Studying the effect of vasopressors on therapeutic drug monitoring of two local anesthetics using hybrid micelle liquid chromatography as an analysis tool.

A hybrid micelle based mobile phase was used to develop and validate a liquid chromatographic method for the separation and quantification of two local anesthetics namely; lidocaine hydrochloride (LID), and bupivacaine hydrochloride (BPV) in presence of the frequently co administered vasopressors phenyl ephrine (PHR) and ephedrine (EPH). Optimization of chromatographic separation conditions was performed applying experimental one factor at a time tool, and design of experiment, where the retention behavior of all analytes using both optimization protocols was in accordance. Chromatographic separation was carried on a C8 column operating at 40 °C at a flow rate of 1.5 mL/min. using a mobile phase consisting of 0.18 M sodium dodecyl sulphate, 10% acetonitrile, containing 0.3% triethyl amine and adjusted to pH 7 using 2 M ortho phosphoric acid, adopting UV detection at 230 nm. The proposed method was fully validated and applied to both in vitro and in vivo analysis of rat blood samples. The pharmacokinetics of both LID and BPV was followed when they were solitary injected or when co administered with either PHR or EPH. Moreover, the in vitro spiked experiment was also subjected to documented bio-analytical validation procedures.

Augmented Pulmonary Vasoconstrictor Reactivity after Chronic Hypoxia Requires Src Kinase and Epidermal Growth Factor Receptor Signaling.

Chronic hypoxia augments pressure- and agonist-induced pulmonary vasoconstriction through myofilament calcium sensitization. NADPH oxidases contribute to the development of pulmonary hypertension, and both epidermal growth factor receptor and Src kinases can regulate NADPH oxidase. We tested the hypothesis that Src-epidermal growth factor receptor (EGFR) signaling mediates enhanced vasoconstrictor sensitivity after chronic hypoxia through NADPH oxidase-derived superoxide generation. Protocols employed pharmacological inhibitors in isolated, pressurized rat pulmonary arteries to examine the contribution of a variety of signaling moieties to enhanced vascular tone after chronic hypoxia. Superoxide generation in pulmonary arterial smooth muscle cells was assessed using the fluorescent indicator dihydroethidium. Indices of pulmonary hypertension were measured in rats treated with the EGFR inhibitor gefitinib. Inhibition of NADPH oxidase, Rac1 (Ras-related C3 botulinum toxin substrate 1), and EGFR abolished pressure-induced pulmonary arterial tone and endothelin-1 (ET-1)-dependent calcium sensitization and vasoconstriction after chronic hypoxia. Consistently, chronic hypoxia augmented ET-1-induced superoxide production through EGFR signaling, and rats treated chronically with gefitinib displayed reduced right ventricular pressure and diminished arterial remodeling. Src kinases were also activated by ET-1 after chronic hypoxia and contributed to enhanced basal arterial tone and vasoconstriction in response to ET-1. A role for matrix metalloproteinase 2 to mediate Src-dependent EGFR activation is further supported by our findings. Our studies support a novel role for an Src kinase-EGFR-NADPH oxidase signaling axis to mediate enhanced pulmonary vascular smooth muscle Ca2+ sensitization, vasoconstriction, and pulmonary hypertension after chronic hypoxia.

Risk of vasopressin use: a case of acute pulmonary oedema, post intramyometrial infiltration of vasopressin in laparoscopic myomectomy.

A 34-year-old patient underwent a laparoscopic myomectomy, complicated by a profound episode of bradycardia and hypotension following intramyometrial infiltration of vasopressin (20 IU), promptly corrected with intravenous ephedrine (6 mg) and glycopyrrolate (200 µg). At extubation, pink frothy fluid was noted in the endotracheal tube; she was visibly distressed, desaturated to 89% in air and was coughing up pink stained fluid. Acute pulmonary oedema secondary to vasopressin was suspected. A tight-fitting oxygen mask (100%) with positive end expiratory pressure was applied and intravenous furosemide (20 mg) and diamorphine (4 mg, 1 mg increments) were administered to facilitate diuresis and oxygenation. Chest X-ray confirmed acute pulmonary oedema. Arterial blood gas demonstrated type 2 respiratory failure. Over 12 hours, the oxygen was weaned to 1 L/min. She demonstrated excellent diuresis. Troponin and brain-natriuretic peptide were elevated, but echocardiogram was normal. The cardiology diagnosis was vasopressin-induced coronary vasospasm, precipitating acute pulmonary oedema. She was discharged home on day 5.

Pharmacokinetics of levobupivacaine with epinephrine in transversus abdominis plane block for postoperative analgesia after Caesarean section.

BACKGROUND: Transversus abdominis plane block is increasingly used for post-Caesarean section analgesia. Cases of toxicity and the limited pharmacokinetic information during pregnancy motivated this study. The objective of the study was to characterise and compare the pharmacokinetics of levobupivacaine with epinephrine in tranversus abdominis plane block, in post-Caesarean section patients and healthy volunteers. METHODS: After approval by the Ethics Committee, we collected data from 12 healthy parturients after elective Caesarean section (Study 1) and data from 11 healthy male volunteers from a previous study (Study 2). Transversus abdominus plane block was performed under ultrasound guidance. The following injectates were used: levobupivacaine 0.25%, 20 ml with epinephrine 5 µg ml-1 (Study 1) per side; 20 ml of the same solution (unilateral block) (study 2). The plasma venous concentration of levobupivacaine was measured serially for 90 min. Pharmacokinetic parameters (volume of distribution, clearance, and absorption half-life) were estimated using a non-linear mixed effects model (NONMEM). Simulation in 1000 patients estimated the maximum concentration and the time to reach it after bilateral transversus abdominis plane block. RESULTS: Venous concentrations were below toxic levels (2.62 mg L-1). Levobupivacaine volume of distribution after Caesarean section was higher than in healthy volunteers [172 L (70 kg)-1 (95% confidence interval: 137-207) vs 94.3 L (70 kg)-1 (95% CI: 62-128); P<0.01]. Clearance and absorption half-life were similar. The simulation showed that maximum levobupivacaine concentration is lower and occurs later in postpartum patients (P<0.01). Postoperative analgesia was effective. CONCLUSIONS: Postpartum women reached relatively low plasma concentrations of levobupivacaine after transversus abdominal plane block given a volume of distribution 80% higher than volunteers, which could confer a greater margin of safety. CLINICAL TRIAL REGISTRATION: NCT02852720.

Vitamin D and Postoperative Vasopressor Use in Cardiopulmonary Bypass.

The use of cardiopulmonary bypass (CPB) in cardiac surgery often leads to a systemic inflammatory response. Up to 25% of patients undergoing CPB for cardiac surgery are reported to develop vasoplegic syndrome in the acute postoperative period, in which the patients are refractory to vasopressors. The purpose of this study is to assess vitamin D deficiency as a risk factor for vasoplegia after using CPB. We performed a retrospective review of 1322 patients undergoing adult cardiac surgery requiring CPB. Forty-six patients with previously recorded 25-hydroxy vitamin D (25(OH)D) levels within 6 months of surgery met the conditions of this study. The mean level of 25(OH)D was 32.7 ng/mL (standard deviation [SD] = 15.1). The mean age of patients was 67 (SD = 10.1) years old, most were male (63%) and white (78%). Average CPB time was 140 ± 44 minutes. Postoperative vasopressor use was compared to individual preoperative 25(OH)D levels. As a secondary end point, postoperative vasopressor use and vasoplegia were analyzed between 3 groups: Vitamin D deficient defined as 25(OH)D ≤20 ng/mL (n = 7), vitamin D insufficient defined as 25(OH)D between 20 and 29 ng/mL (n = 15), and vitamin D sufficient defined as 25(OH)D ≥30 ng/mL (n = 24). There was no correlation between vitamin D levels and postoperative vasopressor use. The mean doses of postoperative vasopressor use were 0.088 µg/kg/min (standard error of the mean [SEM] = 0.032), 0.085 µg/kg/min (SEM = 0.037), and 0.072 µg/kg/min (SEM = 0.024) of norepinephrine equivalents for the vitamin D deficient, insufficient, and sufficient groups, respectively. Incidence of vasoplegia for each group was the following: 0.143 for vitamin D deficient, 0.067 for vitamin D insufficient, and 0.125 for vitamin D sufficient. In this pilot study, there does not appear to be a relationship between vitamin D and vasopressor use following cardiac surgery utilizing CPB; however, there appears to be a trend toward an increased vasopressor usage in patients with decreased vitamin D levels. A larger sample size and a prospective analysis are warranted to further assess the significance of the relationship between vasoplegia and vitamin D deficiency. With further investigation, vitamin D has the potential to become a low-cost, low-risk therapeutic for improving outcomes in CPB surgery.

The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children.

BACKGROUND: Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children. METHODS: Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg-1 , 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed-effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an EMAX model. RESULTS: A two-compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T1/2 keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h-1 , central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h-1 , peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (EMAX ) of 25 mm Hg, and an EC50 of 10.3 µg L-1 . The effect on vasculature was immediate and T1/2 keo was not estimable. CONCLUSION: Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (EMAX ) in children was half that in adults (EMAX 50 mm Hg).

Application of vasoactive and matrix-modifying drugs can improve polyplex delivery to tumors upon intravenous administration.

Low efficacy of cationic polymer-based formulations (polyplexes) for systemic gene delivery to tumors remains the crucial concern for their clinical translation. Here we show that modulating the physiological state of a tumor using clinically approved pharmaceuticals can improve delivery of intravenously injected polyplexes to murine melanoma tumors with different characteristics. Direct comparison of drugs with different mechanisms of action has shown that application of nitroglycerin or losartan improved extravasation and tumor uptake of polyplex nanoparticles, whereas angiotensin II had almost no effect on polyplex accumulation and microdistribution in the tumor tissue. Application of nitroglycerin and losartan caused from 2- to 6-fold enhanced efficacy of polyplex-mediated gene delivery depending on the tumor model. The results obtained on polyplex behavior in tumor tissues depending on physiological state of the tumor can be relevant to optimize delivery of polyplexes and other nanomedicines with similar physicochemical properties.

Intra-articular administration of lidocaine plus adrenaline in dogs: Pharmacokinetic profile and evaluation of toxicity in vivo and in vitro.

The aim of this study was to evaluate the safety of intra-articular (IA) lidocaine plus adrenaline for improving peri-operative analgesia in anaesthetized dogs undergoing arthroscopy of the elbow. A solution of lidocaine (L) 1.98% plus adrenaline 1:100.000 was administered via the IA route and its safety evaluated in terms of cardio-, neuro-, and chondro-toxicity. No bradycardia or hypotension was recorded from induction to the last observational time point. Signs of toxicity of the nervous system could have been masked by the general anaesthesia but lidocaine concentrations detected in the blood were lower than those thought to be capable of producing toxicity. The assessment of in vitro chondrotoxicity showed a dose- and time-dependent effect of lidocaine on the viability of articular cells. Adrenaline appeared to reduce the chondrotoxicity of 1% lidocaine, following an exposure of up to 30 min.

[Rapid regression of infantile haemangioma with 2% propranolol ointment]. / Régression rapide d'un hémangiome infantile sous propranolol topique à 2 %

BACKGROUND: Oral propranolol produces dramatic results in severe infantile haemangioma. We report a case of rapid and significant regression of an infantile haemangioma in infant treated topically with 2% propranolol ointment. PATIENTS AND METHODS: A female infant aged 11 weeks was seen as an outpatient for two infantile haemangiomas on the front of the left knee and the vulva. After parental consent was given, the child was treated with a topical preparation of 2% propranolol ointment prepared by the pharmacy. Regression was rapid and on the 45th day, lesion size had been reduced by an estimated 75%. No adverse effects were observed. DISCUSSION: Topical propranolol appears to be effective and safe for the treatment of superficial haemangiomas. Clinical trials are required to determine the optimal dosage and pharmaceutical form, method of use and treatment duration.

Pharmacokinetics of 450 mg ropivacaine with and without epinephrine for combined femoral and sciatic nerve block in lower extremity surgery. A pilot study.

AIMS: No pharmacokinetic data exist on doses of ropivacaine larger than 300 mg for peripheral nerve block in man, although in clinical practice higher doses are frequently used. The purpose of the present study was to describe the pharmacokinetic profile in serum of 450 mg ropivacaine with and without epinephrine in patients undergoing anterior cruciate ligament reconstruction. METHODS: Twelve patients were randomly allocated to receive a single shot combined sciatic/femoral nerve block with 60 ml of either ropivacaine 0.75% alone (group R, n = 6) or ropivacaine 0.75% plus epinephrine 5 µg ml(-1) (group RE, n = 6). Venous blood samples for total and free ropivacaine serum concentrations were obtained during 48 h following block placement. Pharmacokinetic parameters were calculated using a non-compartmental approach. RESULTS: Results are given as mean (SD) for group R vs. group RE (95% CI of the difference). Total Cmax was 2.81 (0.94) µg ml(-1) vs. 2.16 (0.21) µg ml(-1) (95% CI -0.23, 1.53). tmax was 1.17 (0.30) h vs. 1.67 (0.94) h (95% CI -1.40, 0.40). The highest free ropivacaine concentration per patient was 0.16 (0.08) µg ml(-1) vs. 0.12 (0.04) µg ml(-1) (95% CI -0.04, 0.12). t(1/2) was 6.82 (2.26) h vs. 5.48 (1.69) h (95% CI -1.23, 3.91). AUC was 28.35 (5.92) µg ml(-1) h vs. 29.12 (7.34) µg ml(-1) h (95% CI -9.35, 7.81). CONCLUSIONS: Free serum concentrations of ropivacaine with and without epinephrine remained well below the assumed threshold of 0.56 µg ml(-1) for systemic toxicity. Changes in pharmacokinetics with epinephrine co-administration did not reach statistical significance.

Evidence-based neonatal pharmacotherapy: postnatal corticosteroids.

Corticosteroids are used in the neonatal intensive care unit primarily to treat two conditions: bronchopulmonary dysplasia (BPD) and hypotension (cardiovascular insufficiency). Historically, high-dose dexamethasone was used for BPD, but its use was later associated with adverse neurodevelopmental outcomes and decreased substantially. Data from randomized controlled trials regarding efficacy and safety of lower-dose dexamethasone therapy are insufficient to recommend its use. Hydrocortisone may be an alternative to dexamethasone, but again data are insufficient to support use. Hydrocortisone therapy is increasingly used to treat hypotension in critically ill newborns; however, the outcomes of this therapy must be evaluated in randomized trials.

Distribution and absorption of local anesthetics in inferior alveolar nerve block: evaluation by magnetic resonance imaging.

PURPOSE: The aim of this study was to evaluate the distribution and absorption of local anesthetic solutions in inferior alveolar nerve block using magnetic resonance imaging. MATERIALS AND METHODS: Forty healthy volunteers were divided into 4 groups and injected with 1.5 mL for inferior alveolar nerve block and 0.3 mL for lingual nerve block. The solutions used for the different groups were 2% lidocaine, 2% lidocaine with 0.125 mg/mL epinephrine, 4% articaine with 0.006 mg/mL epinephrine, and 4% articaine with 0.012 mg/mL epinephrine. All subjects had axial T2-weighted and fat-suppressed images at 0, 60, and 120 minutes after injection. The localization, area, and intensity (signal characteristics) of the solutions were analyzed and onset and duration times of the anesthesia were recorded. RESULTS: There were no significant differences between groups with regard to the intensity and area of the solutions at 0, 60, and 120 minutes after injection, but differences were found within each group. CONCLUSIONS: No between-group differences were found on magnetic resonance imaging in the distribution and absorption of lidocaine with or without epinephrine and articaine with 0.006 and 0.012 mg/mL epinephrine. All solutions were noticeably absorbed at 120 minutes after injection.

Oral clonidine attenuates the fall in mean arterial pressure due to scalp infiltration with epinephrine-lidocaine solution in patients undergoing craniotomy: a prospective, randomized, double-blind, and placebo controlled trial.

BACKGROUND: Scalp infiltration with epinephrine-lidocaine solution in patients undergoing neurosurgery may result in transient but significant hypotension. We investigated whether premedication with alpha2-adrenoreceptor agonist clonidine, which also exhibits alpha1-adrenoreceptor mediated vasoconstriction, would prevent or attenuate this fall in mean arterial pressure (MAP). METHODS: Sixty-six American Society of Anesthesiologists I and II adult patients, 18 to 50 years, undergoing elective tumor decompression were recruited into this prospective, randomized, double-blind, placebo controlled study, and scheduled to receive either oral pantoprazole 40 mg (placebo group) or oral clonidine 3 microg/kg (clonidine group), 90 minutes before induction of anesthesia. Primary end points studied were heart rate (HR) and MAP in both groups measured just before scalp infiltration (preinfiltration baseline) and then every 30 seconds for 5 minutes after initiation of scalp infiltration with 2.5 microg/mL epinephrine contained in 15 mL of 1% lidocaine solution. RESULTS: There was no significant change in HR in the 2 groups during the study period compared with baseline values; however, patients in clonidine group had significantly lower HR compared with placebo (*P<0.05). In both groups, MAP fell significantly below baseline 1 minute after start of infiltration. It recovered in the clonidine group after 2.5 minutes but not in the placebo group where it continued to remain low even at 5 minutes. MAP in the placebo group was also significantly lower compared with the clonidine group from 2.5 minutes to 5 minutes. CONCLUSION: In conclusion, oral clonidine 3 microg/kg administered 90 minutes before induction of anesthesia attenuates the fall in MAP due to scalp infiltration with a dilute concentration of epinephrine-lidocaine solution in patients undergoing craniotomy under isoflurane anesthesia.

A unique iontophoretic patch for optimal transdermal delivery of sumatriptan.

PURPOSE: Migraines affect approximately 10% of the adult population worldwide. The purpose of this study was to assess the pharmacokinetic and safety profile of a novel iontophoretic sumatriptan delivery system, NP101, which uses an electrical current to propel sumatriptan across intact skin and into underlying tissue. Four unique prototype iontophoretic sumatriptan patch conditions were compared to a 6 mg subcutaneous injection and an oral 50 mg tablet of sumatriptan succinate. MATERIALS AND METHODS: This was a randomized, single-center, single-dose, six-period Phase I study. RESULTS: Patches were well tolerated with fewer adverse events than the subcutaneous injection. Adverse events that were more prevalent for NP101 than other formulations included localized sensations and reactions at the patch site. A linear relationship was observed between total applied current and sumatriptan delivery. Patches delivering 6 and 12 mA per h yielded favorable sumatriptan systemic profiles, delivering drug at a rate that maintained plasma levels above the target level (> or = 10 ng/ml) for greater than 7 h. CONCLUSIONS: This study met the initial objective to define the dose-current relationship in humans as well as delimiting specific current and current density targets for a well tolerated patch design that can deliver therapeutic drug levels for longer periods than currently possible.

Endothelium-derived steroidogenic factor enhances angiotensin II-stimulated aldosterone release by bovine zona glomerulosa cells.

Endothelium-derived steroidogenic factor (EDSF) is an endothelial peptide that stimulates aldosterone release from bovine adrenal zona glomerulosa (ZG) cells. The regulation of aldosterone release by combinations of EDSF and angiotensin II (AII) or EDSF and ACTH was investigated. Endothelial cells (ECs) and EC-conditioned media (ECCM) increased aldosterone release from ZG cells, an activity attributed to EDSF. AII (10(-12) to 10(-8) M) and ACTH (10(-12) to 10(-9) M) also stimulated the release of aldosterone from ZG cells. The stimulation by AII, but not ACTH, was greatly enhanced when ZG cells were coincubated with ECs. AII was metabolized by ECs to peptides identified by mass spectrometry as angiotensin (1-7) and angiotensin IV. There was very little metabolism of AII by ZG cells. Neither of these two AII metabolites altered aldosterone release from ZG cells, so they could not account for the enhanced response with ECs. AII-induced aldosterone release from ZG cells was enhanced by ECCM but not cell-free conditioned medium. This enhanced response was not due to increased EDSF release from ECs by AII. The synergistic effect of EDSF and AII was apparent when AII was added during or after the generation of ECCM and not observed when the AII component of the enhancement was blocked by the AII antagonist, losartan. These studies indicate that EDSF enhances the steroidogenic effect of AII. In the adrenal gland, ECs are in close anatomical relationship with ZG cells and may sensitize ZG cells to the steroidogenic action of AII by releasing EDSF.

Cardiovascular effects of epinephrine under sedation with nitrous oxide, propofol, or midazolam.

OBJECTIVE: During implant surgery, a large amount of local anesthetics containing epinephrine are often required, and the resulting cardiovascular effects of administered epinephrine are not negligible. On the other hand, sedation has wide applications in implant surgery. Nitrous oxide, propofol, or midazolam are commonly used as sedative drugs, and each has also its own cardiovascular effects. The objective of this study was to investigate the cardiovascular effects of epinephrine on patients under sedation with nitrous oxide, propofol, or midazolam. STUDY DESIGN: We studied 9 healthy volunteers. They received epinephrine infusion at a nominal rate of 10, 25, or 50 ng/kg per minute under sedation with 30% nitrous oxide inhalation, 4 mg/kg per hour intravenous propofol or 0.2 mg/kg per hour intravenous midazolam. For each, hemodynamic response and blood pressure and heart rate variability were measured. RESULTS: When epinephrine was infused alone at 50 ng/kg per minute, heart rate (HR) and cardiac index (CI) increased by 19.5% and 40.7%, respectively. Propofol suppressed the epinephrine-induced increase in CI. During midazolam infusion, the highest dose of epinephrine caused a 37.5% increase in HR, which was significantly higher than for epinephrine infusion alone. This response was accompanied by the reduction in high-frequency power of heart rate variability, suggesting decreased parasympathetic activity. Nitrous oxide had no influence on the cardiovascular response to epinephrine. CONCLUSION: Increased cardiovascular activity due to epinephrine can be alleviated by propofol. However, midazolam and nitrous oxide are of no advantage for stabilizing the hemodynamic status of the patient. Intravenous sedation with propofol is useful during oral surgical procedures in which a large amount of epinephrine is required.

Changing the pathophysiology of solid tumours: the potential of TNF and other vasoactive agents.

Solid tumour therapy with chemotherapeutic drugs is hampered by a number of factors resulting in poor results and failure of initially promising drugs. From the application of Tumour Necrosis Factor alpha in the melphalan-based Isolated Limb perfusion some lessons could be learned. Most importantly, combination of treatment approaches, certainly when multiple targets are involved, increases the effectiveness of the therapy. Clinical outcome may improve dramatically when the tumour pathophysiology is changed in such a way that co-administered chemotherapeutics are more active or are capable of reaching the tumour cells better. Here some of the methodologies and drug combinations which improve solid tumour therapy through acting on the tumour pathophysiology are discussed.