Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease.
Esser, Nathalie ; Paquot, Nicolas ; Scheen, André
in Expert opinion on investigational drugs (2015), 24(3), 283-307
Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease ... [more ▼]
Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD. Area covered: The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-alpha (etanercept, infliximab, adalimumab), IL-1beta (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists. Expert opinion: The available data supports the concept that targeting inflammation improves insulin sensitivity and beta-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity. [less ▲]Detailed reference viewed: 32 (4 ULg)
Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.
; ; et al
in Expert Opinion on Investigational Drugs (2012), 21(9), 1391-415
INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to ... [more ▼]
INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. AREAS COVERED: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. EXPERT OPINION: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients. [less ▲]Detailed reference viewed: 12 (0 ULg)
The future of obesity: new drugs versus lifestyle interventions.
in Expert Opinion on Investigational Drugs (2008), 17(3), 263-7
BACKGROUND: Obesity causes serious medical complications and impairs quality of life. However, its management remains challenging. OBJECTIVE: To assist health professionals who counsel patients who are ... [more ▼]
BACKGROUND: Obesity causes serious medical complications and impairs quality of life. However, its management remains challenging. OBJECTIVE: To assist health professionals who counsel patients who are overweight or obese by discussing the possible add-on value of new drugs over lifestyle interventions. METHODS: A critical analysis is made of the available evidence of the long-term efficacy of diet and exercise and/or anti-obesity agents such as orlistat, sibutramine and rimonabant. RESULTS/CONCLUSION: Lifestyle interventions remain the cornerstone of the treatment of obesity, but adherence is poor and long-term success is modest. Pharmacological agents may be useful adjuncts for improving weight loss and maintenance, and health outcomes, and should be continued in good responders. Drug therapy and lifestyle intervention are not opponent strategies, but should probably be combined to tackle obesity. [less ▲]Detailed reference viewed: 62 (6 ULg)
Strontium ranelate: a new paradigm in the treatment of osteoporosis.
REGINSTER, Jean-Yves ; LECART, Marie-Paule ; DEROISY, Rita et al
in Expert Opinion on Investigational Drugs (2004), 13(7), 857-64
In vitro, strontium ranelate increases collagen and non-collagenic protein synthesis by mature osteoblast-enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug ... [more ▼]
In vitro, strontium ranelate increases collagen and non-collagenic protein synthesis by mature osteoblast-enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. The drug was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomised study. At the conclusion of the study, the percentage variation of lumbar bone mineral density (BMD) from baseline was significantly different in the group receiving strontium ranelate 1000 mg/day as compared with placebo (+5.53 versus -0.75%, respectively). Increase in total hip and neck BMD averages were 3.2 and 2.5%, respectively. The effect of strontium ranelate in postmenopausal women with established osteoporosis was assessed during a multinational, prospective, double-blind, randomised, placebo-controlled trial. Strontium ranelate (500, 1000, 2000 mg/day) or placebo were given to 353 Caucasian women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving strontium ranelate 2000 mg was 7.3% (p < 0.001). A significant increase in bone alkaline phophatase (p = 0.002) over a 6-month period and a significant decrease in N-telopeptide crosslinks (p = 0.004) throughout the 2-year period were seen in the group receiving 2000 mg of strontium ranelate. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralisation defects. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patients experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture was also demonstrated in the patients treated for > or = 18 months. [less ▲]Detailed reference viewed: 17 (6 ULg)
Therapeutic potential of thromboxane inhibitors in asthma
Dogné, Jean-Michel ; ; et al
in Expert Opinion on Investigational Drugs (2002)Detailed reference viewed: 19 (0 ULg)
Current therapies for shingles
Nikkels, Arjen ; Pierard, Gérald
in Expert Opinion on Investigational Drugs (1996), 5
Current management of shingles relies on antiviral therapy. The efficacy of acyclovir in varicella-zoster virus replication is now well established, with a beneficial impact on zoster-associated pain, but ... [more ▼]
Current management of shingles relies on antiviral therapy. The efficacy of acyclovir in varicella-zoster virus replication is now well established, with a beneficial impact on zoster-associated pain, but its moderate bioavailability renders five oral daily doses mandatory. Recent anti-VZV drug research has been oriented towards agents with increased oral bioavailability. Famciclovir and valaciclovir were originally developed as oral prodrugs for^penciclovir and acyclovir, respectively, but, together with the new antivirals, sorivudine and brovavir, they appear to be effective as oral therapy for shingles. Ongoing clinical trials will determine their relative merits in the management of shingles. The experimental agents H2G, HPMPC, mappicine ketone and A-73209 have potential in the treatment of VZV and are undergoing further investigation and development. [less ▲]Detailed reference viewed: 30 (0 ULg)