Methadone is a local anaesthetic-like inhibitor of neuronal Na+ channels and blocks excitability of mouse peripheral nerves.

BACKGROUND: Opioids enhance and prolong analgesia when applied as adjuvants to local anaesthetics (LAs). A possible molecular mechanism for this property is a direct inhibition of voltage-gated Na(+) channels which was reported for some opioids. Methadone is an effective adjuvant to LA and was recently reported to inhibit cardiac Na(+) channels. Here, we explore and compare LA properties of methadone and bupivacaine on neuronal Na(+) channels, excitability of peripheral nerves, and cell viability. METHODS: Effects of methadone were explored on compound action potentials (CAP) of isolated mouse saphenous nerves. Patch clamp recordings were performed on Na(+) channels in ND7/23 cells, the α-subunits Nav1.2, Nav1.3, Nav1.7, and Nav1.8, and the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2). Cytotoxicity was determined using flow cytometry. RESULTS: Methadone (IC50 86-119 µM) is a state-dependent and unselective blocker on Nav1.2, Nav1.3, Nav1.7, and Nav1.8 with a potency comparable with that of bupivacaine (IC50 177 µM). Both bupivacaine and methadone also inhibit C- and A-fibre CAPs in saphenous nerves in a concentration-dependent manner. Tonic block of Nav1.7 revealed a discrete stereo-selectivity with a higher potency for levomethadone than for dextromethadone. Methadone is also a weak blocker of HCN2 channels. Both methadone and bupivacaine induce a pronounced cytotoxicity at concentrations required for LA effects. CONCLUSIONS: Methadone induces typical LA effects by inhibiting Na(+) channels with a potency similar to that of bupivacaine. This hitherto unknown property of methadone might contribute to its high efficacy when applied as an adjuvant to LA.

[Cardiovascular assessment and management prior to non-cardiac surgery. Comment on the new 2014 ESC/ESA guidelines]. / Kardiovaskuläre Beurteilung und Management vor nichtkardialen Eingriffen. Kommentar zur neuen ESC/ESA-Leitlinie 2014.

In 2014 the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA) published an update of the guidelines on "non-cardiac surgery: cardiovascular assessment and management". Epidemiological data underline the relevance of these guidelines: a total of 5.7 million surgical procedures are performed per year in patients with increased cardiac risk and approximately 167,000 cardiac complications occur per year in Europe of which 19,000 are life-threatening. This new version of the guidelines highlights the patient characteristics, such as functional capacity and comorbidities and procedure-specific aspects for perioperative risk stratification. Decision-making for preoperative stress tests and coronary angiography has been simplified, procedure-specific risks have been revised and the role of multidisciplinary teamwork for high risk procedures is emphasized. A standardized stepwise approach on how to stratify patient-specific and procedure-associated risks has been established. For the first time, the guidelines recommend perioperative regimens on dual antiplatelet therapy and the new oral anticoagulants (NOAC).

Vagal heart rate control in patients with atrial fibrillation: impact of tonic activation of peripheral chemosensory function in heart failure.

Heart failure (HF) and atrial fibrillation (AF), emerging as two epidemics of the twenty-first century, are commonly associated with each other. Both have been mechanistically linked to changes in cardiac vagal control. The importance of peripheral chemosensors, located in the carotid body, has not been elucidated so far. We therefore investigated whether tonic activation of excitatory chemoreceptor afferents contributes to the altered vagal control in HF patients with a history of AF. In 18 patients (72 ±9 year, 7 male) with sinus rhythm and a history of AF (n=9, without any evidence of structural heart disease, AF group; n=9 with structural heart disease and clinical presentation of HF, AFHF group) we investigated the impact of chemosensory deactivation (by breathing 100% oxygen) on heart rate, blood pressure, cardiac output, total peripheral resistance, oxygen saturation and breathing rate. Ten healthy individuals served as a control group. In addition, we performed a deep breathing test demonstrating an impaired heart rate variation in patients with and without HF as compared with controls (expiration/inspiration difference: 23.9±6.9 vs. 6.9±6.1 bpm, and 23.9±6.9 vs. 7.8±4.8 bpm; p<0.05). In both control and AF groups, heart rate decreased during chemoreceptor deactivation (control: -4.8±3.4%; AF: -5.1±3.0%; p<0.05), whereas heart rate did not change in AFHF patients. This resulted in impaired cardiac chemoreflex sensitivity in AFHF patients (1.9±1.6 vs. 0.5±1.2 ms/mmHg; p<0.05). In conclusion, our data suggest that tonic activation of excitatory chemoreceptor afferents contributes to a low vagal tone in heart failure patients with a history of AF (Clinical Trials NCT01262508).

Rhabdomyolysis as a cause of acute renal failure.

Traumatic rhabdomyolysis with myoglobinuria and renal failure has been recognized for many years. In the past decade, rhabdomyolysis has been found to have various nontraumatic causes as well, including genetic conditions, metabolic disorders, exercise, toxins, infections, and drugs. Characteristic clinical and laboratory features include muscle tenderness, pigmenturia with urine that is orthotoluidine (Hematest) positive, greatly elevated creatine kinase levels, and often, renal failure. Treatment consists of fluid replacement and establishment of adequate urine flow early. If acute renal failure occurs, it should be treated appropriately. Particularly important are reversal of hyperkalemia and withholding of calcium during the hypocalcemic phase to prevent exacerbation of hypercalcemia later.

The opioid methadone induces a local anaesthetic-like inhibition of the cardiac Na⁺ channel, Na(v)1.5.

BACKGROUND AND PURPOSE: Treatment with methadone is associated with severe cardiac arrhythmias, a side effect that seems to result from an inhibition of cardiac hERG K⁺ channels. However, several other opioids are inhibitors of voltage-gated Na⁺ channels. Considering the common assumption that an inhibition of the cardiac Na⁺ channel Na(v)1.5, is the primary mechanism for local anaesthetic (LA)-induced cardiotoxicity, we hypothesized that methadone has LA-like properties leading to a modulation of Na(v)1.5 channels. EXPERIMENTAL APPROACH: The whole-cell patch clamp technique was applied to investigate the effects of methadone on wild-type and mutant human Na(v)1.5 channels expressed in HEK293 cells. A homology model of human Na(v)1.5 channels was used to perform automated ligand-docking studies. KEY RESULTS: Methadone inhibited Na(v)1.5 channels in a state-dependent manner, that is, tonic block was stronger with inactivated channels than with resting channels and a use-dependent block at 10 Hz. Methadone induced a concentration-dependent shift of the voltage dependency of both fast and slow inactivation towards more hyperpolarized potentials, and impaired recovery from fast and slow inactivation. The LA-insensitive mutants N406K and F1760A exhibited reduced tonic and use-dependent block by methadone, and docking predictions positioned methadone in a cavity that was delimited by the residue F1760. Dextromethadone and levomethadone induced discrete stereo-selective effects on Na(v)1.5 channels. CONCLUSIONS AND IMPLICATIONS: Methadone interacted with the LA-binding site to inhibit Na(v)1.5 channels. Our data suggest that these channels are a hitherto unrecognized molecular component contributing to cardiac arrhythmias induced by methadone.

Characterization of novel MPS1 inhibitors with preclinical anticancer activity.

Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2-[(2-cyanophenyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}phenyl)-2-phenylacetamide (Mps-BAY1) (a triazolopyridine), N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(quinolin-5-yl)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2a) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals.

Surgical treatment of piles: prospective, randomized study of Parks vs. Milligan-Morgan hemorrhoidectomy.

PURPOSE: The present prospective, randomized clinical trial compares the outcome of surgical hemorrhoidectomy according to Parks and Milligan-Morgan in terms of hospital stay, duration of incapacity to work, symptom relief, length of morbidity, and patient convenience. METHODS: Thirty-four consecutive patients with third or fourth degree internal hemorrhoids were randomly allocated to the two groups. Before surgery, all patients were interviewed using a standard questionnaire, followed by rectal examination. All patients underwent a follow-up interview and examinations 1, 2, 4, 8, and 12 weeks after the operation. RESULTS: No serious postoperative complications were seen. Length of hospital stay (3.2 days for Parks hemorrhoidectomy vs. 4.6 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 0.2 and 2.6, respectively; P = 0.02) and mean duration of incapacity to work (12.3 days for Parks hemorrhoidectomy vs. 20.2 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 5.7 and 10.2, respectively; P < 0.001) differed significantly between the Milligan-Morgan and Parks patients. Until two weeks after the operation, Milligan-Morgan hemorrhoidectomy patients experienced significantly more pain. CONCLUSIONS: Our study confirms that both operations are safe, easy to perform, and lead to satisfactory results. However, the Parks procedure is the preferred option, because it minimizes patients' postoperative discomfort, is more economic, has a significantly reduced hospital stay, and has a shorter time for return to work.