Vasomotor effects of iodinated contrast media: just side effects?

Routinely used iodinated contrast media have complex vasomotor effects on several arterial districts. All classes of iodinated radiographic contrast media are vasoactive, with iso-osmolar dimers inducing the smallest changes in vascular tone. The mechanisms responsible for contrast-induced vasomotor changes are not fully elucidated and are likely to be multifactorial. Although contrast-induced vasomotility is usually considered as an unwanted "side effect", recent findings suggest that it might indeed be useful in exploring the functional integrity of the vessel wall. We found that atherosclerosis has an impact on the type of the contrast-induced coronary vasomotor reaction. In fact, angiographically normal coronary segments show divergent vasomotor reactions to iodixanol or iopromide according to the presence/absence of, and distance from, a coronary atherosclerotic lesion located in their proximity. The mechanism responsible for this vasomotor effect does not apparently involve flow-mediated vasodilatation or endothelial nitric oxide synthesis. On the other hand, a cyclooxygenase product may be, at least in part, responsible for the vasodilating effect of non-ionic agents on epicardial coronary arteries, since contrast-induced vasodilatation is strongly inhibited in the presence of indomethacin. These findings have potential clinical implications, since the analysis of contrast-induced coronary vasomotion might result in a new test capable of evaluating vascular functional integrity. Such a test might be alternative or complementary to the tests based on muscarinic agonists (acetylcholine) or serotonin, which are known to evaluate the nitric oxide pathway.     

Dual antiviral therapy for HIV and hepatitis C – drug interactions and side effects

Introduction: Roughly 20% of HIV-positive persons worldwide are coinfected with hepatitis C virus (HCV). The recent advent of direct-acting antivirals (DAA) that cure most hepatitis C patients has attracted much attention. Knowledge on drug interactions between DAA and antiretrovirals (ARV) may allow maximizing antiviral efficacy while minimizing drug-related toxicities.

Areas covered: We review the most frequent side effects and clinically significant drug interactions between DAA and ARV. We further discuss how they can be prevented and managed in HIV/HCV-coinfected patients.

Expert opinion: The safety profile of current DAA and the most recently approved ARV is quite favorable. Interactions between DAA and ARV could be frequent in clinical practice. The most common drug interactions affect drug metabolism by inducing or inhibiting the cytochrome P450 system, leading to abnormal drug exposures. Throughout this mechanism HCV and HIV protease inhibitors interact, especially when co-formulated with ritonavir as a pharmacoenhancer, and non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide polymerase inhibitors, and most HCV NS5A inhibitors (i.e., ledipasvir) and HIV integrase inhibitors (i.e., dolutegravir), do not or only marginally affect CYP450, and therefore are free of significant drug interactions. Exposure to HIV and HCV nucleos(t)ide analogues (i.e., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (i.e., P-glycoprotein).     

Can the electrophysiological action of rosiglitazone explain its cardiac side effects?

Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 μM) shortened AP duration at 90% level of repolarization (APD(90)) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 μM) caused a significant reduction of APA and maximum velocity of depolarization (V(max)) which was accompanied by lengthening of APD(90). In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced V(max). R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC(50) value for this inhibition was 25.2±2.7 μM for the transient outward K(+ ) current (I(to)), 72.3±9.3 μM for the rapid delayed rectifier K(+ ) current (I(Kr)), and 82.5±9.4 μM for the L-type Ca(2+ ) current (I(Ca)) with Hill coefficients close to unity. The inward rectifier K(+ ) current (I(K1)) was not affected by R up to concentrations of 100 μM. Suppression of I(to), I(Kr), and I(Ca) has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.     

Inhaled corticosteroids in COPD: systemic effects of a local therapy?

Background: There are few data on the effects of inhaled corticosteroids on systemic inflammation in chronic obstructive pulmonary disease (COPD). Objective: Evaluation of the systemic anti-inflammatory effects of inhaled corticosteroids alone or in combination with long acting beta2-agonists. Methods: Analysis of the results of a randomized study assessing the short-term effects of inhaled fluticasone propionate, inhaled fluticasone + salmeterol and placebo on three inflammation biomarkers represented by C-reactive protein, IL-6 and surfactant protein-D. Results/conclusions: Inhaled corticosteroids alone or in combination exhibited partial systemic anti-inflammatory effects, reducing significantly only SP-D serum levels. Further evaluation of effects of inhaled corticosteroids on various biomarkers of systemic inflammation is required in more severe stable COPD.     

Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?

The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na(+), Ca(2+) and K(+) channels often leading to life-threatening arrhythmia. To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors. Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na(+), Ca(2+) and K(+) channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders. The primary goal of this review is to shed light on the recently observed clinically important cardiovascular effects of new antidepressants and antipsychotics and discuss the mechanism beyond this phenomenon.     

Safety of perioperative β-blocker use: how do β-blockers compare in terms of side effects?

INTRODUCTION: In the perioperative setting, there is still a high incidence of adverse cardiac events due to sudden coronary plaque rupture or oxygen supply-demand imbalance. β-Blockers play an important role in preventing these cardiac events. Discussion, however, remains on the side effects accompanying this therapy. AREAS COVERED: The evidence for perioperative use of β-blockers is summarized in this review in terms of risk reduction, perioperative safety and current clinical use. Furthermore, data on pharmacokinetics, pharmacodynamics and pharmacogenetics are presented. EXPERT OPINION: In perioperative care, β-blockers are recommended and can be given safely when started early in a low dose, titrated to heart rate. In the future, there could be a place for added perioperative short-acting β-blockers to further optimize heart rate control.     

Symptoms or side effects? Methodological hazards and therapeutic principles

The case is described of a 40 year old man with delusions and hallucinations, who at the start of this study was taking doses of neuroleptic medication greatly in excess of those that have been demonstrated to be optimally effective. Over 48 weeks, using PQ methods and detailed interviewing, his progress was charted as the medication was reduced to more appropriate levels. Across this change, his delusional beliefs remained unchanged, but there were substantial reductions in auditory hallucinations, as well as in hopelessness and anxiety. The case has implications for concepts of therapy in the psychoses and for the methodology of therapy studies. It also illustrates possible benefits of using PQ or other self-assessment methods as a means of calibrating therapy and perhaps enhancing compliance. © 1998 John Wiley & Sons, Ltd.     

The effects of one-year simvastatin therapy on women’s bone mineral density

Only few studies have reported that bone fracture risk is decreased in hypercholesterolemic postmenopausal women treated with statin therapy. Because of a lack of longitudinal studies on the effect of statins on bones, the aim of our investigation was to estimate the simvastatin therapy effects on bone mineral density in hypercholesterolemic postmenopausal women. Our investigation was carried out on 53 postmenopausal women with hypercholesterolemia. The women included in the study were divided into two groups. Group 1 was comprised of women with two or more (n=32) atherosclerosis risk factors, whereas group 2 had women with less than two (n=21) of these risk factors. All the women included in the study were placed on a hypocholesterolemic diet and the women in group 1 were additionally treated with 20 mg of simvastatin daily. The parameters of lipid status, body mass index, and L2–L4 densitometry were determined at baseline and then after one year. The simvastatin-treated group showed significant improvement of lipid parameters and increased bone mineral density. Finally, changes in bone mineral density between the groups showed significant differences (p<0.05). Although our investigation was carried out on a small group, our results showed a positive effect of the simvastatin therapy on the bone mineral density of postmenopausal women.     

The effects of one-year simvastatin therapy on women’s bone mineral density

Only few studies have reported that bone fracture risk is decreased in hypercholesterolemic postmenopausal women treated with statin therapy. Because of a lack of longitudinal studies on the effect of statins on bones, the aim of our investigation was to estimate the simvastatin therapy effects on bone mineral density in hypercholesterolemic postmenopausal women. Our investigation was carried out on 53 postmenopausal women with hypercholesterolemia. The women included in the study were divided into two groups. Group 1 was comprised of women with two or more (n=32) atherosclerosis risk factors, whereas group 2 had women with less than two (n=21) of these risk factors. All the women included in the study were placed on a hypocholesterolemic diet and the women in group 1 were additionally treated with 20 mg of simvastatin daily. The parameters of lipid status, body mass index, and L2–L4 densitometry were determined at baseline and then after one year. The simvastatin-treated group showed significant improvement of lipid parameters and increased bone mineral density. Finally, changes in bone mineral density between the groups showed significant differences (p<0.05). Although our investigation was carried out on a small group, our results showed a positive effect of the simvastatin therapy on the bone mineral density of postmenopausal women.     

Influence of C3435T and G2677T／A MDR1 polymorphism on morphine side effects

AIM: Morphine efficacy and side effects present large interindividual pharmacodynamic variability. Single nucleotide polymorphisms (SNPs) of P-glycoprotein (MDR 1), an efflux transporter considered as a major component of the blood-brain-barrier, may explain a part of this variability. We aimed to determine the potential relationships between MDR1 C3435T and     

In vivo antitumour potential of camel’s milk against hepatocellular carcinoma in rats and its improvement of cisplatin renal side effects

Context: Camel milk (CM) is recommended for liver disease patients in Egypt for a strong belief that it has a curative effect.

Objective: The effect of consumption of CM with or without chemotherapeutic drug cisplatin was evaluated on induced hepatocarcinogenesis in rats.

Materials and methods: Wistar male rats (56) were divided into eight groups (7 rats each). Group I was control. Hepatocarcinogenesis was initiated by a single dose of intraperitoneal injection of diethylnitrosamine (DENA) (200?mg/kg BW) and promoted by phenobarbitone (500?ppm) in drinking water in groups V, VI, VII and VIII. Treatment started from 28th till 38th week using CM (5?mL/day) and/or cisplatin (5?mg/kg/3?weeks) in groups II, III IV, VI, VII and VIII. Biochemical analysis, lipid peroxidation and superoxide dismutase (SOD) activity in liver tissue were performed. Histopathology of liver and kidney and immunohistochemistry of placental glutathione-S-transferase (P-GST) in liver were performed and analyzed using image analysis.

Results: Albumin concentration and SOD activity were 3.13?±?0.23 and 311.45?±?41.71 in group VII (DENA &; cisplatin), whereas they were 4.3?±?0.15 and 540.5?±?29.94 in group VII (DENA, CM and cisplatin). The mean area of altered hepatocellular foci and P-GST altered foci decreased in group VI (DENA and CM) (1049.6?±?174.78 and 829.1?±?261) and group VIII (cisplatin and CM) (1615.12?±?436 and 543.9?±?127) compared to group V (DENA only) (4173.74?±?510.7 and 3169.49?±?538.61). Cisplatin caused chronic interstitial nephritis, which was slightly alleviated in group VIII (CM and cisplatin).

Conclusions: CM had an antioxidant effect and together with cisplatin managed to decrease hepatocarcinogenesis.     

Is AL-438 likely to have fewer side effects than the glucocorticoids?

The glucocorticoids are effective anti-inflammatory agents but their use may be limited by systemic side effects. AL-438 and prednisolone inhibit binding to glucocorticoid and mineralcorticoid receptors with similar potency. In rat models of acute and chronic inflammation, AL-438 was effective but less potent than prednisolone. In fasted overnight rats, prednisolone was hyperglycaemic but AL-438 was not. Prednisolone also inhibited bone formation in rats, whereas AL-438 did not. The differing profile of AL-438 relative to prednisolone may be due to altered interactions between the receptor and selected co-activators. AL-438 may have lesser side effects than prednisolone.     

Is AL-438 likely to have fewer side effects than the glucocorticoids?

The glucocorticoids are effective anti-inflammatory agents but their use may be limited by systemic side effects. AL-438 and prednisolone inhibit binding to glucocorticoid and mineralcorticoid receptors with similar potency. In rat models of acute and chronic inflammation, AL-438 was effective but less potent than prednisolone. In fasted overnight rats, prednisolone was hyperglycaemic but AL-438 was not. Prednisolone also inhibited bone formation in rats, whereas AL-438 did not. The differing profile of AL-438 relative to prednisolone may be due to altered interactions between the receptor and selected co-activators. AL-438 may have lesser side effects than prednisolone.     

Prolonged circulation half-life of interferon γ activity by gene delivery of interferon γ-serum albumin fusion protein in mice

Gene delivery of mouse interferon (IFN) γ has been shown to inhibit metastatic tumor growth and onset of atopic dermatitis in mouse models. In this study, we tried to increase the circulation half-life of IFNγ after its gene delivery by designing a novel fusion protein of IFNγ with mouse serum albumin (MSA). Western blot analysis confirmed that IFNγ-MSA was expressed as a fusion protein, but hardly formed dimer as IFNγ did. The biological activity of IFNγ-MSA, which was examined using a plasmid expressing luciferase under the control of gamma-activated sequence elements, was about 200-fold lower than the activity of IFNγ. Intravenous injection of the proteins into mice confirmed that the circulation half-life of IFNγ was significantly prolonged by the modification. A hydrodynamic injection of a plasmid expressing IFNγ-MSA resulted in a sustained concentration in mouse serum; it resulted in about sixfold greater area under the concentration-time curve and about threefold longer mean residence time of IFNγ activity than those of IFNγ. Gene delivery of IFNγ-MSA inhibited tumor metastasis to a similar level to that of IFNγ despite the reduced activity of IFNγ-MSA. These results indicate that gene delivery of IFNγ-MSA is a promising approach to prolong the circulation half-life of IFNγ activity.     

Neuroprotective effects of the anti‐cancer drug sunitinib in models of HIV neurotoxicity suggests potential for the treatment of neurodegenerative disorders

Background and Purpose

Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood–brain barrier.

Experimental Approach

We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity.

Key Results

Among 12 different compounds, sunitinib inhibited CDK5 with an IC₅₀ of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology.

Conclusions and Implications

Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders.Tables of Links