Safety and Efficacy of Renuvion Helium Plasma to Improve the Appearance of Loose Skin in the Neck and Submental Region.

BACKGROUND: Minimally invasive procedures that deliver thermal energy to subcutaneous tissue offer a solution when deciding between excisional and noninvasive options to address face and neck aging-related changes. A minimally invasive helium plasma device, Renuvion, was first utilized for subdermal tissue heating to reduce skin laxity under an FDA general clearance for cutting, coagulation, and ablation of soft tissue. OBJECTIVES: The purpose of this study was to demonstrate the safety and effectiveness of the helium plasma device for improving the appearance of loose skin in the neck and submental region. METHODS: Patients undergoing the procedure with the helium plasma device in the neck and submentum were studied. They were seen for 6 months following the procedure. The primary effectiveness endpoint for improvement in lax skin in the treatment area was determined by 2 of 3 blinded photographic reviewers. The primary safety endpoint was the level of pain after treatment. RESULTS: The primary effectiveness endpoint was met; 82.5% demonstrated improvement at Day 180. The primary safety endpoint was met; 96.9% of patients experienced no pain to moderate pain to Day 7. There were no serious adverse events reported related to the study device or procedure. CONCLUSIONS: The data demonstrate benefit to patients by improvement of the appearance of lax skin in the neck and submental region. Outcomes resulted in US Food and Drug Administration 510(k) clearance in July 2022, expanding indications for the device to include subcutaneous dermatological and aesthetic procedures to improve the appearance of loose skin in the neck and submental region.

Pharmacokinetics and pharmacodynamics of indomethacin: effects on cerebral blood flow in anaesthetized sheep.

1. Indomethacin has been used to manage raised intracranial pressure (ICP) in humans during neuroanaesthesia and neurosurgery. Indomethacin causes cerebral vasoconstriction and reduces cerebral blood flow (CBF) and, therefore, ICP. 2. The systemic kinetics, cerebral kinetics and cerebral dynamics of indomethacin (0.2 mg/kg) were measured and modelled using a population approach. Data were collected using an instrumented sheep preparation with raised ICP and under either isoflurane or propofol anaesthesia to parallel the clinical use of indomethacin in neurosurgery. 3. The systemic kinetics of indomethacin could be described by a two-compartment model, with small distribution volumes and a clearance of 0.68 L/min. The cerebral kinetics of indomethacin could be described using a model with a cerebral distribution volume between 5 and 8 mL and a loss term of 3.3 mL/min, the latter probably representing slow diffusion across the blood-brain barrier. 4. The changes in CBF lagged behind the blood concentrations of indomethacin. Indirect response models with turnover times of 1.70-4.08 min were generally better able to describe the effect of indomethacin on CBF than effect compartment models. 5. There was a non-linear concentration-effect relationship, with the maximum possible reduction in CBF being to 73-74% of baseline. 6. The data and model support the concept of indomethacin having limited uptake into the brain, with its effect on CBF being the result of its action on the endothelium, where it indirectly modifies the turnover of a compound regulating vascular tone.

Blood-brain equilibration kinetics of levo-alpha-acetyl-methadol using a chronically instrumented sheep preparation.

1.--The delayed onset and long duration of action of the opioid agonist levo-alpha-acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood-brain equilibration of LAAM itself. 2.--The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0-75 min) were measured using a validated HPLC assay. 3.--LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. 4.--Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood-brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min(-1)) and a large cerebral distribution volume (724 ml). 5.--In conclusion, pharmacokinetic-pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.

Cerebral kinetics of oxycodone in conscious sheep.

Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of opioid action is a function of the systemic kinetics of the opioid, and the rate and extent of its entry into the brain and central nervous system. The latter is incompletely understood for oxycodone. Therefore, the cerebral kinetics of oxycodone was quantified using a conscious chronically instrumented sheep preparation. Five sheep were administered oxycodone as intravenous infusions (30 mg over 4 min). Using hybrid physiologically based kinetic models, cerebral kinetics was estimated from arterio-sagittal sinus concentration gradients and cerebral blood flow (CBF). A two-compartment membrane-limited model best described the data. The volume of the first brain compartment was 35.4 mL with a half-life of equilibrium of 0.6 min. The brain:blood equilibration of oxycodone was relatively slow (half-life of 7.2 min), with a large deep cerebral distribution volume (222.8 mL) for the second compartment and a moderate membrane permeability of 54.8 mL/min, which exceeded the nominal CBF (40 mL/min). Drug retention in the brain was 1.3% after 45 min. In conclusion, pharmacokinetic modelling of oxycodone showed a delayed equilibration between brain and blood of a nature that would be affected by changes in both CBF and blood brain barrier permeability.

The effects of indomethacin on intracranial pressure and cerebral hemodynamics during isoflurane or propofol anesthesia in sheep with intracranial hypertension.

The effect of indomethacin in reducing intracranial pressure (ICP) may be dependent on the choice of anesthetic regimen. We studied the effects of indomethacin on ICP and cerebral blood flow (CBF) during isoflurane or propofol anesthesia in a sheep model of intracranial hypertension. A crossover design was applied in which six sheep were anesthetized with isoflurane and propofol in a random order. Anesthetic depth was measured with response and state entropy. Changes in CBF, ICP, mean arterial blood pressure, arterio-venous oxygen difference, and Paco2 were measured at specific times before and after an IV indomethacin bolus (0.2 mg/kg). Response and state entropy values during anesthesia were similar in both groups. Isoflurane and propofol reduced CBF by 11% and 34%, respectively. Indomethacin caused a reduction in ICP within 15 s during both anesthetic regimens, with the decrease in ICP being significantly more pronounced during isoflurane (P = 0.009). In both anesthetic groups, indomethacin caused a simultaneous increase in mean arterial blood pressure and a further 17% versus 14% decrease in CBF from predrug values for isoflurane and propofol, respectively. The reduction in CBF was significantly more pronounced for propofol (P = 0.02). The effect on ICP, however, was most pronounced during isoflurane anesthesia. We suggest that the effect of indomethacin is partly mediated by an autoregulatory response.

The effect of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under propofol anaesthesia in an ovine model.

OBJECTIVE: To compare the effects of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under steady-state propofol anaesthesia with the awake state. DESIGN: Prospective, randomised, interventional animal study. SETTING: University laboratory. SUBJECTS: Six studies in two cohorts of adult ewes: awake and steady-state propofol anaesthesia (15 mg/min). INTERVENTIONS: In random order, each animal received ramped infusions of adrenaline, noradrenaline (0-40 microg/min) and dopamine (0-40 microg/kg per min). MEASUREMENTS AND RESULTS: Cerebral blood flow (CBF) was measured continuously from changes in Doppler velocities in the sagittal sinus and normalised to a PaCO(2) 35 mmHg. Propofol decreased CBF by 55% relative to pre-anaesthesia values (p=0.0001). All three catecholamines significantly and equivalently increased mean arterial pressure (MAP) from baseline in a dose-dependent manner in both awake and propofol cohorts. Adrenaline significantly increased CBF from baseline in both awake sheep (p<0.01) and during propofol anaesthesia (p<0.001); noradrenaline and dopamine did not statistically increase CBF. When comparing the effects of individual catecholamines with each other within each cohort, no statistically significant difference between the catecholamines was demonstrated. (p>0.05). Using linear regression analysis, normalised CBF was correlated against associated changes in MAP. No significant differences were demonstrated between the slopes of regression lines for adrenaline, noradrenaline and dopamine in either cohort (ANCOVA). There was a statistically significant difference between the intercepts of the awake and propofol cohorts (p<0.0001), but no difference between the slopes (p=0.69). CONCLUSIONS: Over a specific dose range, catecholamine-induced hypertension caused increased CBF during steady-state propofol anaesthesia. This effect was offset by an associated reduction in CBF caused by propofol. The concomitant administration of propofol and catecholamines was not associated with altered autoregulatory function compared to the awake state.

Brain pharmacokinetics of lignocaine before and following intravenous perfluorocarbon emulsion infusion in sheep.

1. Perfluorocarbon emulsions have potential medical applications, particularly as temporary oxygen carriers and are likely to be coadministered with other intravenous drugs. It is possible that perfluorocarbon emulsions may alter the disposition of other drugs in the body. 2. In the present study, we examined the brain pharmacokinetics of a 5 min infusion of 100 mg lignocaine in three chronically instrumented sheep before and after the administration of a new investigational perflurocarbon emulsion (Oxygent; Alliance Pharmaceutical, San Diego, CA, USA). 3. The rate constant for the blood : brain equilibration of lignocaine was larger after perflubron administration. This change could not be attributed to a change in brain blood flow and, therefore, may be the result of a change in the free fraction of lignocaine in the blood.

The acute disposition of (R)- and (s)-methadone in brain and lung of sheep.

The cerebral and lung kinetics of the enantiomers of methadone were quantified using a conscious chronically instrumented sheep preparation, as these organs are the major organs governing the peak brain concentrations (and therefore effects) of methadone after ivbolus administration. Seven sheep were administered intravenous infusions of rac-methadone (30 mg over 4 min). Whole blood (R)- and (S)-methadone concentrations were measured using stereoselective HPLC. Methadone transiently increased cardiac output (CO) and mean arterial pressure, but did not alter cerebral blood flow (CBF) or cause significant respiratory depression. Using physiologically based kinetic models, cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and CBF, lung kinetics from pulmonary artery-aortic gradient and CO. Lung and cerebral kinetics were best described by a partially membrane-limited model for both enantiomers. Lung kinetics displayed clear stereoselectivity, due to the smaller apparent volume of the deep lung compartment for (R)-methadone (45 l) compared to (S)-methadone (79 l). This resulted in systemic differences in the concentrations of the enantiomers. Minimal stereoselectivity was observed in cerebral kinetics. The brain:blood equilibration of methadone was slow (half-life of 18 min) due to intermediate permeability and large apparent cerebral distribution volumes. However, the permeability term was sufficiently high that cerebral kinetics were affected by CBF. Simulations demonstrated that if CBF was doubled, the equilibration half-life of methadone with brain tissue decreased by 30%, and there was a 25% increase in the peak brain concentrations. Future studies are needed to confirm the role of cerebral blood flow alterations in the exposure of the brain to methadone, especially in the case of respiratory depression. In conclusion, pharmacokinetic modelling of methadone confirmed a large equilibration delay between brain and blood.

The contribution of the coronary concentrations of propofol to its cardiovascular effects in anesthetized sheep.

UNLABELLED: Linking physiological pharmacokinetic models to models of the cardiovascular system requires knowledge of the sites in the body that mediate a drug's cardiovascular effects. We examined the role of the coronary concentrations of propofol. Nine sheep anesthetized with isoflurane (2%) were instrumented acutely for cardiovascular measurements. In a random crossover design, they were administered ramped coronary artery (CA) infusions of propofol to selectively enrich the myocardium (as indicated by the coronary sinus blood concentration) or IV infusions to achieve the same concentration range in all sites of the body. Reductions in left ventricular myocardial contractility (LV dP/dt(max)) and mean arterial blood pressure were linearly related to the propofol concentration. For the CA route, LV dP/dt(max) was reduced by 52 mm Hg/s for each milligram per liter increase in coronary sinus propofol concentration. For the IV route, the reduction in LV dP/dt(max) was equivalent to that with the CA route, showing that the coronary propofol concentration was the major contribution to this effect. For the CA route, mean arterial blood pressure was reduced by 0.6 mm Hg for each milligram per liter. There was a larger reduction (2.5 mm Hg x mg(-1) x L(-1)) for the IV route. Therefore, this effect was predominantly mediated by propofol concentrations elsewhere in the body. IMPLICATIONS: With use of selective coronary artery infusions in sheep, the coronary concentrations of propofol were shown to be the major contributor to the cardiac depression caused by propofol but were a less significant contributor to the hypotension caused by this drug. Models of the cardiovascular effects of propofol should account for these relationships.