Expert consensus document: A 'diamond' approach to personalized treatment of angina.

In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease

Regional metabolism of articaine in 10 patients undergoing intravenous regional anaesthesia during day case surgery

Aims To study the pharmacokinetics of articaine and its metabolite articainic acid, in patients undergoing intravenous regional anaesthesia

Similar Motor Block Effects and Disposition Kinetics between Lidocaine and (±)Mepivacaine in Patients Undergoing Axillary Brachial Plexus Block during Day Case Surgery

The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine (one metabolite) and mepivacaine (two metabolites) in 2 groups of 15 patients undergoing axillary brachial plexus anaesthesia. The study had a randomised design. The 30 patients were divided into 2 groups. The patients received either lidocaine (600 mg = 2.561 mMol + 5 µg ml -1 adrenaline) or mepivacaine (600 mg = 2.436 mMol + 5 µg ml -1 adrenaline), injected via the axilla near the brachial plexus over a period of 30 s. Onset of surgical analgesia was defined as the period from the end of the local anaesthetic injection to the loss of pinprick sensation in the distribution of the ulnar, radial, and median nerve. Motor block was measured. Onset of motor block was similar for both drugs. Lidocaine is eliminated biexponentially with a t 1/2α of 9.95 ± 14.3 min and a t 1/2β of 2.86 ± 1.55 h. Lidocaine is metabolised into MEGX (t max 2.31 ± 0.84 h; C max 0.32 ± 0.13 mg l -1 ; t 1/2β 2.36 ± 2.35 h; total body clearance was 67.9 ± 28.9 l h -1 ). Mepivacaine is eliminated rapidly and monoexponentially with a t 1/2 of 4.78 ± 2.38 h, a C max of 3.89 ± 0.83 mg l ; t 1/2β 1.48 ± 0.74 h). For the axillary brachial plexus block, lidocaine and mepivacaine show similar pharmacodynamic and pharmacokinetic behaviour, despite the number of metabolites, and can therefore be used to the clinical preference for this regional anaesthetic technique

Epac-Rap signaling reduces oxidative stress in the tubular epithelium

Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-2'-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-2'-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate-induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-2'-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-2'-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stres

Reversal of rocuronium-induced neuromuscular block by sugammadex is independent of renal perfusion in anesthetized cats

Item does not contain fulltextPURPOSE: Sugammadex is a selective relaxant binding agent designed to encapsulate the aminosteroidal neuromuscular blocking agent rocuronium, thereby reversing its effect. Both sugammadex and the sugammadex-rocuronium complex are eliminated by the kidneys. This study investigated the effect of sugammadex on recovery of rocuronium-induced neuromuscular block in cats with clamped renal pedicles, as a model for acute renal failure. METHODS: Twelve male cats were divided into two groups and anesthetized with medetomidine, ketamine, and alpha-chloralose. The cats were intubated and ventilated with a mixture of oxygen and air. Neuromuscular monitoring was performed by single twitch monitoring. Rocuronium 0.5 mg/kg i.v. was administered. After spontaneous recovery from neuromuscular block, both renal pedicles were ligated. A second dose of rocuronium 0.5 mg/kg i.v. was given. One minute after disappearance of the twitches, in Group 1 placebo (0.9% saline) and in Group 2 sugammadex 5.0 mg/kg i.v. was administered. Onset time, duration of neuromuscular block, and time to recovery to 25, 50, 75, and 90% were determined. Results : After renal pedicle ligation, sugammadex reversed rocuronium-induced neuromuscular block significantly faster than spontaneous recovery. Mean time (SEM) to 90% recovery of the twitch response was 4.7 (0.25) min (Group 2) versus 31.1 (5.0) min (Group 1) (p < 0.0001). No signs of recurrence of neuromuscular block were observed for 90 min after complete twitch restoration. Sugammadex caused no significant cardiovascular effects. CONCLUSION: Sugammadex rapidly and effectively reversed rocuronium-induced neuromuscular block in anesthetized cats, even when both renal pedicles were ligated and renal elimination of the drugs was no longer possible

Sugammadex reverses neuromuscular block induced by 3-desacetyl-vecuronium, an active metabolite of vecuronium, in the anaesthetised rhesus monkey

Item does not contain fulltextBACKGROUND AND OBJECTIVE: 3-Desacetyl-vecuronium is an active metabolite of the neuromuscular blocking agent (NMBA) vecuronium, which might lead to residual paralysis after prolonged administration of vecuronium in critically ill patients with renal failure. This study investigated the ability of sugammadex to reverse 3-desacetyl-vecuronium-induced neuromuscular block (NMB) in the anaesthetised rhesus monkey. METHODS: Experiments were performed in anaesthetised female rhesus monkeys. After bolus intravenous injection of vecuronium (n = 8) or 3-desacetyl-vecuronium (n = 8) 10 mug kg(-1) (ED90), a continuous infusion of the same NMBA was started to maintain the first twitch of the train-of-four (TOF) at 10% of baseline value. The infusion was stopped and NMB recovered spontaneously. The procedure was repeated, but immediately after stopping the infusion, an intravenous bolus dose of sugammadex 0.5 or 1.0 mg kg(-1) was given. For each NMBA, four placebo experiments were performed, in which the second recovery from NMB was also spontaneous. For all experiments, time to recovery of the TOF ratio to 90% was retrieved. RESULTS: After administration of sugammadex for reversal of 3-desacetyl-vecuronium-induced NMB, recovery was significantly faster than spontaneous recovery. Mean time to recovery of TOF to 90% was 3.2 min (sugammadex 0.5 mg kg(-1)) and 2.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (17.6 min). For vecuronium-induced NMB, mean time to recovery of TOF to 90% was 17.1 min (0.5 mg kg(-1)) and 4.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (23.4 min). CONCLUSION: Sugammadex rapidly and effectively reversed 3-desacetyl-vecuronium-induced NMB in the rhesus monkey, at a lower dose than that needed to reverse vecuronium-induced NMB