Poly(ADP-ribose) polymerase inhibitor therapeutic effect: are we just scratching the surface?

Poly(ADP-ribose) polymerase (PARP) research has come a long way since the discovery of the enzyme 50 years ago. Since the development of first-generation PARP inhibitors (PARPi), numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the stage at which a PARPi is now a valuable treatment option for patients with ovarian cancer. Nevertheless, the exact molecular mechanism of the PARPi anti-tumor effect is under debate and PARPi are not specific for a single enzyme. Moreover, the anti-inflammatory activity of PARPi in preclinical experiments has not been explored much so far. Thus, further basic and preclinical research is needed to advance the use of PARPi in the treatment of tumors and potentially other inflammation-associated diseases.     

Blood pressure guidelines - where are we now?

In June 2006, the National Institute for Health and Clinical Excellence (NICE) updated its recommendations on the management of patients with hypertension (published in 2004), in light of "significant new data" relating to drug treatment.1,2 The update, published in collaboration with the British Hypertension Society (BHS), recommended first-line use of a calcium-channel blocker or a thiazide-type diuretic in patients aged over 55 years or an ACE inhibitor in those aged under 55 years, and advised that beta-blockers should no longer be used for routine initial therapy.1 Recently published data from England suggest that primary care prescribing has changed in line with this new guideline.3 However, interpretation of the evidence that underpins some of the key recommendations is open to debate, particularly as there are differences from some other major guidelines in the recommendations for first-line therapy. Here we consider the updated NICE guideline, the rationale for its treatment recommendations, and the subsequent change in clinical practice. In particular, we focus on the initial drug management of adults without conditions such as diabetes mellitus or coronary heart disease that would in themselves be a key determinant of management.     

Rosacea: where are we now?

Advances continue to be made in the classification and treatment of rosacea, a chronic dermatologic syndrome. A new empiric classification system identifies 4 rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) that may aid in more precise diagnosis. Several new therapies have recently been approved for treatment of rosacea. Azelaic acid 15% gel is a new first-tier topical agent proven effective in reducing inflammatory lesions and erythema. New formulations of metronidazole and sulfacetamide 10%/sulfur 5% that offer cosmetic or tolerability advantages are now available. Intense pulsed light therapy has demonstrated effectiveness in reducing flushing, erythema, and telangiectases, with greater tolerability than existing laser systems. Other treatments under investigation include low-dose doxycycline hyclate (which may provide greater safety than existing oral antibiotics), benzoyl peroxide/clindamycin gel, and tacrolimus ointment (for steroid-induced rosacea). With this expanded armamentarium of medical and light-based therapies, clinicians can now implement a multifaceted approach to treatment, crafting new treatment combinations to address the unique and evolving features of rosacea in each individual patient.     

Deuterated drugs: where are we now?

Introduction: Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium– carbon bond modifying their metabolism. There is great interest in the current state of development of this approach.

Areas covered: This review covers recent US patent applications and prosecutions in this area that are based on beneficial modifications in metabolism of deuterated versions of existing drugs. The current state of 35 U.S.C. §103 ‘obviousness’ rejections are emphasized, as is the development of strategies to overcome such rejections. Current trials and market considerations are also discussed.

Expert opinion: Deuterated drugs collectively are worth at least US$1 billion. It would seem that the likelihood of obviousness rejections is increasing in this area. However, careful elucidation of metabolic outcomes from deuteration that would not be anticipated from the prior art, and are instead unexpected and unobvious, has enabled allowance. Showing that drug deuteration alters pharmacokinetics by mechanisms not currently part of the prior art surrounding deuterated drugs has also been successful. Development of these and other strategies, combined with developing the extensive base of issued patents will enable the field to remain commercially attractive for some time.     

Vitiligo therapy: where are we now?

Vitiligo is a disfiguring skin disease. Many insights into its pathogenesis have been identified in recent years; however, treatment remains a challenge. In this article, the various treatment options for the treatment of vitiligo are outlined and newer treatment options are discussed.     

Neuroprotective effects of poly(ADP-ribose) polymerase inhibitors in transient focal cerebral ischemia of rats

目的：研究多聚ＡＤＰ核糖多聚酶（ＰＡＲＰ）在局灶性脑缺血再灌注损伤中的作用．方法：雄性Ｗｉｓｔａｒ大鼠用插丝法阻塞大脑中动脉３５ｈ后再灌注，梗塞灶用ＴＴＣ染色显示，图象分析测量；神经功能缺损采用０－５级评分．结果：低剂量ＰＡＲＰ抑制剂３氨基苯甲酰胺（１０ｍｇ·ｋｇ－１）或尼克酰胺（２０ｍｇ·ｋｇ－１）具有明显的神经保护作用，治疗窗近６ｈ；高剂量反而加重脑损伤，特别是尼克酰胺在再灌注起始给药．选择性单ＡＤＰ核糖酰转移酶抑制剂对脑梗塞无明显作用．结论：暂时非完全性抑制ＰＡＲＰ对脑缺血再灌注损伤产生神经保护作用，然而完全抑制该酶（尤其是在再灌注期）则产生损害作用．     

B cell-ablative therapy: where are we now?

Based on their multifaceted functions, B cells participate in several pathological settings such as lymphoproliferative disorders, autoimmune diseases and graft rejection. B cell-ablative therapy has thus emerged as a mainstay in these diseases. A number of anti-B cell antibodies (Abs) have been generated, among which anti-CD20 Abs appear to be efficient. Rituximab (RTX) is one of these anti-CD20 monoclonal Abs. Originally approved for the treatment of non-Hodgkin lymphoma, RTX is now being administered in other malignant proliferations, applied to an increasing number of autoimmune diseases and required to prevent rejection of a graft. Although this medication is remarkably safe, a handful of laboratory tests have been proposed to monitor RTX-treated patients. The efficacy in different diseases, and the emergence of new anti-CD20 Abs raise many questions. Thus, their detailed understanding can lead to a better issue for inhibition of immune responses.     

Therapeutic targets in triple negative breast cancer - where are we now?

Triple negative breast cancers, defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2/EGFR2/ERBB2), are increasingly gaining attention for its intricate relationship with basal-like and BRCA1-linked breast carcinomas, and its lack of effective tailored therapies. Triple negative breast tumors usually account for 10-20% of all breast cancers in Asian populations, similarly in Caucasian populations (10-23%), but occur at much higher frequencies in individuals of African descent (20-47%). In addition, triple negative breast cancers are usually of high histological grade and are accompanied by aggressive clinical behavior with shorter time to recurrences and death, and preference for metastasis to the brain and lungs. In this report, we would like to review recent patents and the relationship between triple negative and basal-like breast cancers, as well as BRCA1-linked breast carcinomas. Specifically, potential treatment modalities and current innovations that are designed for the predictive and prognostic values of triple negative breast tumors will be discussed.     

5-Benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2)

PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH═CHCO(2)H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC(50(PARP-1))/IC(50(PARP-2)) = 9.3) to date, in a comparative study.     

RAMPs: 5 years on, where to now?

It is now approximately 5 years since the identification of the family of receptor activity modifying proteins (RAMPs). This finding revolutionized concepts of the pharmacology of G-protein-coupled receptors (GPCRs) and revealed that GPCR accessory proteins not only assist trafficking and folding but also define receptor type. Since the identification of RAMPs as modulators of the trafficking and properties of the calcitonin-receptor-like receptor, much work has focused on improving our understanding of the nature of RAMP-GPCR dimers, the extent to which they occur, and the consequence of this association. In this article, we review recent developments, including the identification of new receptor partners and novel roles for RAMPs.     

Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going?

Tamoxifen is a cheap and effective estrogen-receptor antagonist, used as the adjuvant hormonal treatment of choice in women with estrogen-receptor-positive breast cancer. Tamoxifen-induced non-alcoholic steatohepatitis (NASH) may increase the demand on oncologists, not only with regard to screening for diabetes, but also for the suggested link of NASH with high incidence of coronary heart disease. At present, there is no guideline for treatment of hyperlipidaemia associated with tamoxifen-induced NASH. However, exemstane (and other aromatase inhibitors) has been shown to lower triglyceride and have a neutral effect on low-denisty lipoprotein and cholesterol levels. These may be alternative agents if severe progressive liver disease or hyperlipidaemia were encountered with tamoxifen administration. Other lipid-lowering medications may have potential benefits in the treatment of tamoxifen-induced NASH and is discussed in this article.     

Pharmacotherapies for obstructive sleep apnoea: where are we now?

Obstructive sleep apnoea (OSA) is common, causes considerable morbidity and probably contributes to mortality particularly through associated cardiovascular disease. The physical therapy of continuous positive airway pressure (CPAP) is extremely effective in the majority of patients but most patients would prefer an alternative. Intuitively, OSA should be amenable to pharmacotherapy. The upper airway of affected individuals can be narrowed but is patent during wakefulness. Collapse of the airway during sleep occurs when negative intra-luminal pressure generated by inspiratory effort exceeds the tone of the upper airway dilators. This mismatch may be in part due to respiratory drive instability but the state-dependent fall in drive to the airway dilator muscles is the biggest factor in most patients.Various drugs have been investigated as treatment for OSA. Acetazolamide, theophylline, nicotine, opioid antagonists and medroxyprogesterone have been used to increase respiratory drive. Clonidine has been tested with the aim of reducing rapid eye movement sleep when OSA is often most severe. Various antidepressants have been used to suppress rapid eye movement sleep and to preferentially activate the upper airway dilators. The drug trials have often been of poor design and none has included more than a few patients. Most of the drugs have been found to be ineffective and those that have worked for some patients (acetazolamide and protriptyline) have produced intolerable adverse effects.There have been recent advances in the understanding of the neurotransmitters involved in the control of sleep and the upper airway motor neurones, offering the possibility of novel approaches to the drug treatment of OSA for those patients who cannot tolerate or do not benefit from CPAP. It seems likely that a better understanding of the mechanisms of OSA in individual patients and tailoring of drug therapy will be the way forward.     

Pharmacological management of GERD: where does it stand now?

Gastroesophageal reflux disease (GERD) is very common and advances in drug development over recent years have markedly improved GERD management. A wide range of medications are currently used in GERD treatment, including antacids, Gaviscon, sucralfate, histamine-2 receptor antagonists and prokinetics. However, proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD owing to their profound and consistent inhibitory effect on acid secretion. Despite the presence of a wide armamentarium of therapeutic modalities for GERD, many areas of unmet needs remain. Drug development has focused primarily on improving PPI efficacy, reducing the transient lower esophageal sphincter relaxation rate, attenuating esophageal sensitivity and developing esophageal mucosal protectants.     

Cytokine therapies in Crohn's disease: where are we now and where should we go?

In the gut of patients with Crohn's disease (CD), one of the major forms of inflammatory bowel diseases in humans, distinct subsets of T helper (Th) cells produce large amounts of cytokines, which are supposed to orchestrate the immuno-inflammatory process leading to the tissue damage. Indeed, cytokine blockers, including the three licensed anti-TNF-alpha and the neutralizing IL-12/p40 antibodies, have already been tested with success in CD. More than one third of patients do not respond to these treatments and response can wane with time. Moreover, blockade of such cytokines has been reported to associate with development of severe side effects and/or new immune-mediated pathologies. These findings and our better understanding of cytokine-associated effector pathways of tissue destruction suggest the necessity of novel cytokine-based therapies in CD.     

MCL-1 inhibitors – where are we now (2019)?

ABSTRACT

Introduction: Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulates apoptosis. Elevated levels of MCL-1 contribute to tumorigenesis and resistance, not only to conventional chemotherapies but also to targeted therapies, including the BCL-2 selective inhibitor venetoclax. Accordingly, researchers in both the pharmaceutical industry and academia have been actively seeking MCL-1 inhibitors in the quest for new anti-cancer drugs.

Areas covered: This review covers the patent literature on the discovery and development of small-molecule inhibitors of MCL-1 since 2017.

Expert opinion: Pharmacologic inhibition of MCL-1's oncogenic activity has certainly come of age with the discovery of numerous inhibitors spanning a variety of chemotypes that selectively inhibit MCL-1 in the picomolar range and with on-target cell activity. Furthermore, seminal research by Servier has demonstrated for the first time that MCL-1 inhibition is tolerable in animal models of cancer, paving the way for the six Phase 1 clinical trials that are currently underway for hematological malignancies, among other cancers. After more than a decade of research, the hurdles and obstacles are mostly behind us, and uncovering the therapeutic impact of disrupting the protein–protein interactions of MCL-1 in humans is imminent.