Until recently, chemotherapy for metastatic melanoma had disappointing results. The identification of immune checkpoints such as CTLA-4 and PD-1/PD-L1 has led to the development of an array of monoclonal antibodies (Mabs). These immunologic approaches against tumoral cells come with a novel kind of side effects that the clinician needs to be familiarized with. Herein, we report for the first time a case of organizing pneumonia, based on imaging and cytological analyses of bronchoalveolar lavage, possibly associated with the use of pembrolizumab, an anti-PD-1 Mab recently approved for the treatment of metastatic melanoma.

BACKGROUNDWe investigated the effects and safety of linagliptin as an add-on therapy in patients with advanced-stage diabetic nephropathy (DMN) taking renin–angiotensin–aldosterone system (RAAS) blockers.METHODTwenty advanced-stage DMN patients (estimated glomerular filtration rate (eGFR): 24.5 ± 13.4 mL/min/1.73 m2) taking RAAS blockers were administered 5 mg/day linagliptin for 52 weeks. Changes in glucose and lipid metabolism and renal function were evaluated.RESULTSLinagliptin decreased glycosylated hemoglobin levels (from 7.32 ± 0.77% to 6.85 ± 0.87%, P < 0.05) without changing fasting blood glucose levels, and significantly decreased total cholesterol levels (from 189.6 ± 49.0 to 170.2 ± 39.2 mg/dL, P < 0.05) and low-density lipoprotein cholesterol levels (from 107.1 ± 32.4 to 90.2 ± 31.0 mg/dL, P < 0.05) without changing high-density lipoprotein cholesterol and triglyceride levels. Urine protein/creatinine ratio and annual change in eGFR remained unchanged. No adverse effects were observed.CONCLUSIONLinagliptin as an add-on therapy had beneficial effects on glucose and lipid metabolism without impairment of renal function, and did not have any adverse effects in this population of patients with advanced-stage DMN taking RAAS blockers.

Stereotypical behaviors induced by methamphetamine (METH) overdose are one of the overt symptoms of METH abuse, which can be easily assessed in animal models. Currently, there is no successful treatment for METH overdose. There is increasing evidence that elevated levels of brain histamine can attenuate METH-induced behavioral abnormalities, which might therefore constitute a novel therapeutic treatment for METH abuse and METH overdose. In mammals, histamine N-methyltransferase (HMT) is the sole enzyme responsible for degrading histamine in the brain. Metoprine, one of the most potent HMT inhibitors, can cross the blood–brain barrier and increase brain histamine levels by inhibiting HMT. Consequently, this compound can be a candidate for a prototype of drugs for the treatment of METH overdose.

Leuprolide is a gonadotropin-releasing hormone (GnRH) analog which has been shown to reduce symptoms in patients with irritable bowel syndrome (IBS) and chronic intestinal pseudo-obstruction (CIPO). The mechanism is not known, but one hypothesis is through down-modulation of luteinizing hormone (LH) secretion, a hormone whith antagonistic effect on gastrointestinal motility. However, presence of LH receptors in the gastrointestinal tract has never been described. The aim of this study was to find one possible way of action for leuprolide by examining the presence of the LH receptor, and if present, to see whether there was different expression in patients with or without dysmotility. Full-thickness biopsies from the bowel wall of patients with and without severe dysmotility were examined using immunohistochemistry staining. Biopsies showed expression of LH receptors on myenteric neurons and in glial cells, neutrophils, endothelial cells and mast cells. There was no difference in expression between patient groups.

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Some systemic rheumatic diseases and disorders, especially fibrotic and vascular disorders, are often refractory to corticosteroid therapy. Recently, ever accumulating evidence suggests that platelet-derived growth factor (PDGF) is involved in those refractory diseases. Imatinib mesylate inhibits the activation of PDGF receptor as well as c-Abl, Bcr-Abl and c-Kit tyrosine kinases. It has therefore been widely used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Imatinib effectively suppresses the activation and proliferation of fibroblasts, mesangial cells and smooth muscle cells both in vitro and in vivo. Additionally, it has recently been reported that some patients with rheumatoid arthritis or idiopathic pulmonary arterial hypertension demonstrated a good clinical response to imatinib therapy. Imatinib may therefore overcome the limitations of current therapeutic strategy with corticosteroids and immunosuppressive agents for refractory diseases, such as systemic sclerosis and interstitial lung diseases, without clinical intolerability.

The targets for licensed drugs used for the treatment of human immunodeficiency virus type 1 (HIV-1) are confined to the viral reverse transcriptase (RT), protease (PR), and the gp41 transmembrane protein (TM). While currently approved drugs are effective in controlling HIV-1 infections, new drug targets and agents are needed due to the eventual emergence of drug resistant strains and drug toxicity. Our increased understanding of the virus life-cycle and how the virus interacts with the host cell has unveiled novel mechanisms for blocking HIV-1 replication. This review focuses on inhibitors that target the late stages of virus replication including the synthesis and trafficking of the viral polyproteins, viral assembly, maturation and budding. Novel approaches to blocking the oligomerization of viral enzymes and the interactions between viral proteins and host cell factors, including their feasibility as drug targets, are discussed.

Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The process of designing selective inhibitors for the enzyme trypanothione reductase has been discussed. An overview of the different chemical classes of inhibitors of trypanothione reductase with their inhibitory activities against the parasites and their prospects as future chemotherapeutic agents are briefly revealed.

Endothelial dysfunction is a pathological entity that multiply affects the health status. Erectile dysfunction is being recognized as a condition that is strongly interrelated with endothelial dysfunction, being a vascular event itself. Oral pharmacotherapy for erectile dysfunction has provided us with a new armamentarium on this condition. Phosphodiesterase 5 inhibitors have been investigated and proved useful in clinical practice for erectile dysfunction but in addition to this, the results seem promising of a beneficial effect on endothelial dysfunction, as well.

Anti-angiogenic therapy is emerging as a valuable tool in the treatment of patients with cancer. As VEGF is a central target in anti-angiogenic therapy, its levels in the circulation might be relevant in selecting tumor types or patients likely to respond to this treatment. Additional VEGF has been recognized as a key factor in the pathogenesis of diabetic retinopathy. Recently anti-angiogenic therapy has been advocated in this situation.We measured VEGF levels in whole blood in 42 patients with high grade (n = 26) and low grade (n = 16) end stage cancer, and in 28 healthy controls and 37 patients with diabetes related vascular disease. Only 2/26 patients in the group of high grade cancer had significantly elevated VEGF levels, 1/16 in the low grade group and 1/28 in the healthy control group. In contrast, in 10/37 diabetic patients the mean VEGF levels were significantly elevated compared to the other groups. The mean level in these diabetic patients was significantly elevated compared to the other groups.These data indicate the limitation of the use of circulating VEGF levels as a potential selection criterion for anti-angiogenic therapy in cancer patients and suggest further studies into its application in the management of diabetic complications.