Safety of high-dose intravenous labetalol in hypertensive crisis.

PURPOSE: The study assesses the safety of high-dose intravenous (i.v.) labetalol in adults. METHODS: This is a retrospective administrative record review of 28 hospitals in one health care system, from October 2010 through October 2015. Patients were included if they received 300 mg of i.v. labetalol within a 24-hour period. Vital signs, adverse events and cumulative medication doses were obtained for up to 24 hours while on labetalol. Adverse events were defined as any systolic blood pressure measurement less than 90 mm Hg or heart rate less than 60 beats per minute. RESULTS: We analyzed the records of 188 patients who received i.v. labetalol at higher than the maximum recommended dose of 300 mg. The mean dose of labetalol was 996 mg (range 300 to 4465 mg). The cumulative labetalol dose was not associated with adverse safety outcomes (p = 0.428), although eighty-one patients (44.3%) experienced adverse events. Sixty-six patients (36.5%) developed bradycardia and 34 patients (18.6%) developed hypotension. Only five patients (2.7%) required a rescue agent for refractory adverse events. CONCLUSION: A retrospective review of high-dose i.v. labetalol hydrochloride with doses greater than 300 mg in 24 hours observed a high rate of bradycardia and hypotension, but the study found that these events rarely caused clinically significant hemodynamic compromise and was not statistically associated with adverse events.

Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin.

Biliary pancreatitis is the leading cause of acute pancreatitis in both children and adults. A proposed mechanism is the reflux of bile into the pancreatic duct. Bile acid exposure causes pancreatic acinar cell injury through a sustained rise in cytosolic Ca(2+). Thus, it would be clinically relevant to know the targets of this aberrant Ca(2+) signal. We hypothesized that the Ca(2+)-activated phosphatase calcineurin is such a Ca(2+) target. To examine calcineurin activation, we infected primary acinar cells from mice with an adenovirus expressing the promoter for a downstream calcineurin effector, nuclear factor of activated T-cells (NFAT). The bile acid taurolithocholic acid-3-sulfate (TLCS) was primarily used to examine bile acid responses. TLCS caused calcineurin activation only at concentrations that cause acinar cell injury. The activation of calcineurin by TLCS was abolished by chelating intracellular Ca(2+). Pretreatment with 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl ester) (BAPTA-AM) or the three specific calcineurin inhibitors FK506, cyclosporine A, or calcineurin inhibitory peptide prevented bile acid-induced acinar cell injury as measured by lactate dehydrogenase leakage and propidium iodide uptake. The calcineurin inhibitors reduced the intra-acinar activation of chymotrypsinogen within 30 min of TLCS administration, and they also prevented NF-κB activation. In vivo, mice that received FK506 or were deficient in the calcineurin isoform Aß (CnAß) subunit had reduced pancreatitis severity after infusion of TLCS or taurocholic acid into the pancreatic duct. In summary, we demonstrate that acinar cell calcineurin is activated in response to Ca(2+) generated by bile acid exposure, bile acid-induced pancreatic injury is dependent on calcineurin activation, and calcineurin inhibitors may provide an adjunctive therapy for biliary pancreatitis.

Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury.

Acute pancreatitis is a major health burden for which there are currently no targeted therapies. Premature activation of digestive proenzymes, or zymogens, within the pancreatic acinar cell is an early and critical event in this disease. A high-amplitude, sustained rise in acinar cell Ca(2+) is required for zymogen activation. We previously showed in a cholecystokinin-induced pancreatitis model that a potential target of this aberrant Ca(2+) signaling is the Ca(2+)-activated phosphatase calcineurin (Cn). However, in this study, we examined the role of Cn on both zymogen activation and injury, in the clinically relevant condition of neurogenic stimulation (by giving the acetylcholine analog carbachol) using three different Cn inhibitors or Cn-deficient acinar cells. In freshly isolated mouse acinar cells, pretreatment with FK506, calcineurin inhibitory peptide (CiP), or cyclosporine (CsA) blocked intra-acinar zymogen activation (n = 3; P < 0.05). The Cn inhibitors also reduced leakage of lactate dehydrogenase (LDH) by 79%, 62%, and 63%, respectively (n = 3; P < 0.05). Of the various Cn isoforms, the ß-isoform of the catalytic A subunit (CnAß) was strongly expressed in mouse acinar cells. For this reason, we obtained acinar cells from CnAß-deficient mice (CnAß-/-) and observed an 84% and 50% reduction in trypsin and chymotrypsin activation, respectively, compared with wild-type controls (n = 3; P < 0.05). LDH release in the CnAß-deficient cells was reduced by 50% (n = 2; P < 0.05). The CnAß-deficient cells were also protected against zymogen activation and cell injury induced by the cholecystokinin analog caerulein. Importantly, amylase secretion was generally not affected by either the Cn inhibitors or Cn deficiency. These data provide both pharmacological and genetic evidence that implicates Cn in intra-acinar zymogen activation and cell injury during pancreatitis.