Emerging drug treatments for cystic fibrosis

Cystic fibrosis (CF) is one of the most common life-shortening inherited disorders. Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene disrupt the localisation and function of the cAMP-mediated chloride channel. Most of the morbidity and mortality arise from the lung disease which is characterised by excessive inflammation and chronic infection. Research into the mechanisms of wild-type and mutant CFTR biogenesis suggest that multiple drug targets can be identified. This review explores the current understanding of the nature of the different mutant CFTR forms and the potential for repair of the chloride channel defect. High-throughput screening, pharmacogenomics and proteomics bring recent technological advances to the field.     

Differential effects of serotonergic and catecholaminergic drugs on ingestive behavior

The serotonergic agonists fenfluramine and fluoxetine and the catecholaminergic agonists amphetamine and phenylpropanolamine are well known to cause a reduction in intake in rats. In the studies reported here we investigated the effects of these drugs on the microstructure of licking behavior of the rat ingesting 0.4 M sucrose. The purpose was to examine the similarities in the behavioral effects within and between these two classes of anorectic agents. The serotonergic agonists fenfluramine and fluoxetine caused a reduction in intake primarily by reducing the size of bursts and clusters of licking within the test meal without affecting the duration of the meal, suggesting a reduction in the palatability of the test solution. The catecholamine agonists amphetamine and phenylpropanolamine reduced intake primarily by reducing the number of bursts and clusters without affecting their size, suggesting a fractionation in the organization of the normal pattern of ingestion. The differences between the two serotonin and the two catecholamine agonists on the microstructure of the licking behavior suggest a different effect of the two neurotransmitters on the motor system that controls ingestive behavior. The similarities between the two different agonists within each class suggests a common neurotransmitter mechanism responsible for these two different effects on the behavior of the animals.Supported by NIH Grant DK41563 (JDD).     

Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex

Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex. Received: 27 July 1999 / Accepted: 30 November 1999     

Recent developments in the treatment of sepsis

Despite advances in supportive care, septic shock remains a major cause of morbidity and mortality. With the identification of the systemic inflammatory response as a major component in the pathogenesis of the septic shock syndrome, much of the recent work has focused on modulating this response. This includes antiendotoxin therapies in patients with Gram-negative sepsis, and therapies to modulate the pro-inflammatory mediators produced in response to infection, such as TNF-α, platelet-activating factor and complement. High-flow haemofiltration has the potential advantage of clearing both endotoxin and pro-inflammatory mediators. Antithrombotic strategies have been investigated and have yielded the first major success in the treatment of sepsis with activated protein C. Nitric oxide produces the cardiovascular features of sepsis and investigators have looked at both reducing its production and mopping up the excess. Attempts to reduce apoptosis have been a new focus in the treatment of sepsis. There have also been recent developments in supportive care suggesting a role for vasopressin and replacement corticosteroid therapy.     

Extrapyramidal and mesolimbic involvement with the stereotypic activity of D- and L-amphetamine

The electrolytic brain lesion technique was use to investigate the role of the dopamine-containing areas and pathways of the extrapyramidial and mesolimbic systems in the mediation of the stereotyped behaviour patterns induced by D- and L-amphetamine in the rat.Interruption of the ascending dopaminergic neurones from the mesencephalon at the level of the lateral hypothalamus did not modify the dose-dependent stereotypy induced by D- or L-amphetamine, whilst a lesion placed in the rostral hypothalamus to interrupt the dopaminergic innervation to the mesolimbic brain areas was shown to abolish the wearker intensity component of stereotypy (sniffing and repetitive head movements). Of the areas innervated by this pathway, lesion of the tuberculum olfactorium, but not the nucleus interstitialis stria terminalis or nucleus accumbens septi, also abolished sniffing behaviour. Lesions placed in the neostriatal area of the extrapyramidal system were without significant effect whilst lesion of the paleostriatum abolished all components of stereotypy. Lesion of the central amygdaloid nucleus only abolised the more intense components of both D- and L-amphetamine stereotypy (bitting, gnawing and licking).The brain studies demonstrate a differential involvement of the dopamine-containing areas of the mesolimbic and extrapyramidal brain regions, and the associated dopaminergic neurones which ascend from the mesencephalon, with the stereotyped behaviour patterns induced by both D- and L-amphetamine.     

3种药品不同加菌时机对菌回收率的影响

目的:对2005年版中国药典微生物限度检查法中,细菌、霉菌及酵母菌计数方法验证试验中不同加菌时机对菌回收率的影响进行考察,使得验证结果更加准确、可靠。方法:收集了不同剂型、不同抑菌性的样品共3个,比较了不同加菌时机与菌回收率的关系。结果:这3种药品不同加菌时机的菌回收率结果存在显著性差异,将现行标准中的加菌时机提前,可能存在回收率偏低的情况。结论:这3种药品不同加菌时机对菌回收率存在显著影响。     

The debate on DDT

The paper reviews the early toxicologic and pharmacologic studies carried out by the author and his associates from 1943 to 1947, which were largely responsible for launching DDT as an agent for the control of typhus, malaria, yellow fever, and related vector-borne diseases. After reviewing recent studies conducted at the University of Miami, which dealt with organochlorine pesticides in human tissues, the tumorigenicity of aldrin, dieldrin and endrin (rat), six-generation mouse and three-generation dog reproduction studies, synergism of DDT and aldrin (dog), and the fate of DDT and aldrin during a period of severe starvation (rat), it is pointed out that it is primarily the overuse and misuse of DDT in pest control that have caused the pollution in our ecology. It is emphasized that the requirements for pest control differ the world over and that it must therefore be left to the national regulatory agencies to legislate the safe use of DDT and related pesticides. It is recommended that future human and animal studies with DDT and its derivatives give consideration to: (a) the balance and metabolism of the various hormones, (b) reproduction (estrus, libido, mammary development, milk production, (c) hepatic microsomal enzyme activities, (d) cancer prevention and cancer production, (e) excessive body weight changes induced by disease, unbalanced diet or starvation, and (f) the effects of DDT and its derivatives when absorbed in combination with other related and even unrelated compounds.Presented at the joint meeting of the Scandinavian and German Pharmacological Societies, Copenhagen, Denmark, July 20–23, 1971.     

母亲肥胖对后代的影响

摘要： 近年来母亲肥胖发病率明显增加, 母亲肥胖可导致慢性炎症、 氧化应激、 细胞因子内稳态的改变, 增加妊娠不良结局的危险。怀孕前和怀孕过程中母亲肥胖的代谢状态能够改变胎盘 DNA 甲基化水平, 且会引起胎儿 “程序化” 改变, 影响妊娠结局, 增加后代发生肥胖相关的代谢综合征等慢性病风险。积极预防和干预母亲肥胖, 可降低不良妊娠结局, 提高后代生存质量。     

Inhalation toxicity of acetaldehyde in rats. II. Carcinogenicity study: interim results after 15 months

Male and female Wistar rats were exposed to acetaldehyde vapour at concentrations of 0, 750, 1500 and 3000/1000 ppm during 6 h/day, 5 days/week for up to 27 months. The present paper deals with the results obtained during the first 15 months of the study, including interim kills after 13, 26 and 52 weeks. Major compound-related lesions occurred in the nose and larynx. The nasal lesions comprised: (1) degenerative changes of the olfactory epithelium at all dose levels, frequently accompanied by focal hyperplasia of basal cells and thickening of the submucosa with loss of Bowman's glands and nerve bundles in the dorsomedial region, (2) stratified squamous metaplasia of the respiratory epithelium lining the caudoventral part of the nasal septum and the inner aspect of the ventral endoturbinates often accompanied by severe keratinisation and occasionally by papillomatous hyperplasia, almost exclusively observed at the top-dose level, and (3) malignant tumours (squamous cell carcinomas and adenocarcinomas) at all dose levels. Hyperplasia and keratinised stratified squamous metaplasia of the laryngeal epithelium were seen at the 2 highest dose levels.     

Influence of ethanol on the in vivo and in vitro metabolism of nitriles in mice

The effect of ethanol on metabolism of 20 nitriles was studied in vivo and in vitro in mice. The hepatic microsomal metabolizing activity for nitriles was at a maximum 13 h after ethanol dosing (4.0 g/kg). Using microsomes from mice pretreated with ethanol under the above conditions, enhancement of the in vitro metabolism of nitriles was 1.00–1.83 compared with the glucose-treated control. When mice were orally given nitriles 13 h after dosing with either ethanol (4.0 g/kg) or glucose (7.0 g/kg), the hepatic metabolizing activity of nitriles for the ethanol-treated group was always higher than that for the glucose group, although no change in the content of hepatic microsomal P-450 was observed between the two groups. However, ethanol added to the incubation mixture inhibited the in vitro metabolism of most nitriles. The results in the present study suggest that ethanol can enhance the acute toxicity of nitriles.     

Drug delivery across the skin

Since the introduction of the first through the skin (TTS) therapeutic in 1980, a total of 34 TTS products have been marketed and numerous drugs have been tested by more than 50 commercial organisations for their suitability for TTS delivery. Most of the agents which have been tested have had low molecular weights, due to the impermeability of the skin barrier. This barrier resides in the outermost skin layer, the stratum corneum. It is mechanical, anatomical, as well as chemical in nature; laterally overlapping cell multi-layers are sealed by tightly packed, intercellular, lipid multi-lamellae. Chemical skin permeation enhancers increase the transport across the barrier by partly solubilising or extracting the skin lipids and by creating hydrophobic pores. This is often irritating and not always well-tolerated. The TTS approach allows drugs (< 400 kDa in size) to permeate through the resulting pores in the skin, with a short lag-time and subsequent steady-state period. Drug bioavailability for TTS delivery is typically below 50%, avoiding the first pass effect. Wider, hydrophilic channels can be generated by skin poration, with the aid of a small electrical current (> 0.4 mA/cm2) across the skin (iontophoresis) or therapeutic ultrasound (few W/cm2; sonoporation). High-voltage (> 150 V, electroporation) widens the pores even more and often irreversibly. These standard poration methods require experience and equipment and are therefore, not practical; at best, charged/small molecules (≤ 4000 kDa in size) can be delivered efficiently across the skin. In spite of the potential harm of gadget-driven skin poration, this method is used to deliver molecules which conventional TTS patches are unable to deliver, especially polypeptides. Lipid-based drug carriers (liposomes, niosomes, nanoparticle microemulsions, etc.) were proposed as alternative, low-risk delivery vehicles. Such suspensions provide an improved drug reservoir on the skin, but the aggregates remain confined to the surface. Conventional carrier suspensions increase skin hydration and/or behave as skin permeation enhancers. The recently developed carriers; Transferomes, comprise pharmaceutically-acceptable, established compounds and are thought to penetrate the skin barrier along the naturally occurring transcutaneous moisture gradient. Transfersomes are believed to penetrate the hydrophilic (virtual) channels in the skin and widen the former after non-occlusive administration. Both small and large hydrophobic and hydrophilic molecules are deliverable across the stratum after conjugation with Transfersomes. Drug distribution after transdermal delivery probably proceeds via the lymph. This results in quasi-zero order kinetics with significant systemic drug levels reached after a lag-time of up to a few hours. The relative efficiency of TTS drug delivery with Transfersomes is typically above 50 %; with the added possibility of regional drug targeting.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Influences of cholecystokinin and analogues on memory processes

Evidence is reviewed to assign the role of cholecystokinins in the cognitive and memory processes. Rat brain contains about 550 ng of CCK-8. When injected, icv or sc, in doses of less than 100 ng of CCK or caerulein, these peptides prevent experimental amnesia and prolong extinction of the already-learned tasks. Caerulein is nearly 10 times as potent as CCK-8, and the effects of both peptides are long-lasting. Pretreatment with these peptides also prevents scopolamine-induced amnesia, and reverses the ACh depletion in the frontal and temporal cortices as well as in the hippocampus. CCK-8 antagonists in small doses produce complete amnesia, further supporting the hypothesis that endogenous CCK-8 modulates the memory processes in the brain. Neurochemical data suggest participation of the NMDA receptors, protein kinase C, and protein synthesis in the action of CCK-8 and caerulein. Sub-diaphragmatical vagotomy abolishes the memory-enhancing effects of these peptides when administered peripherally. Thus, CCK-8 and caerulein are likely to affect not only the receptors localized in the CNS, but also to stimulate peripheral receptors associated with the vagus. Alternatively, the vagus may be the major pathway for CCK transport from the visceral organs to the brain.     

Inhibition of the solid state transformation of carbamazepine in aqueous solution: impact of polymeric properties

Abstract

The effects of polymers on the anhydrate-to-hydrate transformation of carbamazepine (CBZ) was investigated. The three types of polymers studied were polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and substituted celluloses which included hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC). Anhydrous CBZ was added to dilute aqueous polymer solutions and Raman spectroscopy measurements were collected to monitor the kinetics of the solution-mediated transformation to CBZ dihydrate. Polymers exhibiting the greatest inhibition were able to reduce the growth phase of the solution-mediated transformation and change the habit of the hydrate crystal indicating polymer adsorption to the hydrate crystal surface as the mechanism of inhibition. The results of the various polymers showed that short chain substituted celluloses (HPMC and MC) inhibited the CBZ transformation to a much greater extent than longer chains. The same trend was observed for PVP and PVA, but to a lesser extent. These chain length effects were attributed to changes in polymer confirmation when adsorbed on the crystal surface. Additionally, decreasing the percentage of hydroxyl groups on the PVA polymer backbone reduced the ability of the polymer to inhibit the transformation and changing the degree of substitutions of methyl and hydroxypropyl groups on the cellulosic polymer backbone had no effect on the transformation.     

Physicochemical properties of maltosyl and glucosaminyl derivatives of beta-lactoglobulin

Maltosyl and glucosaminyl derivatives of beta-lactoglobulin (b-LG) were analyzed for their physicochemical properties: reduced viscosity, ultraviolet difference spectra, intrinsic fluorescence, hydrophobicity and circular dichroism. The viscosity of these derivatives increased as the mass of the carbohydrates covalently linked to b-LG increased. The ultraviolet difference spectra and the intrinsic fluorescence of these proteins revealed that the microenvironments of aromatic amino acid residues of b-LG were increasingly exposed to the surface of the protein as the extent of modification increased; and the polarity of these residues also increased as modification increased. The hydrophobicities of M-b-LG derivatives decreased as the extent of modification increased while the hydrophobicities of G-b-LG derivatives were relatively unchanged. The circular dichroic analysis of these proteins indicated that the ordered secondary structures of the extensively modified derivatives of b-LG were partially unfolded. Thus, the carbohydrates covalently linked to b-LG altered many physiochemical properties. These physicochemical changes of b-LG apparently resulted from an alteration of forces stabilizing the structure of the protein.     

Continentalic acid exhibited nephroprotective activity against the LPS and E. coli-induced kidney injury through inhibition of the oxidative stress and inflammation

The present study investigated the effect of the continentalic acid (CNT) isolated from the Aralia Continentalis against the LPS and E. coli-induced nephrotoxicity. The LPS and E. coli administration markedly altered the behavioral parameters including spontaneous pain, tail suspension and survival rate. However, the treatment with CNT dose dependently improved the behavioral parameters. The CNT treatment significantly improved the renal functions test (RFTs) and hematological parameters following LPS and E. coli-induced kidney injury. Furthermore, the LPS and E. coli administration markedly compromised the anti-oxidant enzymes and enhanced the oxidative stress markers. However, the CNT treatment markedly enhanced the anti-oxidants enzymes such as GSH, GST, Catalase and SOD, while attenuated the oxidative stress markers such as MDA and POD. The MPO enzyme is widely used marker for the neutrophilic infiltration, the LPS and E. coli administration markedly increased the MPO activity. However, the CNT treatment markedly attenuated the MPO activity in both LPS and E. coli-induced kidney injury. Furthermore, the CNT treatment markedly attenuated the NO production compared to the LPS and E. coli-induced kidney injury group. Additionally, the CNT treatment improved the histological parameters markedly (H and E, PAS and Masson’s trichome staining) and protect the kidney from the inflammatory insult of the LPS and E. coli evidently. The comet assay revealed marked DNA damage, however, the CNT treatment markedly prevented the LPS and E. coli-induced kidney damage. The CNT treatment markedly enhanced the expression of Nrf2, while attenuated the iNOS expression in both models of kidney injury.     

Bioavailability of propranolol and bendrofluazide formulations

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles of both propranolol and bendrofluazide were studied following the multiple oral administration of the drugs as a fixed combination (Inderetic®) and as a free combination at doses of 80 mg propranolol twice daily and 2.5 mg bendrofluazide twice daily. There were no statistically significant differences between the two regimens in terms of individual propranolol blood levels, half-lives and area under the curve. The half-lives were between 5 and 8 h. Thus the bioavailability of propranolol from the fixed combination is equivalent to that from the free combination. The mean peak bendrofluazide blood levels were slightly higher following the administration of the fixed combination. This difference was statistically significant only at 1 and 2 h after the first dose. There were no statistically significant differences between these two bendrofluazide regimens in terms of half-life and area under the curve. Thus the bioavailability of bendrofluazide from the fixed combination is equivalent to that from the free combination. It is concluded therefore that by combining bendrofluazide and propranolol in a fixed capsule formulation does not affect significantly the systemic bioavailability of either component.     

Novel anticonvulsant medications in development

Epilepsy is currently the most prevalent neurological disorder worldwide. Pharmacological therapy remains the cornerstone of epilepsy treatment, however, refractory epilepsy is still a significant clinical problem despite the release of the second generation of anticonvulsants. Anticonvulsant treatment failures may result from lack of efficacy and presence of significant side effects. One rationale for incomplete effectiveness of the currently available anticonvulsants is that they were identified using the same classical models and therefore work largely by the same actions. These mechanisms fail to consider variations in the pathophysiological process that results in epilepsy, nor have they been shown to prevent the process of developing epilepsy (epileptogenesis). The next generation of anticonvulsants has taken into account the shortcomings of existing agents and attempted to improve on the currently available treatments using rationale drug design. This group of investigational anticonvulsants may be broadly classified as possessing one or more of the following: 1) increased tolerability through improvement in drug chemical structure or better delivery to the site of action, 2) new mechanisms (or combinations of mechanisms) of action, 3) improved pharmacokinetic properties. This article will discuss the next generation of anticonvulsants (carabersat, CGX-1007, fluorofelbamate, harkoseride, losigamone, pregabalin, retigabine, safinamide, SPD-421, talampanel, valrocemide) and the possible populations in which they would be clinically useful.     

Cholinergic,dopaminergic, noradrenergic,or glutaminergic stimulation ventral to the anterior septum does not specifically suppress defensive behavior

Three experiments investigated neurotransmitters which might function in the neural system ventral to the anterior septum modulating defensiveness in the rat. In the first experiment, a dose dependent suppression of defensive behavior to the experimenter was produced by intracranial infusion of carbachol or physostigmine but not dopamine, norepinephrine, or glutamate. The suppression of defensiveness did not occur when a carbachol-atropine sulfate mixture was infused. In a second experiment the cholinergic antagonists, atropine methyl nitrate or atropine sulfate, did not increase reactivity when infused ventral to the anterior septum although the nonspecific blocking agent lidocaine was effective. In a final experiment, the infusion of carbachol ventral to the anterior septum which had suppressed defensiveness was found to suppress eating and general activity as well, thus suggesting that the effect of carbachol on defensiveness was the result of a nonspecific suppression of behavior. It is concluded that the specific modulation of defensiveness by the neural system ventral to the anterior septum is not mediated by acetylcholine, dopamine, noradrenaline, or glutamate.