Modeling radiative and non-radiative pathways at both the Franck-Condon and Herzberg-Teller approximation level.

Here, we present a concise model that can predict the photoluminescent properties of a given compound from first principles, both within and beyond the Franck-Condon approximation. The formalism required to compute fluorescence, Internal Conversion (IC), and Inter-System Crossing (ISC) is discussed. The IC mechanism, in particular, is a difficult pathway to compute due to difficulties associated with the computation of required bosonic configurations and non-adiabatic coupling elements. Here, we offer a discussion and breakdown on how to model these pathways at the Density Functional Theory (DFT) level with respect to its computational implementation, strengths, and current limitations. The model is then used to compute the photoluminescent quantum yield (PLQY) of a number of small but important compounds: anthracene, tetracene, pentacene, diketo-pyrrolo-pyrrole (DPP), and Perylene Diimide (PDI) within a polarizable continuum model. Rate constants for fluorescence, IC, and ISC compare well for the most part with respect to experiment, despite triplet energies being overestimated to a degree. The resulting PLQYs are promising with respect to the level of theory being DFT. While we obtained a positive result for PDI within the Franck-Condon limit, the other systems require a second order correction. Recomputing quantum yields with Herzberg-Teller terms yields PLQYs of 0.19, 0.08, 0.04, 0.70, and 0.99 for anthracene, tetracene, pentacene, DPP, and PDI, respectively. Based on these results, we are confident that the presented methodology is sound with respect to the level of quantum chemistry and presents an important stepping stone in the search for a tool to predict the properties of larger coupled systems.

Evaluation of Cartilage Repair by Mesenchymal Stem Cells Seeded on a PEOT/PBT Scaffold in an Osteochondral Defect.

The main objective of this study was to evaluate the effectiveness of a mesenchymal stem cell (MSC)-seeded polyethylene-oxide-terephthalate/polybutylene-terephthalate (PEOT/PBT) scaffold for cartilage tissue repair in an osteochondral defect using a rabbit model. Material characterisation using scanning electron microscopy indicated that the scaffold had a 3D architecture characteristic of the additive manufacturing fabrication method, with a strut diameter of 296 ± 52 µm and a pore size of 512 ± 22 µm × 476 ± 25 µm × 180 ± 30 µm. In vitro optimisation revealed that the scaffold did not generate an adverse cell response, optimal cell loading conditions were achieved using 50 µg/ml fibronectin and a cell seeding density of 25 × 10(6) cells/ml and glycosaminoglycan (GAG) accumulation after 28 days culture in the presence of TGFß3 indicated positive chondrogenesis. Cell-seeded scaffolds were implanted in osteochondral defects for 12 weeks, with cell-free scaffolds and empty defects employed as controls. On examination of toluidine blue staining for chondrogenesis and GAG accumulation, both the empty defect and the cell-seeded scaffold appeared to promote repair. However, the empty defect and the cell-free scaffold stained positive for collagen type I or fibrocartilage, while the cell-seeded scaffold stained positive for collagen type II indicative of hyaline cartilage and was statistically better than the cell-free scaffold in the blinded histological evaluation. In summary, MSCs in combination with a 3D PEOT/PBT scaffold created a reparative environment for cartilage repair.

Valvular and perivalvular involvement in patients with chronic kidney disease / 老年心脏病学杂志（英文版）

Abstract Mitral annular calcification (MAC) and aortic valve alcification (AVC) are the most common valvular and perivalvular bnormalities in patients with chronic kidney disease (CKD). Both MAC and AVC occur at a younger age in CKD patients than in the general population. AVC progresses to aortic stenosis and mild aortic stenosis progresses to severe aortic stenosis at a more rapid rate in patients with CKD than in the general population. The use of calcium-free phosphate binders in such patients may reduce the calcium burden in valvular and perivalvular tructures and retard the rate of progression of aortic stenosis. Despite high rates of morbidity and mortality, the prognosis associated with valve surgery in patients with CKD is better than without valve surgery. Infective endocarditis remains an important complication of CKD, particularly in those treated with hemodialysis.

Correlation of activity of chlorpromazine and respective hydroxy, dimethoxy and sulphoxide analogues on dopamine, muscarinic, histamine and calmodulin sites of action.

1. Chlorpromazine (CPZ) is a unique molecule which has many potential sites of action, as well as a propensity to be transformed into a host of metabolites possessing varying degrees of pharmacological and/or toxic reactions. This investigation examined the rank order of potency of CPZ and eight metabolic derivatives with respect to displacement of 3H-spiperone at central dopamine-2 (DA-2) receptors, 3H-pirenzepine at central muscarinic-1 (M-1) receptors, and inhibition of calmodulin-induced activation of cyclic AMP-dependent phosphodiesterase. 2. The most potent CPZ analogues to displace labelled spiperone from DA-2 receptors in rat striatum were: 3-hydroxy-CPZ, CPZ, 3,7-dihydroxy-CPZ, and 7-hydroxy-CPZ. Intermediate potency was observed with 8-hydroxy-CPZ, 3,7,8-trihydroxy-CPZ, and 7,8-dihydroxy-CPZ. Chlorpromazine sulphoxide and 7,8-dimethoxy-CPZ displayed the least activity at DA-2 receptors. 3. Displacement of labelled pirenzepine from M-1 receptors in rat frontal cortex occurred to the greatest extent with CPZ which was one to two orders of magnitude more potent than noted for 3-hydroxy-CPZ greater than 7-hydroxy-CPZ greater than CPZ-sulphoxide greater than 8-hydroxy-CPZ greater than 7,8-dimethoxy-CPZ. The least potent agents were 3,7-and 7,8-dihydroxy-CPZs and 3,7,8-trihydroxy-CPZ. 4. A partially purified calmodulin-sensitive preparation of cyclic AMP-dependent phosphodiesterase from guinea pig heart was most sensitive to inhibition by 7,8-dihydroxy-CPZ, 7,8-dimethoxy-CPZ, 3-hydroxy-CPZ, 7-hydroxy-CPZ, 8-hydroxy-CPZ and CPZ. Least inhibition occurred with 3,7-dihydroxy-CPZ, 3,7,8-trihydroxy-CPZ and CPZ-sulphoxide. 5. The DA-2 receptors were more sensitive to the active CPZ analogues than were the M-1 receptors while calmodulin-activated phosphodiesterase was the least sensitive preparation. 6. Comparisons of data were made with existing information from other laboratories and in general CPZ, 7-hydroxy-CPZ and 3-hydroxy-CPZ were the most potent compounds across different test conditions.

Comparison of inhibitory actions of chlorpromazine or its 7,8-dihydroxy and 7,8-dioxo-didesmethyl analogs on DA-sensitive adenylate cyclase and calmodulin activation of phosphodiesterase in rat striatum.

Two chlorpromazine analogs, 7,8-diOH- and 7,8-dioxo-didesmethyl-chlorpromazine were compared to chlorpromazine (CPZ) with regard to inhibition of three parameters of enzyme activity in rat striatum: 1) dopamine + GTP-sensitive adenylate cyclase in homogenates; 2) dopamine, GTP, calmodulin and Ca++-sensitive adenylate cyclase in washed particulate fractions; and 3) calmodulin-Ca++ activation of high Km cyclic AMP dependent phosphodiesterase in dialyzed supernatant fractions. Chlorpromazine was clearly the most potent antagonist in all three experimental conditions. The CPZ derivatives displayed greatest potency on the particulate adenylate cyclase and all three drugs were 1 to 2 orders of magnitude more effective as inhibitors of the adenylate cyclase preparations than with the calmodulin-Ca++ phosphodiesterase.

Antileishmanial activity of chlorpromazine.

The antiprotozoal activity of chlorpromazine against the pathogenic protozoan Leishmania donovani, in both its amastigote and promastigote stages, was characterized. Chlorpromazine at concentrations greater than or equal to 3.12 micrograms/ml (9.8 X 10(-6) M) produced a significant reduction in viable promastigotes. The minimal protozoacidal concentration for promastigotes, defined as that concentration which produced greater than or equal to 90% reduction in viable parasites after 18 h, was 13.8 micrograms/ml. The results were similar when promastigote viability was assessed by flagellar motility or by the ability of drug-exposed or control promastigotes to incorporate [3H]uridine and [3H]leucine. Exposure of promastigotes to 50 micrograms of chlorpromazine per ml reduced O2 consumption by 87% within 30 min and immobilized 97% of parasites. Morphological disruption of promastigotes was observed by electron microscopy. The mean minimal protozoacidal concentration of chlorpromazine for amastigotes was 13.2 micrograms/ml. Chlorpromazine given orally (20 mg/kg per day for 14 days) reduced the parasite burden in L. donovani-infected hamsters by 64.2% (P less than 0.01) as measured by the number of amastigotes in touch preparations of livers and by 67.9% (P = 0.03) as measured by the number of promastigotes derived from homogenates of spleens. This dose is ca. 10-fold greater than that tolerated by patients being treated for psychiatric illness. Although chlorpromazine will probably not be useful in the treatment of human visceral leishmaniasis, the data suggest that less-toxic phenothiazines might prove to be effective.

Effects of compounds structurally related to 5,6-dihydroxytryptamine on behavior and brain biogenic amines in the rat.

A variety of analogues of the serotonin neurotoxin, 5,6-dihydroxytryptamine were administered to rats by injection into the lateral ventricle of the brain. Each compound evoked a unique pattern of behavioral effects. Only 5,6-dihydroxytryptamine lowered brain 5HT levels, while both 5,6-dihydroxytryptamine and its benzo[b]thiophene analogue caused a transient lowering of brain NE.

Lethal effect of phenothiazine neuroleptics on the pathogenic protozoan Leishmania donovani.

Phenothiazine drugs, which are widely used for their antipsychotic, antianxiety, and antiemetic effects, have been found to have protozoacidal effects on the human pathogen Leishmania donovani. These compounds are lethal to both the extracellular stage of the organism, which is inoculated into humans by the sand fly, and the intracellular stage, which is found solely in human macrophages during established infection.

Benzo [b]-promazines, chlorpromazine free radical and analino-N, N-dimethylpropylamine analogs influence rat striatal DA-adenylate cyclase and calmodulin-phosphodiesterase.

A series of Benzo [b]-promazines and analino-N, N-dimethylpropylamine analogs and the free radical of chlorpromazine were compared to chlorpromazine and promazine in the rat striatum for their ability to inhibit either dopamine activated adenylate cyclase or calmodulin stimulation of a partially purified high Km cyclic AMP phosphodiesterase. Chlorpromazine and the corresponding free radical were generally the most potent inhibitors of the two enzyme preparations, however, Piperazino-Benzo [b]-promazine, 1-Oxo-Benzo [b]-promazine, N-38-76-3A and Benzo [b]-promazine were relatively effective inhibitors. To a lesser extent, tyrosine, N-57-77, Piperidino-Benzo [b]-promazine, Diethyl-Benzo [b]-promazine, promazine and 1-Oxo-Diethyl-Benzo [b]-promazine exerted varying degrees of antagonism of the two enzymes. In all instances the compounds inhibited dopamine-sensitive adenylate cyclase to a greater extent than the calmodulin activated phosphodiesterase.

Carnitine transport in isolated adult rat heart myocytes and the effect of 7,8-diOH chlorpromazine.

We studied the carnitine transport system in isolated adult rat heart myocytes able to tolerate physiological concentrations of calcium. Carnitine uptake occurred against a concentration gradient and was inhibited by 2,4-dinitrophenol (2,4-DNP). The transport system had a Km of 60 microM and a Vmax of 110 pmol/mg protein per hour. The carnitine precursor deoxycarnitine, acetylcarnitine, and both the D and L isomers were effective inhibitors of uptake. The transport of carnitine was not dependent on sodium ions, but was stimulated by decreasing concentrations of calcium ions. Decreased uptake was observed in the presence of beta-adrenergic agonists and antagonists, dibutyrl cyclic AMP, local anesthetics, and ouabain. No significant alteration of uptake was effected by atropine, carbachol or a variety of tricyclic agents. The auto-oxidation product of 7,8-dihydroxychlorpromazine (7,8-diOH CPZ) decreased carnitine efflux from myocytes, which were highly permeable to low molecular weight compounds. We found that this effect was not substrate specific, and is discussed as possibly resulting from a change in the arrangement or state of polymerization of subcellular structural components.

Di- and trihydroxy analogs of chlorpromazine influence the central activity of adenylate cyclase and cyclic AMP phosphodiesterase.

We previously demonstrated that chlorpromazine (CPZ), 7,8 diOH-CPZ and 3,7,8 triOH-CPZ were potent inhibitors of central adenylate cyclase systems. The present studies were thus designed to observe whether further substitutions of dihydroxy groups on the CPZ molecule would influence adenylate cyclase in broken cell preparations of the rat frontal cortex. The inhibition of adenylate cyclase by 7,8 diOH-CPZ was further found to be noncompetitive with respect to ATP concentration. Raising the Ca++ concentration obliterated adenylate cyclase activation by either dopamine or 5'-guanylylimidodiphosphate (Gpp(NH)p) alone or in combination, while inhibition by 7,8 diOH-CPZ was overcome. The enzyme inhibition by 7,8 diOH-CPZ was not influenced, however, by increasing Mg++ concentration. Incubation of rat cortical homogenates with CPZ, 3,7,8 triOH-CPZ or 6,9 diOH-CPZ inhibited stimulation of adenylate cyclase activity while either 3,7- or 3,8 diOH-CPZ resulted in an enhancement of enzyme activity. In further study, using the high speed cortical supernatant, the high Km form of cyclic AMP phosphodiesterase and its activation by the Ca++-dependent, heat stable regulator protein were inhibited by CPZ, 6,9 dioxo-, 7,8 dioxo-, 3,7diOH-, 3,8 diOH-, 6,9 diOH-, 7,9 diOH- and 7,8 diOH-CPZs, but not by 3,7,8 triOH-CZP. The high affinity-low Km form of the enzyme was inhibited to a considerably lesser extent by these analogs. The studies reveal rather diverse and complicated actions of CPZ and its putative metabolites on central enzyme systems.

Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity.

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.

Electrochemical oxidation of hydroxylated phenothiazine and imipramine derivatives.

The electrochemical oxidations of several hydroxylated derivatives of promazine, chlorpromazine, imipramine, and 3-chloroimipramine are examined and compared. Oxidation of the monohydroxyphenothiazine derivatives leads to both dihydroxy species and substituted benzoquinones, while oxidation of hydroxylated imipramines leads to only the corresponding benzoquinones. The oxidation potentials of 17 tricyclic psychoactive drugs and metabolites are tabulated and compared. The potential importance of these results to drug activity and side effects is discussed.

Histamine-, norepinephrine-, and dopamine-sensitive central adenylate cyclases: effects of chlorpromazine derivatives and butaclamol.

A series of recently available derivatives (quaternary and hydroxylated) of chlorpromazine (CPZ) and butaclamol were evaluated with respect to antagonism of norepinephrine- (NE) (rat cerebral cortex), dopamine- (DA) (rat striatum) and histamine- (H) sensitive (rabbit cerebral cortex) adenylate cyclases. With incubated tissue slices (rat and rabbit cortices) CPZ-CH3, 7-OH-CPZ-CH3, beta-OH-CPZ and butaclamol displayed a capacity to inhibit either NE- or H- induced accumulation of adenosine cyclic 3',5'-monophosphate (cAMP). With the broken cellular enzyme responsive to DA, rather potent inhibition of enzyme activity (IC50 less than 24 micron) occurred with butaclamol, beta-OH-CPZ, 7,8,beta-triOH-CPZ, 7,8-dioxo-beta-OH-CPZ and 3,7,8-triOH-CPZ. It is concluded that the metabolites of CPZ contribute to the central therapeutic and/or side effects of the parent compound.

3H-Haloperidol binding to dopamine receptors in rat corpus striatum: influence of chlorpromazine metabolites and derivatives.

A series of chlorpromazine metabolites and derivatives have been assayed for their ability to compete with 3H-haloperidol binding to dopamine receptors in membranes of rat corpus striatum. 3-Hydroxylation of chlorpromazine doubles affinity for receptor sites, while 7-hydroxychlorpromazine has a potency similar to that of chlorpromazine itself. Other patterns of hydroxylation reduce affinity. Side chain demethylation lowers affinity for binding sites. Several metabolites which lack neuroleptic activity in vivo, such as chlorpromazine-5-oxide, also are inactive in competing for 3H-haloperidol binding. Since blood levels of 7-hydroxychlorpromazine tend to be similar to those of chlorpromazine itself in patients, these observations indicate that 7-hydroxychlorpromazine may account for a major portion of the antischizophrenic efficacy of chlorpromazine. The structure--activity relationships observed in the present study support a model in which chlorpromazine interacts with dopamine receptors by assuming a conformation with its side chain tilted toward ring A.