帕潘立酮（paliperidone）

帕潘立酮(paliperidone)是2006年12月20日由美国食品药品管理局(FDA)批准上市的治疗精神分裂的新药。该药由强生公司的子公司杨森公司开发研制,商品名In-vega,为口服控释片。帕潘立酮是自2003年以来FDA批准的第一个治疗精神分裂症的处方药[1]。帕潘立酮中文化学名称:(±)-3-[2-[4-(6-氟-1,2-苯并异唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-9-羟基-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮;英文化学名称:(±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyri midi…     

Review of synthesis, assay, and prediction of β and γ-secretase inhibitors

Alzheimer's disease (AD) is characterize with several pathologies this disease, amyloid plaques, composed of the β-amyloid peptide and β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised Desing, synthesis, and Biological assay of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compound to find out the structural requirements. Next, we revised QSAR studies using method of Artificial Neural Network (ANN) in order to understand the essential structural requirement for binding with receptor for β and γ-secretase inhibitors.     

Development and validation of a rapid and sensitive UHPLC–MS/MS method for the determination of paliperidone in beagle dog plasma

In order to evaluate the pharmacokinetic profile of paliperidone extended-release tablets in vivo, a simple and rapid ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) method was developed and validated for the determination of paliperidone in beagle dog plasma. Paliperidone and diazepam (internal standard) were extracted from plasma samples with diethyl ether, and then separated on a C₁₈ column (2.1 × 50 mm, 2.6 μm) under gradient elution with methanol–0.1% formic acid at a flow rate of 0.3 ml/min. The compounds were detected using a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source. The validated method was linear over the concentration range of 1.00–1000.00 ng/ml and the lower limit of quantitation was 1.00 ng/ml. The intra-day and inter-day precision values were not more than 15% (relative standard deviation < 20% at low levels), while the accuracy was within ±10% of nominal values. The validated UHPLC–MS/MS method was successfully applied to an oral pharmacokinetic study of paliperidone extended-release tablets in a beagle dog.     

Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene

  Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through μ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through μ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects. Received: 14 August 1998 / Final version: 4 December 1998     

Hydrolysis of Carbonates,Thiocarbonates, Carbamates,and Carboxylic Esters of α-Naphthol, β-Naphthol,and p-Nitrophenol by Human,Rat, and Mouse Liver Carboxylesterases

Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K _m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased.     

Effect of β-Endorphin and naloxone on acquisition,memory, and retrieval of shuttle avoidance and habituation learning in rats

Naloxone impairs acquisition of shuttle avoidance behavior (0.8 mg/kg IP) and habituation to a rearing response to a tone (1.6 mg/kg IP) in rats. -Endorphin (2 g/kg IP) has no effect on acquisition, but, when given prior to test sessions, facilitates retrieval of the two tasks. Naloxone has no effect of its own upon retrieval. In addition to these effects, the pretraining administration of -endorphin disrupts, and that of naloxone facilitates retention of the two tasks. The results are consistent with the hypothesis that these two forms of learning are state-dependent on the release of -endorphin (and, perpaps, of other opiate peptides as well), that this substance is released during training in a sufficient amount for this purpose, and that, in addition, there is a physiological amnesic mechanism mediated by opiate peptides. Furthermore, the results are also consistent with previous observations that -endorphin is released from the rat brain during training, but not during test sessions of the two tasks (Izquierdo et al., 1980b). The possibility is discussed that state-dependency and the amnesic effect comprise one single, rather than two separate mechanisms.     

Biological actions and molecular effects of resveratrol,pterostilbene, and 3′-hydroxypterostilbene

Stilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and -dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene.     

Levels and circadian rhythmicity of plasma ACTH,cortisol, and β-endorphin as a function of family history of alcoholism

Rationale Individuals with a family history of alcoholism may present a dysfunction in the activity of the hypothalamic–pituitary–adrenal (HPA) axis that predates the development of alcoholism. Objective The present study investigated the hypothesis that this HPA-axis dysfunction is associated with alterations in the pattern of the circadian (24 h) secretions of adrenal corticotropic hormone (ACTH), cortisol, and β-endorphin. Methods Men with [high risk (HR)] or without [low risk (LR)] family history of alcoholism participated in the study. Blood samples were drawn every 30 min for 24 h for estimation of the plasma hormone levels. Participants ingested meals at predetermined intervals and filled out mood questionnaires prior to the placement of the catheter and 1 h after each meal. Results The circadian peaks for β-endorphin, ACTH, and cortisol occurred between 0800 and 0830 hours in both LR and HR participants. The plasma ACTH and β-endorphin concentrations were lower in HR than LR participants, while the plasma cortisol concentrations were similar between HR and LR participants. For each hormone, the total 24-h secretion was estimated from the area under the 24-h time–concentration curve (AUC). For ACTH and β-endorphin, but not the cortisol, AUC were lower in HR than LR participants. LR participants reported being more nervous than HR participants. For the LR participants, but not HR participants, the initial mood ratings of “nervous” were positively correlated with the initial plasma cortisol and β-endorphin concentrations as well as with the cortisol and β-endorphin AUC. Conclusions HR participants presented lower plasma concentrations as well as lower AUC for β-endorphin and ACTH but not for cortisol. This suggests a dysfunction of the HPA-axis in HR participants that predates the development of alcoholism and a dissociation between plasma ACTH and cortisol levels as a function of family history of alcoholism.     

Comparative studies of saponins in 1–3-year-old main roots, fibrous roots, and rhizomes of Panax notoginseng, and identification of different parts and growth-year samples

Notoginsenosides R₁, R₄, Fa, and K (N-R₁, N-R₄, N-Fa, and N-K), as well as ginsenosides Rg₁, Rb₁, Rd, Re, Rf, Rg₂ and Rh₁ (G-Rg₁, G-Rb₁, G-Rd, G-Re, G-Rf, G-Rg₂ and G-Rh₁) in 47 Notoginseng samples including 1-, 2- and 3-year-old main roots, rhizomes and fibrous roots of Panax notoginseng were determined by high-performance liquid chromatography-diode array detection method. Total contents (%) of the 11 saponins were 9.82–14.57 for 2-year old and 14.20–16.00 for 3-year-old rhizomes; 2.72–4.50 for 2-year-old and 1.98–4.92 for 3-year-old fibrous roots; 1.75–3.05 for 1-year-old whole roots; and 3.71–8.98 for 2-year-old and 7.03–11.23 for 3-year-old main roots. Contents of most saponins and total content of 11 saponins were in the order 3- >2- >1-year-old main root samples. G-Rf content, sum of G-Rf and G-Rh₁ were, respectively, 0.08–0.18 and 0.14–0.32 for 2- or 3-year-old rhizomes, and 0.01–0.07 and 0.03–0.10 for 2- or 3-year-old main roots. Combined contents of N-R₁, G-Rg₁ and G-Rb₁ were 5.78–9.37 in 3-year-old main roots, and 2.99–7.13 in 2-year-old main roots, of which nearly one-third of samples were lower than the limit (5 %) in the Chinese Pharmacopoeia. Those of 2- or 3-year-old fibrous roots (1.47–3.83) and 1-year-old whole roots (1.41–2.44) were much lower than the limit, and were considered not suitable for use as Notoginseng. Two-year-old main roots are not appropriate for collection as Notoginseng. Different parts and growth years of P. notoginseng can be identified from each another according to differences in saponin content.     

Design, synthesis, and antiviral evaluation of purine-β-lactam and purine-aminopropanol hybrids

Purine-β-lactam chimera were prepared as a novel class of hybrid systems through N-alkylation of 6-benzylamino- or 6-benzyloxypurine with (ω-haloalkyl)-β-lactams, followed by reductive ring opening of the β-lactam ring by LiEt(3)BH to provide an entry into the class of purine-aminopropanol hybrids. Both new types of hybrid systems were assessed for their antiviral activity and cytotoxicity, resulting in the identification of eight purine-β-lactam hybrids and two purine-aminopropanol hybrids as promising lead structures.     

Théodore Guilloz, pharmacist and physician, pioneer and victim of radiology

After the discovery of X rays, the first radiographies were obtained in France in January 1896. In Nancy, Guilloz obtained some of them on March 11. Pharmacist and physician, assistant professor and fellow at the Faculty of medicine, all his professional life was devoted to electrotherapy and radiology. This paper reports successively his studies in Besan?on and his coming to Nancy, his career in hospital and university, his researchs and honours, his relations with the College of pharmacy, his illness consecutive to repeated irradiations, his activity during world War I and finally his death on March 26 1916.     

Preparation, characterization, pharmacokinetics, and bioactivity of honokiol-in-hydroxypropyl-β-cyclodextrin-in-liposome

Entrapping inclusion complexes in liposomes has been proposed to increase the entrapment efficiency (EE) and stability of liposomes compared with conventional liposomes. In the present study, a stable honokiol-in-hydroxypropyl-β-cyclodextrin-in-liposome (honokiol-in-HP-β-CD-in-liposome) was developed as honokiol delivery system by a novel method. The final molar ratio of honokiol/HP-β-CD/lipid was selected as 1:2:2. The mean particle size was 123.5 nm, the zeta potential was -25.6 mV, and the EE was 91.09 ± 2.76%. The release profile in vitro demonstrated that honokiol is released from honokiol-in-HP-β-CD-in-liposome with a sustained and slow speed. Crystallographic study indicated that honokiol was first bound within HP-β-CD and then the inclusion complex was encapsulated within liposomes. Honokiol-in-HP-β-CD-in-liposome without freeze dry kept stable for at least 6 months at 4°C. Pharmacokinetic study revealed that honokiol-in-HP-β-CD-in-liposome significantly retarded the elimination and prolonged the residence time in circulating system. The data of bioactivity showed that honokiol-in-HP-β-CD-in-liposome remained similar antiproliferative activity in A549 and HepG2 tumor cells compared to free honokiol. These results suggested that we had successfully prepared honokiol-in-HP-β-CD-in-liposome. The novel honokiol formulation was easy to push industrialization forward and might be a potential carrier for honokiol delivery in tumor chemotherapy.     

Design,Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors

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Synthesis and Benzodiazepine Receptor Affinity of Nb,Nb'-Diamides of Bistryptamine

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Differential Effects of Anionic,Cationic, Nonionic,and Physiologic Surfactants on the Dissociation, α-Chymotryptic Degradation,and Enteral Absorption of Insulin Hexamers

Various surfactants were investigated to compare their effects on insulin dissociation, -chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate procine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of -chymotrypsin (0.5 µM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/ proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1–5 mM. However, extensive charge–charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An -chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the -chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min. The results further emphasize the importance of the degree of insulin aggregation on its enteral transport.     

Comparison of tolerance development and dependence capacities of morphine, β-endorphin,and [D-MET2, PRO5]-enkephalinamide

The tolerance-development capacities of -endorphin, [D-Met², Pro⁵]-enkephalinamide, and morphine were compared in rats, and the dependence capacity of morphine was compared with that of the enkephalin analogue in mice. Tolerance to the analgesic effect, as measured by the tail-flick test, developed somewhat more rapidly in the [D-Met², Pro⁵]-enkephalinamide-treated group than in the others. A similar relationship was found for the dependence capacity. Considering that the enkephalin analogue displayed the strongest analgesic activity, the wellknown correlation between antinociceptive and tolerance development/dependence capacities of opiates seems to be valid for opioid peptides as well.