Kondo quasiparticle dynamics observed by resonant inelastic x-ray scattering.

Effective models focused on pertinent low-energy degrees of freedom have substantially contributed to our qualitative understanding of quantum materials. An iconic example, the Kondo model, was key to demonstrating that the rich phase diagrams of correlated metals originate from the interplay of localized and itinerant electrons. Modern electronic structure calculations suggest that to achieve quantitative material-specific models, accurate consideration of the crystal field and spin-orbit interactions is imperative. This poses the question of how local high-energy degrees of freedom become incorporated into a collective electronic state. Here, we use resonant inelastic x-ray scattering (RIXS) on CePd3 to clarify the fate of all relevant energy scales. We find that even spin-orbit excited states acquire pronounced momentum-dependence at low temperature-the telltale sign of hybridization with the underlying metallic state. Our results demonstrate how localized electronic degrees of freedom endow correlated metals with new properties, which is critical for a microscopic understanding of superconducting, electronic nematic, and topological states.

Physics-informed machine learning for inorganic scintillator discovery.

Applications of inorganic scintillators-activated with lanthanide dopants, such as Ce and Eu-are found in diverse fields. As a strict requirement to exhibit scintillation, the 4f ground state (with the electronic configuration of [Xe]4fn 5d0) and 5d1 lowest excited state (with the electronic configuration of [Xe]4fn-1 5d1) levels induced by the activator must lie within the host bandgap. Here we introduce a new machine learning (ML) based search strategy for high-throughput chemical space explorations to discover and design novel inorganic scintillators. Building upon well-known physics-based chemical trends for the host dependent electron binding energies within the 4f and 5d1 energy levels of lanthanide ions and available experimental data, the developed ML model-coupled with knowledge of the vacuum referred valence and conduction band edges computed from first principles-can rapidly and reliably estimate the relative positions of the activator's energy levels relative to the valence and conduction band edges of any given host chemistry. Using perovskite oxides and elpasolite halides as examples, the presented approach has been demonstrated to be able to (i) capture systematic chemical trends across host chemistries and (ii) effectively screen promising compounds in a high-throughput manner. While a number of other application-specific performance requirements need to be considered for a viable scintillator, the scheme developed here can be a practically useful tool to systematically down-select the most promising candidate materials in a first line of screening for a subsequent in-depth investigation.

Quantum critical fluctuations in the heavy fermion compound Ce(Ni0.935Pd0.065)2Ge2.

Electric resistivity, specific heat, magnetic susceptibility, and inelastic neutron scattering experiments were performed on a single crystal of the heavy fermion compound Ce(Ni0.935Pd0.065)2Ge2 in order to study the spin fluctuations near an antiferromagnetic (AF) quantum critical point (QCP). The resistivity and the specific heat coefficient for T ⩽ 1 K exhibit the power law behavior expected for a 3D itinerant AF QCP (ρ(T) ∼ T(3/2) and γ(T) ∼ γ0 - bT(1/2)). However, for 2 ⩽ T ⩽ 10 K, the susceptibility and specific heat vary as log T and the resistivity varies linearly with temperature. Furthermore, despite the fact that the resistivity and specific heat exhibit the non-Fermi liquid behavior expected at a QCP, the correlation length, correlation time, and staggered susceptibility of the spin fluctuations remain finite at low temperature. We suggest that these deviations from the divergent behavior expected for a QCP may result from alloy disorder.

Anisotropic thermal conductivity in uranium dioxide.

The thermal conductivity of uranium dioxide has been studied for over half a century, as uranium dioxide is the fuel used in a majority of operating nuclear reactors and thermal conductivity controls the conversion of heat produced by fission events to electricity. Because uranium dioxide is a cubic compound and thermal conductivity is a second-rank tensor, it has always been assumed to be isotropic. We report thermal conductivity measurements on oriented uranium dioxide single crystals that show anisotropy from 4 K to above 300 K. Our results indicate that phonon-spin scattering is important for understanding the general thermal conductivity behaviour, and also explains the anisotropy by coupling to the applied temperature gradient and breaking cubic symmetry.

Q-dependence of the spin fluctuations in the intermediate valence compound CePd3.

We report inelastic neutron scattering experiments on a single crystal of the intermediate valence compound CePd3. At 300 K the magnetic scattering is quasielastic, with half-width Γ = 23 meV, and is independent of momentum transfer Q. At low temperature, the Q-averaged magnetic spectrum is inelastic, exhibiting a broad peak centered near Emax = 55 meV. These results, together with the temperature dependence of the susceptibility, 4f occupation number, and specific heat, can be fit by the Kondo/Anderson impurity model. The low temperature scattering near Emax, however, shows significant variations with Q, reflecting the coherence of the 4f lattice. The intensity is maximal at (1/2, 1/2, 0), intermediate at (1/2, 0, 0) and (0, 0, 0), and weak at (1/2, 1/2, 1/2). We discuss this Q-dependence in terms of current ideas about coherence in heavy fermion systems.

Qualitative comparison of bremsstrahlung X-rays and 800 MeV protons for tomography of urania fuel pellets.

We present an assessment of x-rays and proton tomography as tools for studying the time dependence of the development of damage in fuel rods. We also show data taken with existing facilities at Los Alamos National Laboratory that support this assessment. Data on surrogate fuel rods have been taken using the 800 MeV proton radiography (pRad) facility at the Los Alamos Neutron Science Center (LANSCE), and with a 450 keV bremsstrahlung X-ray tomography facility. The proton radiography pRad facility at LANSCE can provide good position resolution (<70 µm has been demonstrate, 20 µm seems feasible with minor changes) for tomography on activated fuel rods. Bremsstrahlung x-rays may be able to provide better than 100 µm resolution but further development of sources, collimation, and detectors is necessary for x-rays to deal with the background radiation for tomography of activated fuel rods.

Role of antisite disorder on preamorphization swelling in titanate pyrochlores.

Ion irradiation experiments and atomistic simulations were used to demonstrate that irradiation-induced lattice swelling in a complex oxide, Lu2Ti2O7, is due initially to the formation of cation antisite defects. X-ray diffraction revealed that cation antisite formation correlates directly with lattice swelling and indicates that the volume per antisite pair is approximately 12 Å3. First principles calculations revealed that lattice swelling is best explained by cation antisite defects. Temperature accelerated dynamics simulations indicate that cation Frenkel defects are metastable and decay to form antisite defects.

Itinerant spin excitations near the hidden order transition in URu(2)Si(2).

By means of neutron scattering we show that the high temperature precursor to the hidden order state of the heavy fermion superconductor URu(2)Si(2) exhibits heavily damped incommensurate paramagnons whose strong energy dispersion is very similar to that of the long-lived longitudinal f spin excitations that appear below T(0). This suggests that there is a strongly hybridized character to the itinerant excitations observed previously above the hidden order transition. Here we present evidence that the itinerant excitations, like those in chromium, are due to Fermi surface nesting of hole and electron pockets; hence the hidden order phase probably originates from a Fermi surface instability. We identify wavevectors that span nested regions of a f-d hybridized band calculation and that match the neutron spin crossover from incommensurate to commensurate on approach to the hidden order phase.

Indobufen: an updated review of its use in the management of atherothrombosis.

UNLABELLED: Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme thereby suppressing thromboxane synthesis. Clinical trials have evaluated the efficacy of oral indobufen in the secondary prevention of thromboembolic complications in patients with or without atrial fibrillation, in the prevention of graft occlusion after coronary artery bypass graft (CABG) surgery and in the treatment of intermittent claudication. In the secondary prevention of thromboembolic events indobufen 200 mg once or twice daily was significantly more effective than no treatment although not as effective as ticlopidine 250 mg once or twice daily, during 1-year nonblind clinical trials. Compared with placebo, indobufen 100 mg twice daily significantly reduced the risk of stroke in a small 28-month trial of patients at increased risk of systemic embolism (50% had atrial fibrillation). Furthermore, in patients with nonrheumatic atrial fibrillation and a recent cerebrovascular event enrolled in the 1-year Studio Italiano Fibrillazione Atriale (SIFA) trial, indobufen 100 or 200 mg twice daily was as effective as warfarin (titrated to produce an international normalised ratio of 2.0 to 3.5) in the secondary prevention of thromboembolic events; the incidences of the composite end-point of major vascular events (10.6 vs 9.0%) and recurrent stroke (5 vs 4%) were similar between treatments. In 2 large 12-month trials, the Studio Indobufene nel Bypass Aortocoronarico (SINBA) and the UK study, indobufen 200 mg twice daily was as effective as aspirin (acetylsalicylic acid) 300 or 325 mg plus dipyridamole 75 mg 3 times daily in the prevention of early and late occlusion of saphenous grafts in patients after CABG surgery. Indobufen 200 mg twice daily for 6 months significantly improved walking capacity compared with placebo, and caused a more pronounced improvement in both pain-free and total walking distance than either pentoxifylline 300 mg or aspirin 500 mg twice daily in separate 6- and 12-month studies of patients with intermittent claudication. Oral indobufen up to 200 mg twice daily was generally well tolerated in >5000 patients with atherosclerotic disease. Adverse events (predominantly gastrointestinal), reported by 3.9% of patients, rarely required withdrawal from treatment. In the SINBA and UK studies, fewer adverse events and less gastrointestinal bleeding were seen with indobufen than with aspirin plus dipyridamole treatment, while in the SIFA trial, noncerebral bleeding events occurred significantly less frequently in indobufen than warfarin recipients (0.6 vs 5.1%) and major bleeding events occurred only in the warfarin group. CONCLUSION: Indobufen is as effective as warfarin in the prophylaxis of thromboembolic events in at risk patients with nonrheumatic atrial fibrillation, as aspirin plus dipyridamole in the prevention of CABG occlusion and may be more effective than aspirin or pentoxifylline in improving walking capacity in patients with intermittent claudication. The improved tolerability profile of indobufen (favourable gastric tolerance and reduced haemorrhagic complications) compared with aspirin 300 to 325 mg 3 times daily or warfarin, in addition to a similar antiplatelet effect, suggests indobufen can be considered a drug with a definite role in the management of atherothrombotic events. In particular, indobufen may be an effective alternative for at risk patients with nonrheumatic atrial fibrillation in whom anticoagulant therapy is contraindicated or who are at higher risk of bleeding.

Lercanidipine: a review of its use in hypertension.

UNLABELLED: Lercanidipine is a vasoselective dihydropyridine calcium antagonist which causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug and as such has a slower onset and longer duration of action than a number of other calcium antagonists. Preclinical evidence suggests that lercanidipine has antiatherogenic potential and it may also protect against end-organ damage. In well controlled clinical studies, once daily administration of lercanidipine 10 or 20mg effectively reduced blood pressure (BP) compared with placebo in patients with mild to moderate hypertension without affecting heart rate. Response rate (percentage of patients with diastolic BP < or =90mm Hg or reduced by > or =10mm Hg from baseline) ranged from 50 to 66% with lercanidipine 10 mg/day and up to 86% with lercanidipine 20 mg/day. The drug had a long duration of action: clinical measurements for diastolic BP yielded a trough/peak ratio of >0.8 for both lercanidipine dosages in 1 study. Comparative trials, either published in full or as abstracts, found lercanidipine 10mg once daily for > or =4 weeks to be at least as effective as atenolol 50mg once daily, candesartan cilexetil 16 mg/day, captopril 25mg twice daily, enalapril 20 mg/day, hydrochlorothiazide 12.5mg once daily, irbesartan 150 mg/day and slow release nifedipine 20mg twice daily in patients with mild to moderate hypertension. In addition, lercanidipine 20 mg/day was as effective as amlodipine 10 mg/day. Lercanidipine is effective in the treatment of elderly patients (aged 60 to 85 years) with mild to moderate essential hypertension and in those with isolated systolic hypertension. In addition, monotherapy with lercanidipine 20 or 40 mg/day has shown efficacy in patients with severe hypertension, and add-on therapy helped control BP in a large proportion of patients with severe hypertension not responding sufficiently to beta-blockers, diuretics or ACE inhibitors. Unpublished data indicate that the drug reduces blood pressure in patients with type 2 (non-insulin-dependent) diabetes mellitus, without adversely affecting glucose homeostasis. Lercanidipine was well tolerated in clinical trials, with most treatment-related adverse events typical of dihydropyridine calcium antagonists, namely headache, flushing, dizziness and ankle oedema. CONCLUSIONS: Lercanidipine is an effective and well tolerated once daily antihypertensive agent in patients with mild to moderate hypertension. In addition, the drug may reduce BP when used as monotherapy in patients with severe hypertension or when used adjunctively in patients with resistant hypertension. Importantly, lercanidipine appears to be at least as effective and well tolerated as other commonly used antihypertensive agents. The drug therefore represents a useful therapeutic option in the management of patients with hypertension and will be particularly useful in patients not responding to, or intolerant of, antihypertensive agents from other drug classes.

Ropivacaine: an update of its use in regional anaesthesia.

UNLABELLED: Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anaesthetic with a high pKa and low lipid solubility which blocks nerve fibres involved in pain transmission (Adelta and C fibres) to a greater degree than those controlling motor function (Abeta fibres). The drug was less cardiotoxic than equal concentrations of racemic bupivacaine but more so than lidocaine (lignocaine) in vitro and had a significantly higher threshold for CNS toxicity than racemic bupivacaine in healthy volunteers (mean maximum tolerated unbound arterial plasma concentrations were 0.56 and 0.3 mg/L, respectively). Extensive clinical data have shown that epidural ropivacaine 0.2% is effective for the initiation and maintenance of labour analgesia, and provides pain relief after abdominal or orthopaedic surgery especially when given in conjunction with opioids (coadministration with opioids may also allow for lower concentrations of ropivacaine to be used). The drug had efficacy generally similar to that of the same dose of bupivacaine with regard to pain relief but caused less motor blockade at low concentrations. Lumbar epidural administration of 20 to 30ml ropivacaine 0.5% provided anaesthesia of a similar quality to that achieved with bupivacaine 0.5% in women undergoing caesarean section, but the duration of motor blockade was shorter with ropivacaine. For lumbar epidural anaesthesia for lower limb or genitourinary surgery, comparative data suggest that higher concentrations of ropivacaine (0.75 or 1.0%) may be needed to provide the same sensory and motor blockade as bupivacaine 0.5 and 0.75%. In patients about to undergo upper limb surgery, 30 to 40ml ropivacaine 0.5% produced brachial plexus anaesthesia broadly similar to that achieved with equivalent volumes of bupivacaine 0.5%, although the time to onset of sensory block tended to be faster and the duration of motor block shorter with ropivacaine. Ropivacaine had an adverse event profile similar to that of bupivacaine in clinical trials. Several cases of CNS toxicity have been reported after inadvertent intravascular administration of ropivacaine, but only 1 case of cardiovascular toxicity has been reported to date. The outcome of these inadvertent intravascular administrations was favourable. CONCLUSION: Ropivacaine is a well tolerated regional anaesthetic with an efficacy broadly similar to that of bupivacaine. However, it may be a preferred option because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block.

Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders.

UNLABELLED: Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials. fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine < or = 300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine < or = 300 mg/day for > or = 8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dysfunction and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. CONCLUSION: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class.

Tropisetron: an update of its use in the prevention of chemotherapy-induced nausea and vomiting.

UNLABELLED: Tropisetron is a serotonin (5-hydroxytryptamine; 5-HT) antagonist that is primarily used in the prevention of chemotherapy-induced nausea and vomiting. Antagonism of 5-HT3 binding sites in the peripheral and central nervous system is the probable mechanism of prevention of acute nausea and vomiting. Effects on delayed nausea and vomiting are less well understood as these are probably not mediated solely by 5-HT3 receptors. Tropisetron monotherapy is effective for the control of acute, and to a lesser extent delayed, nausea and vomiting in patients receiving moderately to severely emetogenic chemotherapy. The combination of dexamethasone and tropisetron is more effective than monotherapy. Complete control of cisplatin-induced nausea and vomiting was obtained in 69 to 97% of patients receiving the combination compared with 46 to 80% receiving tropisetron monotherapy in randomised trials. There were generally no significant differences between the control of acute or delayed nausea and vomiting provided by tropisetron, ondansetron or granisetron in randomised, comparative trials. The antiemetic efficacy of tropisetron was maintained over multiple cycles of chemotherapy. Most comparative studies showed tropisetron monotherapy to be more effective than metoclopramide in controlling acute nausea and vomiting, with the exception of 1 study which showed similar efficacy. However, high dose metoclopramide plus dexamethasone provided similar control of delayed emesis to tropisetron plus dexamethasone. Tropisetron is also effective in children, including those who responded poorly to previous antiemetic treatment. Tropisetron and ondansetron generally have similar efficacies in this population. The drug enhanced patients' quality of life and was well tolerated by adults and children alike. The recommended oral and IV dosage of tropisetron is 5 mg once daily; there is no increase in efficacy with doses >5 mg. CONCLUSIONS: Tropisetron is similar to other 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting in both adults and children. It is suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting.

Losartan: a review of its use, with special focus on elderly patients.

UNLABELLED: Losartan is an orally active, nonpeptide, selective angiotensin subtype 1 (AT1) receptor antagonist. It provides a more specific and complete blockade of the actions of angiotensin II than renin or ACE inhibitors. Short term (up to 12 weeks' duration) clinical trials have shown losartan to be as effective at lowering blood pressure (BP) [causes a decrease in BP < or = 26/20 mm Hg] in elderly patients with hypertension as recommended dosages of captopril, atenolol, enalapril, felodipine and nifedipine. In patients with isolated systolic hypertension (ISH) the efficacy of losartan was similar to that of atenolol. The addition of hydrochlorothiazide to losartan therapy provides greater antihypertensive efficacy, equivalent to that seen with captopril plus hydrochlorothiazide. Preliminary evidence also indicates that losartan therapy contributes to the regression of left ventricular hypertrophy associated with chronic hypertension. Exercise capacity is increased by losartan in patients with either asymptomatic or symptomatic heart failure. Results from the Losartan Heart Failure Survival or ELITE II (Evaluation of Losartan in the Elderly II) study indicate that there was no statistically significant difference between losartan and captopril in reducing overall deaths or in reducing sudden cardiac death and/or resuscitated cardiac arrest in patients with heart failure. Other than ELITE II, little conclusive long term mortality and morbidity data exist for losartan. Additional long term trials to evaluate the survival benefits of losartan in elderly patients with hypertension, renal disease or after an acute myocardial infarction are currently in progress. In elderly patients with hypertension, the incidence of treatment-related adverse events associated with once daily losartan (alone or in combination with hydrochlorothiazide) [19 to 27%] was similar to felodipine (23%) and nifedipine (21%), however, losartan tended to be better tolerated than captopril (11 vs 16%). Losartan was also better tolerated than atenolol in patients with ISH (10.4 vs 23%). In patients with heart failure the renal tolerability of losartan was similar to that of captopril, but losartan was associated with a lower withdrawal rate because of adverse events. No dosage adjustment is required in elderly or in patients with mild to moderate renal dysfunction, and the risk of first-dose hypotension is low. CONCLUSIONS: comparative data have shown losartan to be as effective as other antihypertensive agents in the treatment of elderly patients with hypertension. Treatment with losartan is therefore an option for first-line therapy in all patients with hypertension, particularly those who are not well managed with or who are intolerant of their current therapy. Morbidity and mortality data from the Losartan Heart Failure Survival (ELITE II) study show that losartan has potential in the treatment of heart failure.

Dexmedetomidine.

Dexmedetomidine is a potent alpha2-adrenoceptor agonist with 8 times higher affinity for the alpha2-adrenoceptor than clonidine. Dexmedetomidine has shown sedative, analgesic and anxiolytic effects after intravenous administration to healthy volunteers or postsurgical patients in the intensive care unit. Dexmedetomidine produced a predictable haemodynamic decline (dose-dependently decreased arterial blood pressure and heart rate) in postsurgical patients coinciding with reductions in plasma catecholamines. In phase III clinical trials, dexmedetomidine 0.2 to 0.7 microg/kg/h produced clinically effective sedation and significantly reduced the analgesic requirements of postsurgical ventilated intensive care unit patients. There was no clinically apparent respiratory depression after cessation of assisted ventilation. Dexmedetomidine produced rapid and stable sedation in postsurgical ventilated patients while maintaining a high degree of patient rousability and anxiety reduction. Dexmedetomidine was well tolerated in phase III studies. The most frequently observed adverse events were hypotension, bradycardia and nausea.

Topical metronidazole. A review of its use in rosacea.

UNLABELLED: Topical application of the antibacterial agent metronidazole is effective in the treatment of moderate to severe rosacea, although its mechanism of action has yet to be clearly established. Metronidazole preparations (0.75 and 1% cream, 0.75% gel and 0.75% lotion) were significantly more effective than placebo in patients with moderate to severe rosacea when administered to the affected area once or twice daily for 7 to 12 weeks. The mean number of papules and pustules decreased by between 48 and 65.1% during the treatment period. Reductions were fairly consistent regardless of formulation, strength or application frequency and were significant compared with placebo (p < 0.05). In 1 study, most of the overall effects of metronidazole were observed within the first 3 weeks. Although data are limited, topical metronidazole appears to improve inflammatory lesions and erythema as effectively as oral tetracyclines. Like tetracyclines, however, metronidazole has no effect on telangiectasia. Metronidazole 0.75% gel seems to be effective in maintaining remission of rosacea symptoms in patients successfully treated with both oral tetracycline and topical metronidazole. In the only study, 77% of patients treated with metronidazole gel compared with 58% of placebo recipients (p < 0.05) remained in remission 6 months after the tetracycline was stopped. The effects of topical metronidazole preparations on rosacea symptoms are palliative, not curative, but preliminary data suggest that relapse rates after cessation of therapy are no worse than those after cessation of oral oxytetracycline. Topical metronidazole formulations are generally well tolerated locally, with stinging, dryness, burning and itching reported in < or = 2% of patients. Because minimal concentrations of metronidazole are absorbed after topical administration, systemic adverse events and drug interactions seen with oral or intravenous metronidazole are unlikely. CONCLUSIONS: Topical metronidazole formulations are significantly more effective than placebo when used in the initial treatment of patients with moderate to severe rosacea. Furthermore, limited evidence suggests that the use of topical metronidazole alone may be as effective as oral tetracyclines against the disorder's inflammatory component. Therefore, for those patients with a preference for topical rather than oral therapy, the use of a topical metronidazole formulation must be a consideration.

Perindopril 2mg/indapamide 0.625mg. Fixed low-dose combination.

Low-dose drug combinations have been proposed in International Guidelines for use in patients with hypertension. The fixed low-dose combination of perindopril 2mg with indapamide 0.625mg combines an angiotensin converting enzyme (ACE) inhibitor with a non-thiazide diuretic. Coadministration of perindopril and indapamide did not have any clinically significant effects on the pharmacokinetic profile of either agent in healthy volunteers. In experimental models of hypertension, perindopril/indapamide restored endothelial function, improved microvascular density, reduced left ventricular and aortic hypertrophy, and reversed renal end-organ damage. Once daily oral perindopril 2mg/indapamide 0.625mg normalised blood pressure (BP) in 83.6% of elderly patients with essential hypertension (diastolic BP was reduced to < or =90mm Hg) and 81.7% of those with isolated systolic hypertension (systolic BP was reduced to <160mm Hg) after approximately 1 year of treatment. BP normalisation was sustained in 79.8% of patients throughout the study. Fixed low-dose perindopril/indapamide had a tolerability profile similar to that of placebo in clinical trials; most adverse events were of mild to moderate severity. Coadministration of the 2 agents reduced the incidence of hypokalaemia seen with indapamide alone.

Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions.

UNLABELLED: The orally administered antianginal agent trimetazidine increases cell tolerance to ischaemia by maintaining cellular homeostasis. In theory, this cytoprotective activity should limit myocyte loss during ischaemia in patients with angina pectoris. Data from studies in patients with coronary artery disease indicate that, unlike the effects of other antianginals, the anti-ischaemic effects of trimetazidine 20 mg are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. Furthermore, limited evidence suggests trimetazidine may improve left ventricular function in patients with chronic coronary artery disease or ischaemic cardiomyopathy and in patients experiencing acute periods of ischaemia when undergoing percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20 mg 3 times daily reduces the frequency of anginal attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. Its clinical effects are broadly similar to those of nifedipine 40 mg/day and propranolol 120 to 160 mg/day but, unlike these agents, trimetazidine does not affect the rate-pressure product during peak exercise or at rest. Adjunctive trimetazidine 60 mg/day reduces the frequency of anginal attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antianginal agents. Furthermore, the drug appears to be more effective than isosorbide dinitrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranolol 120 mg/day. The tolerability profile of trimetazidine 60 mg/day was similar to that of placebo when used as add-on therapy in patients with angina pectoris insufficiently controlled by other antianginal agents and was superior to that of either nifedipine 40 mg/day or propranolol 120 to 160 mg/day when used as monotherapy. The most frequently reported adverse events in trimetazidine recipients were gastrointestinal disorders, although the incidence of these events was low. CONCLUSIONS: Trimetazidine is an effective and well tolerated anti-ischaemic agent which, in addition to providing symptom relief and functional improvement in patients with angina pectoris, has a cytoprotective action during ischaemia. The drug is suitable for initial use as monotherapy in patients with angina pectoris and, because of its different mechanism of action, as adjunctive therapy in those with symptoms not sufficiently controlled by nitrates, beta-blockers or calcium antagonists. The role of trimetazidine in other coronary conditions has yet to be clearly established.

Terbinafine. An update of its use in superficial mycoses.

UNLABELLED: Terbinafine is an allylamine antifungal agent which has fungicidal activity against a wide variety of dermatophytes, moulds and certain dimorphic fungi, and fungistatic activity against Candida albicans. Oral terbinafine 250 mg/day is effective in the treatment of superficial dermatophyte infections such as onychomycosis, tinea pedis and tinea corporis/cruris, generally achieving mycological cure in > 80% of patients. The drug is also effective in children with tinea capitis when administered orally in the dosage range 62.5 to 250 mg/day for 4 weeks. Comparative data indicate that oral terbinafine is more effective than continuous or intermittent intraconazole in dermatophyte onychomycosis, and is as effective as itraconazole 400 mg/day in tinea pedis. The drug has shown greater efficacy than griseofulvin in dermatophyte onychomycosis, tinea pedis and tinea corporis/cruris, and comparable efficacy in children with tinea capitis. Additionally, oral terbinafine is more effective than ketoconazole 200 mg/day in tinea corporis/cruris. Topical terbinafine 1% formulations are effective when applied once or twice daily for up to 2 weeks, achieving mycological cure in > 80% of patients with tinea pedis, tinea corporis/cruris, cutaneous candidiasis and pityriasis versicolor. Its formulations are at least as effective as miconazole 2% cream and naftifine 1% gel in tinea pedis, and more effective than clotrimazole 1% cream, bifonazole 1% cream and oxiconazole 1% lotion. Mycological cure rates achieved with terbinafine generally improve after treatment cessation, reflecting the drug's fungicidal mechanism of action and its residual effect in tissue. Terbinafine is well tolerated after oral or topical administration and has a relatively low potential for drug interactions. Pharmacoeconomic data support the use of terbinafine in dermatophyte infections of the skin or nails. CONCLUSIONS: Evidence suggests that oral terbinafine is the treatment of choice for dermatophyte onychomycosis, as it achieves high rates of mycological and clinical cure, is generally well tolerated and has a relatively low potential for drug interactions. It must also be considered a first-line treatment option, along with itraconazole, in cutaneous mycoses which warrant systemic treatment; topical terbinafine is a treatment of choice in less extensive mycoses. The use of terbinafine in non-dermatophyte or mixed infections has not been fully defined.

Valsartan/hydrochlorothiazide.

Valsartan/hydrochlorothiazide (HCTZ) combines an angiotensin II AT1 receptor blocker with a thiazide diuretic to produce additive blood pressure reductions without major effects on heart rate. HCTZ did not significantly alter valsartan pharmacokinetics; during combination therapy, HCTZ pharmacokinetics differed from those seen with HCTZ monotherapy. In clinical trials in patients with essential hypertension, adding HCTZ 12.5 or 25 mg/day to valsartan 80 mg/day resulted in a greater blood pressure reduction than increasing the valsartan dosage from 80 to 160 mg/day. The valsartan/HCTZ combination was generally more effective than either drug given alone. Efficacy of the combination was maintained during up to 3 years of treatment. Valsartan/HCTZ was well tolerated in both short and long term trials. The most common adverse events were dizziness, headache and fatigue. The overall incidence of adverse events with the combination was similar to that with placebo. HCTZ-induced hypokalaemia was less common during combination therapy.