Cholinesterase inhibitors do not prolong neuromuscular block produced by mivacurium

Cholinesterase inhibitors antagonize neuromuscular block producedby mivacurium, but some may also decrease its metabolism byinhibiting pseudocholinesterase. These opposing interactionswere examined in rats anaesthetized with pentobarbitone. Afterspontaneous recovery from an initial bolus dose of 0.03 mg kg^–1,mivacurium was infused to produce 80–90% block of gastrocnemiusmuscle twitch. After 15 min, the infusion was discontinued andsaline, edrophonium. pyridostigmine or neostigmine was administered.Fifteen minutes later, a second bolus dose of mivacurium wasgiven. Edrophonium, pyridostigmine and neostigmine reduced thesubsequent maximum block, compared with the change in salinecontrol, by 3%, 19% and 35%, respectively. Correspondingly,the time to recovery of T1 to 50% was decreased by 20%, 58%and 62%. In rats, acetylcholinesterase mediated antagonism ofneuromuscular block predominated over decreased pseudocholinesterasemediated metabolism, such that prior administration of a cholinesteraseinhibitor did not prolong the neuromuscular blocking effectsof mivacurium.     

VEGF receptor inhibition slows the progression of polycystic kidney disease

Although the receptors for vascular endothelial growth factor (VEGF) exert their effects on vasculogenesis and angiogenesis through receptors located on endothelial cells, recent studies have shown that these receptors are also present on renal tubular epithelial cells. We investigated the role of VEGF on increased tubule cell proliferation in the Han:SPRD heterozygous (Cy/+) rat model of polycystic kidney disease. The levels of VEGF in the kidneys and the serum, and the expression of the two receptors on tubules were increased in Cy/+ rats. These rats were given ribozymes that specifically inhibited VEGFR1 and VEGFR2 mRNA expression. Tubule cell proliferation within the cysts was significantly decreased in the ribozyme-treated animals leading to decreased cystogenesis, blunted renal enlargement, and prevented the loss of renal function. Our studies show that inhibition of VEGF function may be an important therapeutic option to delay the progression of polycystic kidney disease.     

Selective lymphocyte inhibition by FTY720 slows the progressive course of chronic anti-thy 1 glomerulosclerosis

BACKGROUND: Progression is a hallmark of chronic renal disease and histologically characterized by fibrosis and inflammation of the tubulointerstitial compartment. To define the role of lymphocytes in this process, the novel lymphocyte-specific inhibitor FTY720 was administered to rats with anti-thy 1-induced chronic progressive glomerulosclerosis. In this model, the initial and short-term inflammatory glomerular injury progresses self-perpetuatedly toward tubulointerstitial fibrosis by not primarily immune-mediated, intrarenal mechanisms. METHODS: Chronic progressive glomerulosclerosis was induced by murine anti-thy 1 antibody injection into uninephrectomized rats. Treatment with FTY720 (0.3 mg/kg body weight) was started 7 days after disease induction. Proteinuria was measured every 4 weeks. In week 20, the following parameters were determined: blood lymphocyte number, kidney function, both glomerular and tubulointerstitial histologic matrix accumulation, protein expression of transforming growth factor-beta1 (TGF-beta1), fibronectin, and plasminogen activator inhibitor-1 (PAI-1) as well as infiltration with macrophages and lymphocytes. RESULTS: Treatment with FTY720 lowered blood lymphocyte count and renal lymphocyte infiltration highly significantly. In comparison to the untreated chronic progressive glomerulosclerosis animals, the lymphocyte depletion achieved significantly limited the progression of the disease, as shown by lowered proteinuria, tubulointerstitial matrix expansion, and TGF-beta1, fibronectin, and PAI-1 expression, as well as improved renal function. Glomerular matrix protein expression and accumulation was moderately lowered by FTY720. Glomerular macrophage infiltration was not, tubulointerstitial macrophage infiltration was moderately, but not significantly, decreased by FTY720 treatment. CONCLUSION: Lymphocyte depletion by FTY720 limits the progression of anti-thy 1-induced glomerulosclerosis toward chronic tubulointerstitial fibrosis and renal insufficiency. The data suggest that lymphocytes actively participate in the progression of chronic experimental kidney disease, and that FTY720 may be a novel approach to slow the progressive course of human chronic renal diseases.     

The effect of fluoride and hypothermia on the in vitro metabolism of mivacurium

IMPLICATIONS: The fluoride inhibition of mivacurium hydrolysis by pseudocholinesterase increases in hypothermia, but it will very rarely occur in clinical practice because it requires rather large fluoride concentrations (>50 micromol/L) and very low temperatures (<28 degrees C).     

Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.     

Early inhibition of subchondral bone remodeling slows load-induced posttraumatic osteoarthritis development in mice

Posttraumatic osteoarthritis (PTOA) is associated with abnormal and increased subchondral bone remodeling. Inhibiting altered remodeling immediately following joint damage can slow PTOA progression. Clinically, however, inhibiting remodeling when significant joint damage is already present has minimal effects in slowing further disease progression. We sought to determine the treatment window following PTOA initiation in which inhibiting remodeling can attenuate progression of joint damage. We hypothesized that the most effective treatment would be to inhibit remodeling immediately after PTOA initiation. We used an animal model in which a single bout of mechanical loading was applied to the left tibia of 26-week-old male C57Bl/6 mice at a peak load of 9 N to initiate load-induced PTOA development. Following loading, we inhibited bone remodeling using daily alendronate (ALN) treatment administered either immediately or with 1 or 2 weeks' delay up to 3 or 6 weeks post-loading. A vehicle (VEH) treatment group controlled for daily injections. Cartilage and subchondral bone morphology and osteophyte development were analyzed and compared among treatment groups. Inhibiting remodeling using ALN immediately after load-induced PTOA initiation reduced cartilage degeneration, slowed osteophyte formation, and preserved subchondral bone volume compared to VEH treatment. Delaying the inhibition of bone remodeling at 1 or 2 weeks similarly attenuated cartilage degeneration at 6 weeks, but did not slow the development of osteoarthritis (OA)-related changes in the subchondral bone, including osteophyte formation and subchondral bone erosions. Immediate inhibition of subchondral bone remodeling was most effective in slowing PTOA progression across the entire joint, indicating that abnormal bone remodeling within the first week following PTOA initiation played a critical role in subsequent cartilage damage, subchondral bone changes, and overall joint degeneration. These results highlight the potential of anti-resorptive drugs as preemptive therapies for limiting PTOA development after joint injury, rather than as disease-modifying therapies after joint damage is established. © 2021 American Society for Bone and Mineral Research (ASBMR).     

In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine

The in vitro rates of metabolism of mivacurium chloride and succinylcholine in pooled human plasma were compared. In addition, the rate of metabolism of mivacurium in buffered solutions of butyrylcholinesterase (E.C. 3.1.1.8) and acetylcholinesterase (E.C. 3.1.1.7) was determined. Succinylcholine concentrations were measured spectrophotometrically, and mivacurium concentrations were determined with a high-pressure liquid chromatographic assay. The hydrolysis of mivacurium in plasma followed first-order kinetics, and the rate of hydrolysis decreased as plasma was serially diluted. The Michaelis-Menten constant (Km) for mivacurium metabolism in plasma was 245 mumol/L, and the maximum velocity (Vmax) was 50 U/L; the Km for succinylcholine was 37 mumol/L, and Vmax was 74 U/L. At comparable multiples of the Km the hydrolysis rate of mivacurium was 70% of that of succinylcholine. Mivacurium was metabolized significantly in solutions containing butyrylcholinesterase, but only minimally in solutions containing acetylcholinesterase.     

Cholinesterase Inhibition by Potato Glycoalkaloids Slows Mivacurium Metabolism

Background: The duration of action for many pharmaceutical agents is dependent on their breakdown by endogenous hydrolytic enzymes. Dietary factors that interact with these enzyme systems may alter drug efficacy and time course. Cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze and inactivate several anesthetic drugs, including cocaine, heroin, esmolol, local ester anesthetics, and neuromuscular blocking drugs. Natural glycoalkaloid toxins produced by plants of the family Solanaceae, which includes potatoes and tomatoes, inhibit both AChE and BuChE. Here the authors assess the extent to which two solanaceous glycoalkaloids (SGAs), [alpha]-solanine and [alpha]-chaconine, can alter the effects of neuromuscular blocking drugs and cholinesterase inhibitors in vivo and in vitro.

Methods: Inhibition of purified human AChE and BuChE by SGAs, neuromuscular blocking drugs, and cholinesterase inhibitors was assessed by an in vitro colorimetric cholinesterase assay. In vivo experiments were carried out using anesthetized rabbits to test whether SGAs affect recovery from mivacurium-induced paralysis.

Results: SGAs inhibited human BuChE at concentrations similar to those found in serum of individuals who have eaten a standard serving of potatoes. Coapplication of SGAs (30-100 nm) with neuromuscular blocking drugs and cholinesterase inhibitors produced additive cholinesterase inhibition. SGA administration to anesthetized rabbits inhibited serum cholinesterase activity and mivacurium hydrolysis. In addition, SGA prolonged the time needed for recovery from mivacurium-induced paralysis (149 +/- 12% of control; n = 12).     

Organ-specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat

To evaluate organ-specific metabolic changes after in vivo cyclosporine (CyA) treatment, male Wistar rats were treated with 10 mg/kg per day CyA orally for 6 days. Blood, kidney, liver, and heart tissues were extracted and analyzed by magnetic resonance spectroscopy (MRS). CyA decreased the energy balance [adenosine triphosphate (ATP)/adenosine diphosphate (ADP)] in all organs (kidney [control]: 50%, liver: 64%, and heart: 62%, all P<0.01) due to decreased activity of the mitochondrial Krebs cycle and oxidative phosphorylation. As a compensatory effect, anaerobic glycolysis (lactate) was increased. This was reflected in the low glucose level in the kidney and heart, but not in the liver where a significant decrease in glycogen was seen. Only in the kidney was mitochondrial inhibition accompanied by decreased polyunsaturated fatty acid (PUFA) concentrations and elevated lipid peroxidation. The metabolic marker for nephrotoxicity, trimethylamine-N-oxide (TMAO), was elevated. While CyA decreased mitochondrial homeostasis in all organ systems, cellular adaptation was different and most efficient in the liver.The results of this study were presented in part at the 2002 Winter Symposium of the American Society of Transplant Surgeons, Miami, 25–27 January 2002     

Effect of sevoflurane on the neuromuscular blockade produced by continuous mivacurium infusion

OBJECTIVE: To evaluate the effect of sevoflurane on a neuromuscular block from mivacurium in continuous infusion. PATIENTS AND METHODS: Fourteen ASA I-II patients receiving general anesthesia for orthopedic procedures on the knee. The neuromuscular block was monitored by acceleromyography in the adductor pollicis muscle after stimulation of the cubital nerve. Anaesthesia was induced with propofol and remifentanil. After orotracheal intubation, mivacurium was given in continuous infusion adjusted to obtain a stable submaximal block defined as a variation in the block of 3% more or less for 10 minutes (first response on a train of four [T1] between 40% and 60% of the calibrated value). Values for T1, the T4/T1 ratio (TR) and temperature over the thenar eminence were recorded at 3 moments: control moment (infusion of mivacurium and sevoflurane at an expired fraction of 1.5% for 30 minutes) and post-sevoflurane moment (perfusion of mivacurium and sevoflurane at an expired fraction of 0% for 15 minutes). Statistical analysis was by analysis of variance and post-hoc contrast (Tukey). RESULTS: Results are expressed as means with standard error between parentheses. We found that values at T1(%) and TR(%) were significantly lower at the sevoflurane moments (T1 = 43.11 [1]; TR = 25.68 [1]) and the post-sevoflurane moment (T1 = 36.29 [2]; TR = 25.06 [2]) than at the control moment (T1 = 53.18 [1]; TR = 38.93 [1]) (P < .05). T1 was significantly lower at the post-sevoflurane moment than at the sevoflurane moment (P < .05) but TR did not differ significantly. CONCLUSION: Sevoflurane causes a significant increase in the neuromuscular block maintained by mivacurium in continuous infusion and the increase lasts at least 15 minutes after the halogenated agent is cleared from blood.     

Halothane inhibition of propranolol metabolism is stereoselective

Propranolol, like many drugs, is used clinically as a racemic mixture. The major pharmacodynamic effects of propranolol, however, are mediated by the (-)-isomer, which is 100 times as potent as the (+)-isomer. The two isomers also differ in their pharmacokinetic characteristics. To determine whether halothane anesthesia stereo-selectively inhibits the metabolism of racemic propranolol, eight male mongrel dogs were studied. On the first day of the study, 40 mg racemic propranolol was infused into the portal vein and arterial blood samples were obtained over the following 4 h for the measurements of (+)- and (-)-propranolol concentrations by HPLC. The study was repeated 24 h later during 2 MAC halothane anesthesia, when the intrinsic clearance of total propranolol was decreased by 67.5 +/- 5%, from 6.14 +/- 1.1 1/min to 1.84 +/- 0.4 1/min (P less than 0.05). The decrease in intrinsic clearance was stereoselective, (-)-propranolol being affected to a greater extent than (+)-propranolol; thus, the decrease in the clearance of (-)-propranolol, from 10.96 +/- 2.71/min to 2.6 +/- 0.71/min (73 +/- 5%) was significantly (P less than 0.05) greater than the decrease in the clearance of (+)-propranolol, (62 +/- 3%) from 4.3 +/- 0.8 1/min to 1.5 +/- 0.3 1/min. Furthermore, the ratio of the intrinsic clearance of (-)-propranolol to the intrinsic clearance of (+)-propranolol was significantly (P less than 0.05) reduced by halothane anesthesia, from 2.42 +/- 0.29 to 1.69 +/- 0.11. Stereoselective inhibition of propranolol metabolism results in proportionally higher concentrations of (-)-propranolol during halothane anesthesia than are present in awake dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of mivacurium pretreatment on intra-ocular pressure changes induced by suxamethonium

Forty patients without eye disease, undergoing elective nonophthalmic surgery, were studied in a double-blind, randomised, placebo-controlled study evaluating the efficacy of mivacurium pretreatment in attenuating the rise in intra-ocular pressure in response to suxamethonium administration, laryngoscopy and intubation. The patients were randomly allocated to receive either mivacurium 0.02 mg.kg⁻¹ or normal saline as pretreatment 3 min before a rapid sequence induction technique using alfentanil, propofol and suxamethonium. Suxamethonium induced a significant increase in intra-ocular pressure in the control group but not in the mivacurium pretreatment group (mean (SEM) increase = 3.5 (1.2) mmHg vs. 0.4 (0.8) mmHg, p < 0.05). There was a decrease in intra-ocular pressure in both groups after laryngoscopy and intubation with no significant difference between the two groups. These results show that mivacurium pretreatment is effective in preventing the increase in intra-ocular pressure after suxamethonium administration.     

Time course of potentiation of mivacurium by halothane and isoflurane in children

We studied 40 children, aged 1-15 yr, to analyse the time course of potentiation of mivacurium produced by halothane and isoflurane. A steady infusion requirement of mivacurium to maintain 90% neuromuscular block was established during thiopentone-alfentanil-nitrous oxide- oxygen anaesthesia. Patients were then allocated randomly to receive 1 MAC end-tidal concentration of either halothane (group Hal) or isoflurane (group Iso) while neuromuscular block was maintained at 90%. Both volatile agents decreased the infusion requirements of mivacurium in an exponential manner in that maximal potentiation occurred only after 30-80 min. Maximal reduction in infusion rate (32% in group Hal and 70% in group Iso; P < 0.0001) did not depend on the age of the child but became established sooner the younger the child in the case of isoflurane (P = 0.002).      

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.     

Effect of prolactin inhibition by bromocriptine on testicular metabolism in the adult rat

Administration of bromocriptine resulted in a decrease of testicular tissue somatic index, total, structural and soluble protein concentrations. The catabolic phase of carbohydrate metabolism was enhanced. Consequently, the required metabolites for increased citric acid cycle activity were provided by increased glycolytic activity. The pre-requisite metabolites needed for spermatogenic processes were accumulated in the testis, due to their non-utilization. The results obtained suggest a specific influence of prolactin inhibition on testicular metabolism in the adult rat.