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See detailAntifracture efficacy of currently available therapies for postmenopausal osteoporosis.
Reginster, Jean-Yves ULg

in Drugs (2011), 71(1), 65-78

Osteoporosis is a systemic bone disease characterized by low bone mass and bone mineral density, and deterioration of the underlying structure of bone tissue. These changes lead to an increase in bone ... [more ▼]

Osteoporosis is a systemic bone disease characterized by low bone mass and bone mineral density, and deterioration of the underlying structure of bone tissue. These changes lead to an increase in bone fragility and an increased risk for fracture, which are the clinical consequences of osteoporosis. The classical triad for consideration in osteoporosis is morbidity, mortality and cost. Vertebral fracture is an important source of morbidity in terms of pain and spinal deformity. On the other hand, hip fracture is associated with the worst outcomes and is widely regarded as a life-threatening event in the elderly; it is the source of the bulk of the cost of the disease in contemporary healthcare. The prevention of osteoporosis-associated fracture should include fall prevention, calcium supplementation and lifestyle advice, as well as pharmacological therapy using agents with proven antifracture efficacy. The most commonly used osteoporosis treatments in Europe are the bisphosphonates alendronate, risedronate, ibandronate and zoledronic acid; the selective estrogen receptor modulator (SERM) raloxifene; teriparatide; and strontium ranelate. Recent additions include the biological therapy denosumab and the SERM bazedoxifene. In this review, we explore the antifracture efficacy of these agents with the aim of simplifying treatment decisions. These treatments can be broadly divided according to their mode of action. The antiresorptive agents include the bisphosphonates, the SERMs and denosumab, while the bone-forming agents include parathyroid hormone and teriparatide. Strontium ranelate appears to combine both antiresorptive and anabolic activities. We collated data on vertebral and hip fracture efficacy from the pivotal 3-year phase III trials, all of which had a randomized, double-blind, placebo-controlled design. The relative reductions in risk in the osteoporosis trials range from 30% to 70% for vertebral fracture and 30% to 51% for hip fracture. This translates into 3-year number needed to treat values of between 9 and 21 for vertebral fracture and from 48 upwards for hip fracture. International guidelines agree that agents that have been shown to decrease vertebral, nonvertebral and hip fractures should be used preferentially over agents that only demonstrate vertebral antifracture efficacy. This is the case for alendronate, risedronate, zoledronic acid, denosumab and strontium ranelate. Finally, therapeutic decisions should be based on a balance between benefits and risks of treatment, which must be carefully considered in each particular case both by the physician and the patient. Indeed, no single agent is appropriate for all patients and, therefore, treatment decisions should be made on an individual basis, taking into account all measures of treatment effect and risk before making informed judgments about the best individual treatment option. [less ▲]

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See detailCurrent challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition.
Bebrone, Carine ULg; Lassaux, Patricia ULg; Vercheval, Lionel ULg et al

in Drugs (2010), 70(6)

The use of the three classical beta-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam) in combination with beta-lactam antibiotics is currently the most successful strategy to combat the beta ... [more ▼]

The use of the three classical beta-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam) in combination with beta-lactam antibiotics is currently the most successful strategy to combat the beta-lactamase mediated resistance. However, these inhibitors are efficient in inactivating class A beta-lactamases only and the efficiency of the inhibitor/antibiotic combination can be compromised by several mechanisms among which the production of naturally resistant class B or class D enzymes, the hyperproduction of AmpC or even the production of evolved inhibitor-resistant class A enzymes. There is thus an urgent need in the development of novel inhibitors. For serine active enzymes (classes A, C and D), derivatives of the beta-lactam ring such as 6-beta-halogenopenicillanates, beta-lactam sulfones, penems and oxapenems, monobactams or trinems seem to be potential starting points to design efficient molecules (among which AM-112 and LK-157). Moreover, a promising non-beta-lactam molecule, NXL-104 is now under clinical trial. In contrast, an ideal inhibitor of metallo-beta-lactamases (class B) remains to be found, despite the huge number of potential molecules already described (biphenyl tetrazoles, cysteinyl peptides, mercaptocarboxylates, succinic acid derivatives, etc). The search for such an inhibitor is complicated by the absence of a covalent intermediate in their catalytic mechanisms and the fact that beta-lactam derivatives often behave as substrates rather than as inhibitors. Currently, the most promising broad spectrum inhibitors of class B enzymes are molecules presenting chelating groups (thiols, carboxylates, etc) combined with an aromatic group. This review describes all the types of molecules already tested as potential beta-lactamase inhibitors and thus constitutes an update of the current status in beta-lactamase inhibitor discovery. [less ▲]

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See detailPrevention of type 2 diabetes mellitus through inhibition of the Renin-Angiotensin system.
Scheen, André ULg

in Drugs (2004), 64(22), 2537-65

Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be ... [more ▼]

Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered as a key objective in the near future. Besides lifestyle changes, various pharmacological treatments have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat. Arterial hypertension, a clinical entity in which insulin resistance is common, is strongly associated with type 2 diabetes and may precede the disease by several years. While antihypertensive agents such as diuretics or beta-adrenoceptor antagonists may worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutral or even slightly positive metabolic effects. Numerous clinical trials have investigated the effects of ACE inhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or without diabetes, with no consistent results. Almost half of the studies with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity as assessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while the other half failed to reveal any significant change. The effects of ARAs on insulin sensitivity are neutral in most studies. Mechanisms of improvement of glucose tolerance and insulin sensitivity through the inhibition of the renin-angiotensin system (RAS) are complex. They may include improvement of blood flow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose delivery to the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement of insulin secretion by the beta cells. Six recent large-scale clinical studies reported a remarkably consistent reduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors or ARAs for 3-6 years, compared with a thiazide diuretic, beta-adrenoceptor antagonist, the calcium channel antagonist amlodipine or even placebo. The relative risk reduction averaged 14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril compared with a thiazide or beta1-adrenoceptor antagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) with candesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine. All these studies considered the development of diabetes as a secondary endpoint, except the HOPE trial where it was a post hoc analysis. These encouraging observations led to the initiation of two large, prospective, placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with the ACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial with the ARA valsartan. Finally, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether it is possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACE inhibitor or an ARA or a combination of both. Thus, the recent consistent observations of a 14-34% reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs are exciting. From a theoretical point of view, they emphasise that there are many aspects of the pathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered. From a practical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type 2 diabetes. [less ▲]

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See detailCurrent management strategies for coexisting diabetes mellitus and obesity.
Scheen, André ULg

in Drugs (2003), 63(12), 1165-84

Besides genetic predisposition, obesity is the most important risk factor for the development of diabetes mellitus. Weight reduction has been shown to markedly improve blood glucose control and vascular ... [more ▼]

Besides genetic predisposition, obesity is the most important risk factor for the development of diabetes mellitus. Weight reduction has been shown to markedly improve blood glucose control and vascular risk factors associated with insulin resistance in obese individuals with type 2 diabetes. Therapeutic strategies for the obese diabetic patient include: (i) promoting weight loss, through lifestyle modifications (low-calorie diet and exercise) and antiobesity drugs (orlistat, sibutramine, etc.); (ii) improving blood glucose control, through agents decreasing insulin resistance (metformin or thiazolidinediones, e.g. pioglitazone and rosiglitazone) or insulin needs (alpha-glucosidase inhibitors, e.g. acarbose) in preference to agents stimulating defective insulin secretion (sulphonylureas, meglitinide analogues); and (iii) treating common associated risk factors, such as arterial hypertension and dyslipidaemias, to improve cardiovascular prognosis. Whenever insulin is required by the obese diabetic patient after failure to respond to oral drugs, it should be preferably prescribed in combination with an oral agent, more particularly metformin or acarbose, or possibly a thiazolidinedione. When morbid obesity is present, both restoring a good glycaemic control and correcting associated risk factors can only be obtained through a marked and sustained weight loss. This objective justifies more aggressive weight reduction programmes, including very-low-calorie diets and bariatric surgery, but only within a multidisciplinary approach and long-term strategy. [less ▲]

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See detailIs there a role for alpha-glucosidase inhibitors in the prevention of type 2 diabetes mellitus?
Scheen, André ULg

in Drugs (2003), 63(10), 933-51

Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to ... [more ▼]

Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to stabilise the disease in most patients, prevention should be considered as a key objective in the near future. People who develop type 2 diabetes pass through a phase of impaired glucose tolerance (IGT). Defects in the action and/or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Any intervention in the impaired glucose tolerance phase that reduces resistance to insulin or protects the beta-cells, or both, should prevent or delay progression to diabetes.Acarbose, miglitol and voglibose act by competitively inhibiting the alpha-glucosidases, a group of key intestinal enzymes involved in the digestion of carbohydrates. They decrease both postprandial hyperglycaemia and hyperinsulinaemia, and thereby may improve sensitivity to insulin and release the stress on beta-cells. These compounds do not induce hypoglycaemia and have a good safety profile, although gastrointestinal adverse effects may limit long-term compliance to therapy.The recent placebo-controlled prospective STOP-noninsulin-dependent diabetes mellitus (STOP-NIDDM) trial demonstrated that acarbose 100mg three times daily reduces the risk of developing type 2 diabetes in patients with IGT (relative risk reduction of 25% after a mean follow-up of 3.3 years). The 6-year Early Diabetes Intervention Trial (EDIT), comparing the effect of acarbose 50mg three times daily to that of metformin, showed a trend to a positive effect of acarbose compared with placebo, in a mid-term 3-year analysis, which should be confirmed in the final analysis.To our knowledge, no such prevention intervention trials have been or are currently being performed with miglitol or voglibose. In conclusion, because of its absence of toxicity and its particular mechanism of action on gastrointestinal tract and indirect consequences on both insulin action and beta-cell function, acarbose may be used to prevent type 2 diabetes. If the ongoing EDIT trial confirms the positive results of the recent STOP-NIDDM trial, acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of diabetes in patients with IGT. However, the best dosage of acarbose for this specific indication remains to be specified, especially when all three important parameters, efficacy, tolerance and cost, are taken into consideration. [less ▲]

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See detailOral antidiabetic agents. A guide to selection.
Scheen, André ULg; Lefebvre, Pierre ULg

in Drugs (1998), 55(2), 225-36

Type 2 diabetes mellitus (formerly named non-insulin-dependent diabetes mellitus or NIDDM) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin ... [more ▼]

Type 2 diabetes mellitus (formerly named non-insulin-dependent diabetes mellitus or NIDDM) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. Various pharmacological approaches can be used to improve glucose homeostasis via different modes of action: sulphonylureas essentially stimulate insulin secretion, biguanides (metformin) act by promoting glucose utilisation and reducing hepatic-glucose production, alpha-glucosidase inhibitors (acarbose) slow down carbohydrate absorption from the gut and thiazolidinediones (troglitazone) enhance cellular insulin action on glucose and lipid metabolism. These pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Selection of oral antihyperglycaemic agents as first-line drug or combined therapy should be based on both the pharmacological properties of the compounds (efficacy and safety, profile) and the clinical characteristics of the patient (stage of disease, bodyweight, etc.). Mildly hyperglycaemic patients should preferably be treated with metformin, acarbose or thiazolidinediones (which are not associated with any hypoglycaemic risk), while more severely hyperglycaemic individuals should receive a sulphonylurea. In moderately hyperglycaemic patients, sulphonylureas should be preferred in nonobese patients while metformin, and probably also thiazolidinediones, should have priority in obese insulin-resistant type 2 diabetic patients. Acarbose is mainly indicated to reduce post-prandial glucose fluctuations and improve glycaemic stability. Each antihyperglycaemic agent may also be combined with insulin therapy to improve glycaemic control and/or reduce the insulin requirement of diabetic patients after secondary failure to oral treatment. Finally, safety should be taken into account in elderly patients and/or those with renal impairment, especially as far as the use of sulphonylureas (higher risk of hypoglycaemia) and metformin (higher risk of lactic acidosis) is concerned. [less ▲]

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See detailDrug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Achievements and future developments.
Scheen, André ULg

in Drugs (1997), 54(3), 355-68

Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. There are various ... [more ▼]

Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. There are various pharmacological approaches to improving glucose homeostasis, but those currently used in clinical practice either do not succeed in restoring normoglycaemia in most patients or fail after a variable period of time. For glycaemic regulation, 4 classes of drugs are currently available: sulphonylureas, biguanides (metformin), alpha-glucosidase inhibitors (acarbose) and insulin, each of which has a different mode and site of action. These standard pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Adjunct treatments comprise a few pharmacological approaches which may help to improve glycaemic control by correcting some abnormalities frequently associated with NIDDM, such as obesity (serotoninergic anorectic agents) and hyperlipidaemia (benfluorex). There is intensive pharmaceutical research to find new drugs able to stimulate insulin secretion (new sulphonylurea or nonsulphonylurea derivatives, glucagon-like peptide-1), improve insulin action (thiazolidinediones, lipid interfering agents, glucagon antagonists, vanadium compounds) or reduce carbohydrate absorption (miglitol, amylin analogues, glucagon-like peptide-1). Further studies should demonstrate the superiority of these new compounds over the standard antidiabetic agents as well as their optimal mode of administration, alone or in combination with currently available drugs. [less ▲]

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See detailRecognition and Treatment of Shingles
Nikkels, Arjen ULg; Pierard, Gérald ULg

in Drugs (1994), 48(4), 528-548

Varicella zoster virus (VZV) is responsible for a primary infection (varicella) followed by a latency, eventually resulting in herpes zoster (shingles). The replication cycle of VZV is normally ... [more ▼]

Varicella zoster virus (VZV) is responsible for a primary infection (varicella) followed by a latency, eventually resulting in herpes zoster (shingles). The replication cycle of VZV is normally interrupted after varicella. Consequently, VZV remains dormant in the organism. Reactivation occurs after viraemia, and the development of tissue alterations (skin and viscera) depends on the immunological status of the patient. Diagnosis of herpes zoster relies on clinical recognition and cytological and histological evaluations combined with immunohistochemistry and molecular biology techniques. Treatment of herpes zoster primarily relies upon antiviral drugs and incidentally on immunomodulating agents, specific immunoglobulins, antimicrobial agents, antiviral enzymes and corticosteroids. Drugs with a clinically relevant activity against varicella zoster virus infections include aciclovir, adenosine monophosphate, bromodeoxyuridine, desciclovir, fiacitabine, idoxuridine, interferon-alpha and vidarabine. Among them, aciclovir appears to be a first-line agent. Its efficacy has been well established by many clinical studies. Promising drugs for the future include famciclovir, penciclovir, valaciclovir and other molecules currently under investigation. Recent and promising improvements in antiviral drug development may increase patient compliance, cost-benefit ratios and therapeutic efficacy. [less ▲]

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See detailManagement of non-insulin-dependent diabetes mellitus.
Lefebvre, Pierre ULg; Scheen, André ULg

in Drugs (1992), 44 Suppl 3

The initial management of non-insulin-dependent diabetes mellitus (NIDDM) should include patient education, dietary counselling and, when feasible, individualised physical activity. It is only when such ... [more ▼]

The initial management of non-insulin-dependent diabetes mellitus (NIDDM) should include patient education, dietary counselling and, when feasible, individualised physical activity. It is only when such measures fail that drug therapy should be considered. Dietary management of NIDDM includes a restriction in calories, and these should be appropriately distributed as carbohydrates, lipids and proteins. Supplementation of the diet with soluble fibre and supplementation with magnesium salts if hypomagnesaemia is demonstrated, is recommended. However, supplementation with fish oils or with fish oil-derived omega-3 fatty acids is not currently recommended. Oral drug therapies used in NIDDM include sulphonylurea derivatives, which are a first-line treatment in patients who are not grossly obese, metformin, which is the treatment of choice for obese patients, and alpha-glucosidase inhibitors such as acarbose, which are used mainly to reduce postprandial blood glucose peaks. These types of drugs can be used alone or in combination. Insulin therapy may be required to achieve adequate control of blood glucose levels in some patients. In several instances, it is suggested that insulin therapy be combined with sulphonylureas (essentially when residual insulin secretion is present), with metformin, or with alpha-glucosidase inhibitors. The treatment of disorders associated with NIDDM, such as obesity, hypertension or hyperlipidaemia, requires particular attention in diabetic patients, since some drugs can adversely affect glycaemic control. Oral drugs for the treatment of NIDDM include sulphonylurea derivatives used in first-line treatment in patients who are not grossly obese, metformin, which is often the treatment of choice for obese patients and, more recently, the alpha-glucosidase inhibitors, such as acarbose, which are effective in reducing the postprandial rise in blood glucose. [less ▲]

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See detailInterrelationship of Hypertension, Plasma Lipids and Atherosclerosis
Krzesinski, Jean-Marie ULg; Carlier, P. G.; Rorive, G. L.

in Drugs (1988), 36(Suppl 2), 18-26

The relationship between hypertension and atherosclerosis has been illustrated by epidemiological, clinical and experimental observations. Typical atherosclerotic lesions develop in arterial wall when ... [more ▼]

The relationship between hypertension and atherosclerosis has been illustrated by epidemiological, clinical and experimental observations. Typical atherosclerotic lesions develop in arterial wall when hypercholesterolaemia is present. Hypertension aggravates these lesions by causing vascular structural changes. In clinical studies, however, the correction of high blood pressure does not decrease the incidence of coronary heart disease. Several hypotheses have been formulated to account for this observation: one is that reversibility of the structural vascular changes induced by hypertension is not complete when the blood pressure is lowered; another is that antihypertensive drugs have a deleterious effect on the vascular wall. [less ▲]

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See detailHaemodynamic effects of class I antiarrhythmic agents.
Legrand, Victor ULg; Collignon, P.

in Drugs (1985), 29 Suppl 4

In order to choose the most appropriate antiarrhythmic agent, the basic haemodynamic characteristics of class I antiarrhythmic agents must be known. Class Ia agents, quinidine and procainamide, have minor ... [more ▼]

In order to choose the most appropriate antiarrhythmic agent, the basic haemodynamic characteristics of class I antiarrhythmic agents must be known. Class Ia agents, quinidine and procainamide, have minor haemodynamic effects, while disopyramide causes serious left ventricular depression. Class Ib drugs are exceptionally well tolerated, and class Ic agents have the potential for adverse haemodynamic effects in patients with left ventricular dysfunction. In this article, haemodynamic effects of class I antiarrhythmic agents are described, with particular emphasis on their clinical implications. [less ▲]

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