Improvement for the Synthesis of Centchroman

Ｃｅｎｔｃｈｒｏｍａｎ是一新型非甾体女用口服避孕药，我们对其合成路线进行了改进。其中在ＦｒｉｅｄｅｌＣｒａｆｔｓ烷基化反应中高选择性地获得反式异构体，从而避免了文献报道中的高压氢化和构型转化两个反应单元。共五步反应得到最终产物。收率达４０％。     

Isolation of Actinomycetes for Antibiotic Screening

Actinomycetes are a prolific source of antibiotics, enzymes, and enzyme inhibitors.Screening programs in the past have concentrated mainly on species of the genusStreptomyces. However, discovery of valuable antibiotics such as gentamicin producedby Micromonospora purpurea and other Micromonospora species, rifamycins by Amycolatopsis(formerly Nocardia) mediterrane, and the anticoccidial compound CL259,971, a potentpolyether ronophore produced by Actinomadura yumaense has shown the antibiotic-producingpotential of other genera of Actinomycetales. This communication describes the methodologiesused for the selective isolation of organisms belonging to specific actinomycete genera.     

Targeting translation for treatment of cancer--a novel role for IRES?

Protein synthesis plays an important role in the regulation of cell proliferation. While the role of cap-dependent translation in cell transformation has been studied extensively another translation initiation mechanism, internal initiation of cellular mRNAs, emerged recently and is relatively unappreciated and poorly understood. Internal initiation is mediated by IRES elements that are found in the 5' untranslated region (5' UTR) of mRNA. Curiously, several oncogenes, growth factors and proteins involved in the regulation of programmed cell death contain IRES elements in their 5' UTRs. Internal initiation escapes many control mechanisms that regulate cap-dependent translation. In this review I will discuss the data supporting the hypothesis that selective translation of these factors may contribute to the survival of cancer cells under stressful situations, such as lack of nutrients, hypoxia, or therapy-induced DNA damage and contributes to the development and progression of cancer and to the establishment of cancer cells that are resistant to conventional therapies.     

Standardization of health-related quality of life measures for Asian populations

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The promise of PROMIS(®) for addiction

The field of addiction treatment has a measurement problem that pervades efforts to help patients achieve self-sustainable recovery. The impact of using older measurement technology has increased the measurement burden on both service providers and patients, while at the same time limiting the scope and frequency of measurement. The resulting burden can affect provider performance, patient access, and addiction recovery. This paper underscores the need for applying modern measurement theory techniques to reduce the measurement burden currently affecting most if not all major aspects of treatment and recovery. It is currently possible to obtain information more precisely, over a broad spectrum of recovery-oriented domains, faster and at lower cost than current measurement practices allow. However, a persistent research effort will be necessary to achieve that goal.     

Two for the price of one?

Pulmonary vascular medial hypertrophy due to enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and/or decreased PASMC apoptosis is a primary cause of increased pulmonary vascular resistance and arterial pressure in patients with pulmonary arterial hypertension. While many factors can contribute to this form of vascular remodeling, it is generally agreed upon that altered transmembrane ion flux via ion channels is involved. While much focus has centered on the role of cations and cation channels in controlling PASMC contraction and proliferation, anion efflux via Cl- channels has recently gained interest for its role in SMC proliferation, differentiation, migration, contraction, and angiogenesis. In this issue, Dai et al. report that the putative volume-sensitive ClC-3 channel is upregulated in PASMC from monocrotaline-induced pulmonary hypertensive rats and in inflammatory cytokine-treated canine PASMC. They also provide evidence that ClC-3 upregulation may protect against oxidative stress-induced PASMC necrosis, thereby improving PASMC survival and promoting medial hypertrophy.     

IUPHAR Guidelines for classification of new receptor-subtypes

—Mammalian receptor systems are the basis of IUPHAR classifications. The nomenclature mayextend to other vertebrates if useful and provided it does not compromise the mammalian classification. Evolutionary changes may be so great that invertebrate receptors are difficult to classifywithin mammalian-based nomenclature.     

Evaluation of memantine for the treatment of Alzheimer’s disease

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer’s disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda^?, Axura^®, Ebixa^®; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.     

Evaluation of Skin Permeation of β-Blockers for Topical Drug Delivery

Purpose

β-Blockers have recently become the main form of treatment of infantile hemangiomas. Due to the potential systemic adverse effects of β-blockers, topical skin treatment of the drugs is preferred. However, the effect and mechanism of dosage form pH upon skin permeation of these weak bases is not well understood. To develop an effective topical skin delivery system for the β-blockers, the present study evaluated skin permeation of β-blockers propranolol, betaxolol, timolol, and atenolol.

Methods

Experiments were performed in side-by-side diffusion cells with human epidermal membrane (HEM) in vitro to determine the effect of donor solution pH upon the permeation of the β-blockers across HEM.

Results

The apparent permeability coefficients of HEM for the β-blockers increased with their lipophilicity, suggesting the HEM lipoidal pathway as the main permeation mechanism of the β-blockers. The pH in the donor solution was a major factor influencing HEM permeation for the β-blockers with a 2- to 4-fold increase in the permeability coefficient per pH unit increase. This permeability versus pH relationship was found to deviate from theoretical predictions, possibly due to the effective stratum corneum pH being different from the pH in the donor solution.

Conclusions

The present results suggest the possibility of topical treatment of hemangioma using β-blockers.     

Dose–response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: Results of a workshop

A public workshop, organized by a Steering Committee of scientists from government, industry, universities and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose–response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose–response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of sub-threshold doses for a number of receptor-mediated MOAs. The workshop explored the development of dose–response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance Framework (HRF). Case studies addressed activation of the AHR, the CAR and the PPARα. This article describes the workshop process, key issues discussed and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose–response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the MOA, and similar data gaps in early steps. Three additional papers in this series describe the results and conclusions for each case-study receptor regarding its MOA, relevance of the MOA to humans and the resulting dose–response implications.     

A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient?

The field of erectile dysfunction (ED) has been revolutionised over the last two decades. Several treatment options are available today, most of which are associated with high efficacy rates and favourable safety profiles. A MEDLINE search was undertaken in order to evaluate all currently available data on treatment modalities for ED. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first-choice of most physicians and patients for the treatment of ED. PDE5 inhibitors have differences in their pharmacological profiles, the most obvious being the long duration of action of tadalafil, but there are no data supporting superiority for any one of them in terms of efficacy or safety. Sublingual apomorphine has limited efficacy compared with the PDE5 inhibitors, and its use is limited to patients with mild ED. Treatment failures with oral drugs may be due to medication, clinician and patient issues. The physician needs to address all of these issues in order to identify true treatment failures. Patients who are truly unresponsive to oral drugs may be offered other treatment options.Intracavernous injections of alprostadil alone, or in combination with other vasoactive agents (papaverine and phentolamine), remain an excellent treatment option, with proven efficacy and safety over time. Topical pharmacotherapy is appealing in nature, but currently available formulations have limited efficacy. Vacuum constriction devices may be offered mainly to elderly patients with occasional intercourse attempts, as younger patients show limited preference because of the unnatural erection that is associated with this treatment modality. Penile prostheses are generally the last treatment option offered, because of invasiveness, cost and non-reversibility; however, they are associated with high satisfaction rates in properly selected patients.All treatment options are associated with particular strengths and weaknesses. A patient-centred approach based on patient needs and expectations is necessary for the management of ED. The clinician must educate the patient and provide a supportive environment for shared decision making. The management strategy must be supplemented by careful follow-up in order to identify changes in patient health and relationship/emotional status that may necessitate treatment optimisation.     

Retraction – Horizon scanning for novel therapeutics for the treatment of prostate cancer

The publisher of Expert Opinion on Investigational Drugs and authors have retracted the following article:

Diletta Bianchini, Andrea Zivi, Shahneen Sandhu, Johann S de Bono

Expert Opinion on Investigational Drugs December 2010, Vol. 19, No. 12: 1487-1502.

Upon investigation, it was found that the article constitutes a case of redundant publication, due to its similarity to a paper previously published in Annals of Oncology (‘Horizon scanning for novel therapeutics for the treatment of prostate cancer’, D Bianchini, A Zivi, S Sandhu and JS de Bono), Ann Oncol. 2010 Oct; 21 Suppl 7:vii43-55.

We would like to state that this situation was due to an honest error, and the authors are happy for the article to be retracted and would like to apologise for any inconvenience this causes to readers.     

Teaching of Pharmacology for Using Medicine in Reason

Aim： Teaching of pharmacology is very important to clinic practice, and it is stability basic of theory for using medicine in reason. Methods： To study knowledge frame of pharmacology teachers, the teaching method in existence and experiment in teaching of pharmacology, find out a good many things about theory renegades from practice, then to explore reformation. Results： The teachers who engaged teaching about pharmacology did not joint in the clinic work. They lack knowledge of clinic, and bring on separate theory from clinic practice. It is no uses to cultivate students using medicine in reason. So the teachers pay attention to advance theory, to advance ability of scientific research, at the same time, must be concerned with the clinic jobs. Next, the teachers insist to accumulate knowledge in teaching of tradition. The students did not know about system info in pharmacology, they did not content clinic practice, then to bring out weary emotion. So we can trade a think in the teaching might as well that we handpick representational part from typical clinic example, and to lead to students thinking problem, then settle problem. This course need to understand correlation knowledge, must be found their relation each other. It is important to blaze student learning. The third, the part of experiment in the pharmacology are less, so we must increase content of experiment, and let the students design all experiment approach, and to actualize it. The teacher gives some guidance to students. The result of experiment will be related with discourse. The teachers appraise it according to its quality. It will be reckoned in the achievement of term end. We must give some busywork that let the students researching one or tow drug applied in the hospital, then study result of investigate, complete report at last. Conclusion： Using medicine in reason is a keystone in the clinic practice. To realize it, teaching pharmacology will be joined with clinic practice compactness.     

The safety of istradefylline for the treatment of Parkinson’s disease

Introduction: Antagonism of the A_2A receptor improves motor behavior in patients with Parkinson’s disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline, has the longest half-life out of the available A_2A receptor antagonists. Istradefylline easily crosses the blood–brain barrier and shows a high affinity to the human A_2A receptor.

Areas covered: This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug portfolio for the treatment of PD patients.

Expert opinion: Istradefylline was safe and well tolerated in clinical trials, which have focused on l-DOPA-treated PD patients. The future of istradefylline as a complementary drug for modulation of the dopaminergic neurotransmission also relies on its potential to act like an l-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of predominant l-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istradefylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.