intestinal permeability for α-Tph compared with γ-T3 in rats. Moreover, the NPC1L1 kinetic studies demonstrated higher Vmax and Km values for α-Tph compared with γ-T3. Collectively, these results indicate that intestinal permeability is the main contributing factor for the higher bioavailability of α-Tph. Also, these results emphasize the potentially important role of intestinal permeability in the bioavailability of γ-T3, suggesting that enhancing its permeability would increase its oral bioavailability.     

Interactions of carbon tetrachloride and promethazine in the rat—I: Effects of promethazine on the concentrations of carbon tetrachloride in blood and liver,and on the production of chloroform

The effects of Promethazine (PM, 78 μmoles/kg body wt, i.p.) on the concentrations of CCl₄ in samples of blood and liver of male, fasted rats after oral dosing with CCl₄ have been determined. With an administered dose of CCl₄ of 13 moles/kg body wt the concentrations of CCl₄ in the blood and liver were measured using gas chromatography with a flame ionisation detector. It was found that Promethazine delayed absorption of CCl₄ from the gastro-intestinal tract by approximately 2 hr as judged by blood levels of CCl₄; the maximum blood concentration (C_max) and the total absorption of ccl₄ (assessed by the area under the plot of blood concentration vs time during the first 6 hr after administration of CCl₄) were not significantly changed by Promethazine treatment. Liver and blood measurements were carried out on each rat in this series and the ratio of the CCl₄-concentrations in liver: blood were found to lie within the range 8–12 when studied in the absence of Promethazine treatment.Gas chromatography with electron capture was used on serial samples of blood from the same rat to measure CCl₄ and CHCl₃ concentrations following oral administration of 13, 6.5 or 1.3 mmoles CCl₄/kg body wt. The increase in blood CCl₄ levels at all doses of CCl₄ administered was delayed by about 2 hr by administration of Promethazine. The maximum blood concentrations of CCl₄ and total amount absorbed (judged by area under the plot of blood concentration vs time) were dose-related to the amount of CCl₄ administered with or without Promethazine administration. Blood concentrations of CHCl₃ were relatively constant over the range of CCl₄-doses used indicating that the metabolic production rate of CHCl₃ is saturated at rather low doses of CCl₄ administered.     

The meetings of the Société de Pharmacie de Paris during troubled periods (1803-1946)

With newly found archives and other already usable documents, it was possible to study the repercussions of several troubled periods in France on the meetings of the Société de Pharmacie de Paris (1803-1946). It seems that only three meetings were cancelled for 143 years. As a matter of fact, the number of attending members decreased widely in the troubled times. Allusions to contemporary events are not scarce in the minutes and have been reported.     

Pharmaceutical, medical and cosmetic advertising in the revue "A Illustração (Paris, 1884-1892)

Edited by a Portuguese publisher in Paris, in 15.000 copies, to be sold in Portugal and in Brazil, the revue A Illustra??o propagated the progress accomplished by French science and industry in the pharmaceutical, medical and cosmetic domaine. It followed with particular interest the work of Pasteur and nearly every advertisement that is published on the subject of health made reference to either medicine or products of French origin. Such advertisements reflect the great concern of the times with matters of hygiene, both public and private.     

Correlation of the intrinsic clearance of donepezil (Aricept®) between in vivo and in vitro studies in rat,dog and human

1. Donepezil hydrochloride (Aricept®) is used for the treatment of Alzheimer's disease. Here the correlation of the intrinsic clearance (Cl_int) of donepezil between the in vivo and in vitro states was studied in rat, dog and human. 2. In an experiment with ¹⁴C-donepezil and human microsomes the routes of metabolism were identified as N-dealkylation and O-demethylation, and no unknown metabolites were detected. 3. The Cl_int of donepezil in the male rat, female rat, dog and human liver microsomes were 33.7, 13.4, 37.0 and 6.35 μl/min/mg microsomal protein respectively, and sex difference in rat and interspecies difference in the estimated Cl_int were found. 4. After a single intravenous administration to the male rat, female rat and dog, total plasma clearance (Cl^P_total) was 78.6, 29.5 and 88.3 ml/min/kg respectively, and a sex difference was observed in rat. 5. After a single oral administration to the male rat, dog and healthy volunteer, Cl^P_total/F was 140, 105 and 2.35 ml/min/kg respectively, and remarkable differences were observed between animals and man. 6. The contribution of renal clearance to blood clearance (Cl_r) was low in all species. The predicted in vitro hepatic clearance (Cl_h-pre) was in the rank order: male rat (15.91 ml/min/kg) > dog (7.96) > female rat (7.67) > human (1.04). Although Cl_h-pre was underestimated, Cl_h-pre was significantly correlated with that of ClBtotal in the different animal species and in man, indicating that the in vitro-in vivo ranking order was conserved.     

Comparison of the in vitro binding characteristics of the β-carbolines harman and norharman in rat brain and liver and in bovine adrenal medulla

The in vitro binding of the naturally occurring -carbolines harman and norharman in their tritium-labelled forms to cell membranes from the rat brain and liver and from bovine adrenal medulla was investigated. Displacement of the specific [³H]harman binding in bovine adrenal medulla and rat liver by several -carbolines and monoamine oxidase (MAO) inhibitors revealed the pharmacological profile of a single, high-affinity binding site (K _D 4.92±0.43 nmol/l, B_max 8.47±0.17 pmol/mg protein; adrenal medulla) which corresponded to the active site of MAO type A (MAO-A). Similar characteristics have previously been found for brain tissue from rat, marmoset and pig. In order to determine the temperature dependence of the [³H]harman binding, the K _D and B_max values for rat cerebral cortex were calculated from the results of saturation experiments at 5 temperatures (range: 0°C–37°C). Whereas the B_max values under all conditions were – 4 pmol/mg protein, the K _D values, with increasing temperature, ranged from 3 nmol/l to 30 nmol/l. The calculated linear van't Hoff plot (-In K _D against 1/T) suggested an enthalpy-driven binding of [³H]harman to MAO-A.At least three different [³H]norharman-binding sites were detected. In the rat forebrain, 85% of the specific binding (at about 2 nmol/l of [³H]norharman) can be attributed to a MAO binding site of type B: the binding is displaceable, in nmol/l concentrations by the potent and selective MAO-B inhibitors MDL 72,974A, R(–)-deprenyl and pargyline and, in mol/l concentrations, by S(+)-deprenyl and the potent and selective MAO-A inhibitors clorgyline, harmine, harman, harmaline, brofaromine 5-F--methyltryptamine. After suppression of the MAO binding sites with 1 mol/l clorgyline and mol/l R(–)-deprenyl, a second binding site was found. However, the binding at this site was biphasically displaceable by harman and norharman (Hill-slopes about 0.5 and 0.6, curvilinear Rosenthal plots) suggesting the presence of negative co-operativity or of two binding sites (states). A similar clorgyline/R(–)-deprenyl resistent single (Hill-slopes of displacement by norharman, harman and 6-hydroxy--carboline about unity; linear Rosenthal plots) high affinity binding site (K _D 7.5±2 nmol/l, B_max 130±30 fmol/mg protein) was found in bovine adrenal medullary cell membranes. A third quite different clorgyline/R(–)-deprenyl resistent high-affinity (K _D14 nmol/l) and high-density (B_max 10–30 pmol/mg protein) binding site was detected in the liver. The specific binding at this site was not displaceable by harman or most other substituted -carbolines or by tetrahydro--carbolines, but was displaced by norharman and several newly synthesized 6-substituted aromatic -carbolines (e.g. F-, CH₃-, CH₃O-, HO-). The [³H]norharman binding site in the liver is certainly not identical with any of the binding sites for MAO-inhibitors, benzodiazepines or sigma receptor ligands and is slightly enriched in the microsomal (P₃) fraction whereas most of the specific [³H]harman binding was detected in the crude mitochondrial (P₂) fraction. Correspondence to: T. May at the above address     

Contamination and Biomarkers in the Great Blue Heron, an Indicator of the State of the St. Lawrence River

In 1996–1997, nine breeding colonies of the great blue heron on the St. Lawrence River and its estuary (Québec, Canada) were investigated in the framework of a biomonitoring program. Fledglings from colonies in freshwater were more contaminated with mercury, PCBs and many organic contaminants than those from estuarine colonies. The level of contamination in the St. Lawrence River is generally below the levels of toxicological effects for the great blue heron. The molar ratio of retinol: retinyl palmitate in heron eggs was correlated with total PCBs (r=0.79) and Mirex (r=0.90). In plasma, all biochemical parameters were significantly different between freshwater and marine colonies. Plasma retinol concentrations at the Dickerson and Hérons colonies were significantly lower compared with those at Grande Ile (p<0.05) and Steamboat (p<0.001). Based on retinoid and β-carotene concentrations in eggs, low plasma retinol was not associated with possible dietary deficiency. Plasma retinol was negatively correlated with many PCB congeners, total PCBs (r=−0.78), p,p′-DDE, trans-nonachlor and α-HCH. Similarly, the hormone T3 was correlated with many PCB congeners, total PCBs (r=−0.69) and the same organochlorine chemicals. Plasma LDH concentrations were different among freshwater colonies, Grande Ile and Hérons colonies having LDH values significantly greater than those of Steamboat (respectively, p<0.05 and p<0.01). Globally, the health status of the St. Lawrence great blue heron population was judged to be acceptable, however, several biomarkers indicated positive responses to contaminants.     

Recent progress in understanding of structure, ligand interactions and the mechanism of activation of the β₂-adrenergic receptor

The understanding of β?-adrenergic receptor (β?AR) interactions with ligands as well as the mechanism of receptor activation changed radically from 2007, when the first crystallographic structure of the receptor was reported. Since then numerous crystallographic studies described interactions with all main classes of β?AR ligands and with G proteins, which provided a great insight into the molecular structure of the receptor. However, molecular mechanisms of receptor activations remain to be determined. Functional research supported the concept of ligand-directed signaling at β-adrenoceptors. Agonist can activate alternative signaling pathways with different capacities and trigger cellular effects. It indicates that agonists nominally belonging to the same class may bind to and/or stabilize different active conformations of the receptor which are selectively recognized by signaling proteins in the allosteric manner.     

Effect of hypophysectomy on the stimulation of liver growth by α-hexachlorocyclohexane,phenobarbital, and partial hepatectomy in the rat

Summary -Hexachlorocyclohexane (-HCH) or phenobarbital (PB) elicit growth and cell multiplication in rat liver.In hypophysectomized rats, -HCH and PB induce an increase in liver mass, but no increase in liver DNA. Hypophysectomy without additional treatment results in a decrease of liver size and RNA, while the DNA content remains unchanged, thereby leading to a relative DNA surplus. 1/3-hepatectomy in hypophysectomized animals leads to a small increase of hepatic DNA only; after 2/3-hepatectomy 75–80% of the original liver DNA are restored. In rats with intact hypophysis losses of liver DNA are known to be restored completely.The findings suggest that the relative DNA surplus in hypophysectomized rats prevents the stimulation of DNA synthesis by weak growth stimuli such as -HCH, PB, and 1/3-hepatectomy. If the relative DNA surplus is eliminated by partial hepatectomy, the inducers do produce DNA multiplication. It is concluded that the induction of liver growth and cell multiplication by -HCH and PB does not require the presence of the hypophysis or one of its hormones.Abbreviations HCH 1,2,3,4,5,6-hexachlorocyclohexane=benzene hexachloride - PB phenobarbital - b.w. body weight - BHT butylhydroxytoluene - STH somatotrophic hormone - ACTH adrenocorticotrophic hormone     

Exposure and recovery response of isomers of HCH, metabolites of DDT and estradiol-17β in the female catfish, Heteropneustes fossilis

Effects of 40 days of exposure and 20 days of recovery response at sublethal concentration of technical grades of gamma isomer of hexachlorocyclohexane (γ-HCH, 0.025 ppm, 99.8%) and dichlorodiphenyltrichloroethane (DDT, 5.0 ppm) in tissue (liver, brain and ovary) bioconcentrations, gonadosomatic index (GSI) and plasma levels of estradiol-17β (E2) have been estimated during prespawning phase in the catfish Heteropneustes fossilis (Bloch). The results indicated that the tissue bioconcentrations of both HCHs (HCH isomers) and DDTs (metabolites of DDT) in liver, brain and ovary were in preferential order (liver > brain > ovary). The GSI and plasma levels of E2 were declined in response to exposure of γ-HCH and DDT. On withdrawal of exposure of pesticide there was recovery of HCHs in exposed fish for all tissues studied, whereas DDTs exposed fish showed recovery only in liver. Recovery of E2 production was also recorded in γ-HCH exposed fish whereas very little recorded in DDT exposed fish. It is suggested that HCHs and DDTs have preferential order (liver > brain > ovary) of their tissue bioconcentrations and HCH/DDT-withdrawal-dependent recovery during studied phase.     

Epidemiology and prevalence of extended-spectrum β-lactamase- and carbapenemase-producing Enterobacteriaceae in humans,animals and the environment in West and Central Africa

Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) and carbapenemase-producing Enterobacteriaceae (CPE) are widespread. Here we used the ‘One Health’ approach to determine knowledge gaps on ESBL-E and CPE in West and Central Africa. We searched all articles on ESBL-E and CPE in these African regions published in PubMed, African Journals Online and Google Scholar from 2000 onwards. Among the 1201 articles retrieved, we selected 165 studies (West Africa, 118; Central Africa, 47) with data from 22 of the 26 West and Central Africa countries. Regarding the settings, 136 articles focused only on humans (carriage and/or infection), 6 articles on humans and animals, 13 on animals, 1 on humans and the environment, 8 on the environment and 1 on humans, animals and environments. ESBL-E prevalence ranged from 11–72% in humans and 7–79% in aquatic environments (wastewater). In animals, ESBL-E prevalence hugely varied: 0% in cattle, 11–36% in chickens, 20% in rats, 21–71% in pigs and 32–75% in dogs. The bla_CTX-M-15 gene was the predominant ESBL-encoding gene and was associated with plasmids of incompatibility groups F, H, K, Y, N, I1 and R. CPE were studied only in humans. Class B metallo-β-lactamases (NDM) and class D oxacillinases (OXA-48 and OXA-181) were the most common carbapenemases. Our results show major knowledge gaps, particularly on ESBL and CPE in animals and the environment, that might limit antimicrobial resistance management in these regions. The results also emphasise the urgent need to improve active surveillance programmes in each country and to support antimicrobial stewardship.     

Hypertension and its management in countries in Africa and the Middle East,with special reference to the place of β-blockade

Abstract

Background:

The prevalence and clinical consequences of hypertension in countries in Africa and the Middle East have not been studied as well as in other regions.     

Importance of the Locus coeruleus and involvement of α-adrenergic receptors in the post-decapitation reflex in the rat

The latency, duration, hindlimb kick frequency, and total activity components of the post-decapitation reflex (PDR) were measured in the rat using a movement-sensitive transducer. Reduction of brain and spinal cord norepinephrine (NE) caused by neonatal administration of 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine, which also reduced brain serotonin, decreased all components of the PDR. Depletion of serotonin or dopamine alone reduced the vigor of the reflex, suggesting that these pathways can influence the PDR but are not essential for the response. Lesions of neurons in the Locus coeruleus, made electrolytically or with 6-OHDA, decreased the intensity of the PDR, with the 6-OHDA-induced lesion being more effective. Depletion of forebrain NE terminals with 6-OHDA did not alter the PDR, consistent with a critical involvement of spinal noradrenergic fibers. The PDR was also decreased by phentolamine and prazosin, but not by propanolol, suggesting an involvement of -adrenergic receptors in the response. This hypothesis was further supported by the finding that the efficacy of a variety of drugs (such as tricyclic antidepressants, phenothiazines, and antihypertensive compounds) for blocking the reflex was apparently related to their affinity for -adrenergic receptors. Thus, the PDR is dependent on noradrenergic fibers in the spinal cord and may provide a simple screen for drugs with suspected -adrenergic blocking properties or for agents that disrupt the function of central noradrenergic fibers.Bruce A. Pappas was a visiting Professor on sabbatical leave from the Department of Psychology, Carleton University, Ottawa, Canada K1S 5B6     

Differences in the biotransformation of a 17β-hydroxylated steroid,trenbolone acetate,in rat and cow

1. The metabolism of trenbolone acetate, 17β-acetoxyestra-4,9,11-trien-3-one (TBA), an anabolic compound used as a growth promoter, was compared in rat and cow.

2. [6,7-³H] TBA was injected i.v. into rats and a heifer, and bile was collected for 24?h. In both species, the bile was the major route of excretion. TBA undergoes an extensive hydrolysis to 17β-hydroxyestra-4,9,11-trien-3-one and the unchanged compound was not detected, but subsequent major metabolic pathways are different in the two species.

3. In the rat, oxidation of the 17β-hydroxyl to the 17-oxo group and hydroxylation in the 16α-position are the major routes. The three major metabolites are 17β-hydroxyestra-4,9,11-trien-3-one, 16α,17β-dihydroxyestra-4,9,11-trien-3-one and 16α-hydroxyestra-4,9,11-trien-3,17-dione.

4. In the heifer, 17α-epimerization is the major pathway and the main metabolite is the 17α-hydroxyestra-4,9,11-trien-3-one.

5. In both species, estra-4,9,11-trien-3,17-dione and the other metabolites, resulting either from hydroxylation in 1, 2, 6β, 16α or 16β positions, or from aromatization of the A ring, were minor products.

6. Overall, 60% of the 3-oxotriene structures identified in the rat bile were 17β-hydroxylated and the remainder were 17-keto metabolites, whereas in the heifer bile 90% were 17α-hydroxylated compounds.

7. Thus, in bovine species, the major pathway is similar to those of testosterone or 17β-estradiol which are mainly excreted as their 17α-epimers. This epimerization strongly decreases the biological potency, as with the natural 17β-hormones, and leads to detoxication of tissue residues.     

Ionic liquid – microemulsions assisting in the transdermal delivery of Dencichine: Preparation,in-vitro and in-vivo evaluations,and investigation of the permeation mechanism

A novel microemulsion was developed and characterized for topical delivery of Dencichine (Den). Two imidazaolium ionic liquid, 1-hydroxyethyl-3-methylimidazolium chloride ([HOEIM]Cl) and 1-butyl-3-methylimidazolium dodecanesulfate ([BMIM]C₁₂SO₃) were incorporated into the aqueous and surfactant phases respectively for the remarkable enhancement on skin permeation. The nano-carrier was developed and optimized based on a pseudo-ternary phase diagram. The optimized formulation was composed of 50% water/[HOEIM]Cl mix (1:1) as water phase, 20% Tween 80/[BMIM]C₁₂SO₃ mix (1:1) as surfactant, 10% propylene glycol as co-surfactant and 20% IPM as oil phase. The o/w microemulsion was then characterized for droplets sizes (47.7 ± 1.5 nm), zeta potential (?14.83 ± 3.64 mV), viscosity (31 ± 4 mPa) and pH (6.71 ± 0.04). In-vitro skin permeation assay suggested the strong enhancement of ILs formulation on the topical delivery of Den, which was approximately 10-fold that of the drug aqueous solution. It was found that the nano-carrier can reduce the skin barrier properties by disrupting the regular and compact arrangements of corneocytes, and moderating the surface properties of the stratum corneum, as evidenced by Transdermal Water Loss Evaluation (TEWL), Differential Scanning Calorimetery (DSC) and attenuated total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR). Furthermore, the in-vivo pharmacodynamic evaluation indicated the significant hemostatic activity of Den by the topical application of the vehicle. Additionally, the formulation showed minor cell toxicity and skin irritation. Therefore, our work suggested that the ionic liquid microemulsion can be a promising nano-scale vehicle for the topical application of Den to produce desirable pharmacological effects.