GLOBAL HEALTH IMPACT: A BASIS FOR LABELING AND LICENSING CAMPAIGNS?

Most of the world's health problems afflict poor countries and their poorest inhabitants. There are many reasons why so many people die of poverty‐related causes. One reason is that the poor cannot access many of the existing drugs and technologies they need. Another, is that little of the research and development (R&D) done on new drugs and technologies benefits the poor. There are several proposals on the table that might incentivize pharmaceutical companies to extend access to essential drugs and technologies to the global poor. 1 Still, the problem remains – the poor are suffering and dying from lack of access to essential medicines. So, it is worth considering a new alternative. This paper suggests rating pharmaceutical and biotechnology companies based on how some of their policies impact poor people's health. It argues that it might be possible to leverage a rating system to encourage companies to extend access to essential drugs and technologies to the poor.     

Toxicity interactions and ways of reducing side effects of anticancer drugs

Side effects of cytostatics commonly used in the Haematology Clinic are analysed. The toxic action on the host's organs is discussed in L-asparaginase, azathioprine, bleomycine, busulfan, cyclophosphamide, cytosin-arabinoside, daunorubicine, fluorouracil, mercaptopurine, methotrexate, dichlorplatinum, procarbazine and the vinca alkaloids. In addition to toxic symptoms arising from single organs the most important 21 anticancer drugs are gathered in a table. Metabolism of activation and inactivation are mentioned to interprete symptoms of toxicity. Furthermore, the interactions between commonly administered drugs and carcinostatics which may enhance or suppress their carcinostatic efficacy are exposed. A final survey of possible pharmacological rescue measures, which may improve the tolerance of anticancer drugs by diminishing their toxicity is presented.     

综述——纳米材料与药物输递：脂质纳米粒在口服给药系统中的应用

脂质纳米粒是由固体脂肪酸或其酯类制成的一类纳米制剂,其生物相容性好、安全性好,所以在药物递送领域受到广泛关注．难溶性药物、多肽及蛋白质药物由于溶解度、跨膜能力以及稳定性等问题,导致口服生物利用度低,而利用脂质纳米粒作为其载体,口服给药后能显著改善药物的生物利用度,这使得脂质纳米粒在口服给药系统中得到了广泛的应用与研究．本文从口服脂质纳米粒的处方、制备工艺、吸收机制以及应用四个方面对其进行了详细的综述．     

Connecting pills and people: an ethnography of the pharmaceutical nexus in Odisha, India

This article explores the impact of intensive competition within the pharmaceutical industry and among private providers on health care in an Indian city. In-depth interviewing and clinical observation were used over a period of 18 months. Private practitioners and chemists who provided regular services to inhabitants of a poor neighborhood in central Bhubaneswar were included. Fierce competition in private health in Odisha, India, reduced quality of care for the poor. The pharmaceutical industry exploited weak links in the health system to push drugs aggressively, including through illegal channels. The private health market is organized in small "network molecules" that maximize profit at the cost of health. The large private share of health care in India and stiff competition are detrimental for primary care in urban India. Free government services are urgently needed and a planned health insurance scheme should be linked to quality control measures.     

Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions

The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.     

Microtubules and axoplasmic transport. Inhibition of transport by podophyllotoxin: an interaction with microtubule protein

Pharmacological evidence is presented for the involvement of microtubules in the process of fast axoplasmic transport. A quantitative measure of the inhibition of axoplasmic transport in an in vitro preparation of rat sciatic nerve is described. The alkaloids colchicine, podophyllotoxin, and vinblastine, which are known both to disrupt microtubules and to bind to the protein subunit of microtubules, are inhibitors of axoplasmic transport. Lumicolchine and picropodophyllin, unlike their respective isomers colchicine and podophyllotoxin, are poor inhibitors of axoplasmic transport. The dissociation constants for the binding of colchicine, lumicolchicine, podophyllotoxin, and picropodophyllin to purified microtubule protein from rat brain have been measured. Inhibition of axoplasmic transport by these drugs correlates favorably with their affinities of microtubule protein.     

The decomposition of benzodiazepines during analysis by capillary gas chromatography/mass spectrometry

A capillary gas chromatography column directly interfaced to a mass spectrometer was used for the analysis of sixteen benzodiazepines. The thermal stability of the drugs was found to be related to their chemical structure. Nine of the benzodiazepines were thermally unstable indicating that care should be taken in the interpretation of gas chromatographic data from this class of drugs. The unstable benzodiazepines were: ketazolam which decomposes to diazepam; N-4 oxides (chlordiazepoxide and demoxepam) which lose an oxygen radical; aromatic 7-nitro compounds (nitrazepam and clonazepam) which are partially reduced to the corresponding amine; alpha-hydroxy ketones (lorazepam and oxazepam) which decompose with the loss of water and N-methyl-alpha-hydroxy ketones (lormetazepam and temazepam) which partially decompose with the loss of a hydrogen molecule to produce the corresponding alpha, beta-diketones. Few problems were encountered in distinguishing the drugs by their mass spectra, the exceptions being ketazolam which decomposes to diazepam and demoxepam which decomposes to desmethyldiazepam. In general, good spectra were obtained from 20-50 ng of drug injected. However, for those compounds where the decompositions were not quantitative (nitrazepam, clonazepam, lormetazepam, temazepam) detection limits were poor.     

Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: a Review

Due to the high number of poorly soluble drugs in the development pipeline, novel processes for delivery of these challenging molecules are increasingly in demand. One such emerging method is KinetiSol, which utilizes high shear to produce amorphous solid dispersions. The process has been shown to be amenable to difficult to process active pharmaceutical ingredients with high melting points, poor organic solubility, or sensitivity to heat degradation. Additionally, the process enables classes of polymers not conventionally processable due to their high molecular weight and/or poor organic solubility. Beyond these advantages, the KinetiSol process shows promise with other applications, such as the production of amorphous mucoadhesive dispersions for delivery of compounds that would also benefit from permeability enhancement.     

Good oral absorption prediction on non-nucleoside benzothiadiazine dioxide human cytomegalovirus inhibitors using combined chromatographic and neuronal network techniques

The current drugs available against human cytomegalovirus (HCMV) suffer from a number of shortcomings such as toxic side effect, poor bioavailability and/or risk for emergence of drug-resistance virus strains. Due to these limitations, the development of new drugs against HCMV is of great interest. Taking into account the therapeutic potential of benzothiadiazines dioxides (BTD) derivatives, it is most important to know their oral bioavailability because all the current clinical drugs are poorly absorbed. In this work, the utility of CODES neural networks and biopartitioning micellar chromatography (BMC) in predicting pharmacokinetic properties has been used to estimate the oral absorption of BTD derivatives and their efficacy has been verified. The results indicate higher values for BTD derivatives than the currently licensed anti-viral agents.     

Carrier-mediated delivery of peptidic drugs for cancer therapy

Protein and peptide drugs are used for treatment of a variety of ailments. However, their wider use has been hindered by issues such as poor bioavailability in vivo and the cost involved in producing these drugs. This review discusses the various carrier-mediated methods used for delivery of peptide and protein drugs, with emphasis on liposomal and microspherical drug delivery systems. A brief look at the types of peptidic drugs currently in use clinically, and a brief discourse on several novel ideas for better protein delivery systems for cancer therapy is included.     

The role of health care workers and antiviral drugs in the control of pandemic influenza

Until a vaccine against the new strain becomes available, the response to newly emerged pandemic influenza will consist of the use of antiviral drugs and measures that limit exposure to infectious individuals. These first-line defence measures include isolating cases upon diagnosis, reducing close contacts, the use of personal protective equipment and hygiene, and using antiviral drugs for treatment and prophylaxis. There are significant 'costs' associated with control measures, so to justify such interventions it is important to assess their potential to reduce transmission. In this paper, we determine the effect that a number of different antiviral interventions have on the reproduction number of infectives and the probability that an imported infection fades out, and determine parameter scenarios for which these interventions are able to eliminate an emerging pandemic of influenza. We also assess the role that health care workers play in transmission and the extent to which providing them with antiviral prophylaxis and personal protective equipment modifies this role. Our results indicate that this class requires protection to avoid a greatly disproportionate contribution to early infective numbers, and for the maintenance of a stable health care system. Further, we show that the role children play in increasing transmission is moderate, in spite of closer mixing with other children.     

Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation

Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.     

Biophysical delivery of peptides: applicability for cancer therapy

There is a current trend towards evaluation of molecular agents for treatment of a variety of ailments, including cancer. One class of such biomolecules is proteins, and their shortened versions, peptides. Use of peptidic entities has been hindered by poor bioavailability in vivo and the high cost involved in mass-producing these macromolecular drugs. The need for localized delivery is being met with the development of various biophysical means, which include devices and aids, mainly transdermal and invasive implants. In addition, various cell-based delivery modalities, which include the use of spore-forming bacteria and stem cells, are being explored. This review discusses these methods in turn, and examines ways by which these can be enhanced for peptide delivery to tumors.     

Structure-toxicity relationships for different types of dinuclear platinum complexes

Nine structurally distinct dinuclear platinum complexes have been evaluated in a novel model system for the investigation of renal epithelial toxicity of platinum drugs. The results showed that these compounds are toxic when applied at the basolateral side of renal epithelia, whereas their toxic effects on the apical side are negligible. Such a difference in toxicity of the complexes has been found to result from their poor uptake through the apical membrane, as compared to the basolateral membrane. Toxicity of the compounds on the basolateral side varies depending on their structure. Structure-toxicity relationships for the group of complexes with rigid ligands and for the group of complexes with flexible ligands are discussed. Among the dinuclear complexes with rigid ligands, sterically hindered complexes are less toxic, due to their poor uptake and low reactivity towards glutathione. Within the group of complexes with flexible ligands, cis-configured isomers are more toxic than their trans-counterparts.     

Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness.

OBJECTIVE: To assess the impact of the colour of a drug''s formulation on its perceived effect and its effectiveness and to examine whether antidepressant drugs available in the Netherlands are different in colour from hypnotic, sedative, and anxiolytic drugs. DESIGN: Systematic review of 12 published studies. Six studies examined the perceived action of different coloured drugs and six the influence of the colour of a drug on its effectiveness. The colours of samples of 49 drugs affecting the central nervous system were assessed using a colour atlas. MAIN OUTCOME MEASURES: Perceived stimulant action versus perceived depressant action of colour of drugs; the trials that assessed the effect of drugs in different colours were done in patients with different diseases and had different outcome measures. RESULTS: The studies on perceived action of coloured drugs showed that red, yellow, and orange are associated with a stimulant effect, while blue and green are related to a tranquillising effect. The trials that assessed the impact of the colour of drugs on their effectiveness showed inconsistent differences between colours. The quality of the methods of these trials was variable. Hypnotic, sedative, and anxiolytic drugs were more likely than antidepressants to be green, blue, or purple. CONCLUSIONS: Colours affect the perceived action of a drug and seem to influence the effectiveness of a drug. Moreover, a relation exists between the colouring of drugs that affect the central nervous system and the indications for which they are used. Research contributing to a better understanding of the effect of the colour of drugs is warranted.     

A comparison of narcotic analgesics with neuroleptics on behavioral measures of dopaminergic activity.

Because of many practical difficulties which are encountered in obtaining direct evidence for the involvement of brain neurotransmitters in the action of narcotic drugs, several indirect procedures are often employed. One such method is to compare on the same measures of drug action the narcotic drugs with a non-narcotic drug having a known mechanism of action. Haloperidol is a prototype non-narcotic drug which blocks dopamine receptors and many of its actions are believed to be associated with this receptor blockade. In this paper we compare various actions of haloperidol or other neuroleptics with morphine or other narcotic analgesics using the same testing parameters. We hope that such a comparison would evaluate the role of dopamine receptors in narcotic action and narcotic dependence. This discussion is limited only to the behavioral measures as a comparison of neurochemical measures was recently reviewed in another paper (1).     

Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.     

Enteroviruses: Classification,diseases they cause,and approaches to development of antiviral drugs

The genus Enterovirus combines a portion of small (+)ssRNA-containing viruses and is divided into 10 species of true enteroviruses and three species of rhinoviruses. These viruses are causative agents of the widest spectrum of severe and deadly epidemic diseases of higher vertebrates, including humans. Their ubiquitous distribution and high pathogenici- ty motivate active search to counteract enterovirus infections. There are no sufficiently effective drugs targeted against enteroviral diseases, thus treatment is reduced to supportive and symptomatic measures. This makes it extremely urgent to develop drugs that directly affect enteroviruses and hinder their development and spread in infected organisms. In this review, we cover the classification of enteroviruses, mention the most common enterovirus infections and their clinical man- ifestations, and consider the current state of development of anti-enteroviral drugs. One of the most promising targets for such antiviral drugs is the viral Internal Ribosome Entry Site (IRES). The classification of these elements of the viral mRNA translation system is also examined.     

急性单纯性阑尾炎住院临床路径遵循情况分析

利用2010年全国城镇基本医疗保险参保住院患者医疗服务利用调查数据,对急性单纯性阑尾炎住院手术患者临床诊疗措施的实际使用情况与该病的标准临床路径进行对比分析。平均住院日比临床路径要求的7天约高出1天,其中41.9%手术病例住院天数超出了标准住院日;约47.5%患者未在入院当天急诊手术;18个平均使用率在40%以上的检查项目中,有7个项目不在临床路径规定范围内;99.8%病例在手术中使用过全身抗感染类药,且67%的患者同时使用了2种及2种以上抗菌素。急性单纯性阑尾炎的实际诊疗措施和标准临床路径存在着较大的差异,住院流程有待于进一步优化,住院检查检验项目和抗菌药物的使用需要制订更为细致且可操作的指导原则,并强化监管。