A randomized, controlled trial on the effect of anesthesia on chronic pain after total knee arthroplasty.

Aim: The study sought to evaluate the influence of anesthesia on chronic pain after total knee arthroplasty (TKA). Methods: This was a single-center, randomized controlled study, with patients receiving a spinal anesthetic (SP) alone or a general anesthetic (GA) with femoral block, with follow-up at 3 and at 6 months. The primary outcome was the WOMAC® score at 6 months. Results: 199 patients were enrolled. Group SP had better function (WOMAC: GA: 16.9 vs SP: 14.4, p = 0.015) and less pain (WOMAC pain: GA: 3.04 vs SP: 2.69, p = 0.02) at 3 months, but not at 6 months. Overall, 11% of patients had chronic postsurgical pain (CPSP), with Group GA having a higher incidence of CPSP at 6 months. Neuropathic pain increased during the follow-up and was more common in patients with CPSP. Conclusion: An SP reduces pain and incidence of CPSP after TKA. Clinical Trial Registration: NCT04206046 (ClinicalTrials.gov).

Patients who have knee replacement surgery are at risk of remaining in significant pain even up to one year after surgery. Our study aims to look into the potential of reducing this risk by comparing two common forms of anesthesia. 199 patients were randomized to either have a spinal anesthetic (SP) or a general anesthetic with a femoral nerve block. Patients were then followed-up for 6 months, and then asked to report on a validated functional and pain scoring system (WOMAC^®). Patients who had had an SP had better function and less pain at 3 months after surgery, but not at 6 months. The incidence of chronic pain at six month seems to be less with an SP.

The interplay between pharmacogenetics, concomitant drugs and blood levels of amitriptyline and its main metabolites.

Background: The research considers the impact of genotype-inferred variability on blood levels of amitriptyline and its main metabolites, as may be moderated by phenocopying. Patients & methods:CYP2D6 and CYP2C19 genotypes, and serum concentrations of amitriptyline, nortriptyline and hydroxymetabolites, were determined in 33 outpatients. Co-medications were reviewed to identify CYP inhibition risk. Results: CYP2C19 metabolizer status explained interpatient variation in nortriptyline to amitriptyline concentration ratios. The hydroxymetabolite to parent ratios increased with higher CYP2D6 activity scores and lower CYP2D6 inhibition risk. In patients at high CYP2D6 inhibition risk, the amitriptyline + nortriptyline concentration was, on average, 52% above the higher end of expected ranges. Conclusion: Practical construal of pharmacogenetics and drug interactions tantamount to aberrant metabolism can facilitate patient-tailored use of the established drug.

Amitriptyline is an established drug in managing depression and neuropathic pain. Body exposure to amitriptyline and its by-products is influenced by enzymes activities, which are subject to genetic variation, whereas other medications in a patient's treatment regimen may alter drug breakdown. To study these implications, genetic testing was conducted in 33 outpatients on amitriptyline therapy, alongside measurement of drug concentrations in blood and consideration of any co-administered medications. Breakdown of amitriptyline to nortriptyline was associated with the genetically determined status of patients. Subjects at high risk of having their rate for further breakdown delayed by other drugs had higher blood levels than expected in normal cases. A proportion of variation observed in blood drug concentrations across individuals with same genetic results could be explained by actions of drugs received concurrently. Supportive evidence is provided on the integration of drug interaction information with insights from genetic testing for patient-tailored pharmacotherapy that attempts to mitigate the possibility of missing an intended benefit or the risk of adverse events due to altered blood levels.

Practical liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of amitriptyline, nortriptyline and their hydroxy metabolites in human serum.

Amitriptyline (AMI) has been in use for decades in treating depression and more recently for the management of neuropathic pain. A highly sensitive and specific LC-tandem mass spectrometry method was developed for simultaneous determination of AMI, its active metabolite nortriptyline (NOR) and their hydroxy-metabolites in human serum, using deuterated AMI and NOR as internal standards. The isobaric E-10-hydroxyamitriptyline (E-OH AMI), Z-10-hydroxyamitriptyline (Z-OH AMI), E-10-hydroxynortriptyline (E-OH NOR) and Z-10-hydroxynortriptyline (Z-OH NOR), together with their parent compounds, were separated on an ACE C18 column using a simple protein precipitation method, followed by dilution and analysis using positive electrospray ionisation with multiple reaction monitoring. The total run time was 6 min with elution of E-OH AMI, E-OH NOR, Z-OH AMI, Z-OH NOR, AMI (+ deuterated AMI) and NOR (+ deuterated NOR) at 1.21, 1.28, 1.66, 1.71, 2.50 and 2.59 min, respectively. The method was validated in human serum with a lower limit of quantitation of 0.5 ng/mL for all analytes. A linear response function was established for the range of concentrations 0.5-400 ng/mL (r2 > .999). The practical assay was applied on samples from patients on AMI, genotyped for CYP2C19 and CYP2D6, to understand the influence of metaboliser status and concomitant medication on therapeutic drug monitoring.

Regulatory sciences and translational pharmacogenetics: amitriptyline as a case in point.

Regulatory developments and clinical implementation, or the lack thereof, are primary clinchers, in the enduring endeavors to realize the translational quality of pharmacogenetics. Here, we present the case of amitriptyline, an established drug with pharmacogenetic implications. The integration of pharmacogenetic information in the official product literature and throughout the evaluation of safety concerns is considered. In our opinion, apart from emboldening genomic research in drug development and the valid pursuit towards global harmonization in the field, it is rational to look into the applicability of the data we have today.

Factors Affecting Penetration of Ciprofloxacin in Lower Extremity Ischemic Tissues.

The aims of this study were to evaluate factors influencing the distribution of ciprofloxacin in tissue of patients suffering from varying degrees of peripheral arterial disease (PAD). Blood and tissue samples were collected from patients undergoing debridement or amputation procedures and the amount of ciprofloxacin in them was determined using high-performance liquid chromatography. All patients were administered a 200-mg dose of intravenous ciprofloxacin prior to the debridement or amputation procedure. Data, including patient gender, age, type of diabetes, presence of neuropathy, medications taken, and severity of PAD were collected. These data were then analyzed to determine factors influencing the concentrations of ciprofloxacin in tissue of the lower limbs. The Kruskal-Wallis test, Spearman correlation, and chi-square test were used to relate covariates and fixed factors with the concentration of ciprofloxacin in tissue. Following bivariate analysis, a 3-predictor regression model was fitted to predict tissue concentrations of ciprofloxacin given information about these predictors. Blood and tissue samples were collected from 50 patients having an average age of 68 years. Thirty-three patients were males and 35 patients suffered from type 2 diabetes. The average number of medications that these patients were taking was 10. The majority of patients (n = 35) were suffering from severe PAD. Tissue concentrations of ciprofloxacin were mainly related to plasma concentrations of ciprofloxacin, number of medications that the patients were taking and severity of PAD.

A simple HPLC-UV method for the determination of ciprofloxacin in human plasma.

A rapid and sensitive HPLC-UV method for the determination of ciprofloxacin in human plasma is described. Protein precipitation with acetonitrile was used to separate the drug from plasma protein. An ACE(®) 5 C18 column (250 mm×4.6 mm, 5 µm) with an isocratic mobile phase consisting of phosphate buffer (pH 2.7) and acetonitrile (77:23, v/v) was used for separation. The UV detector was set at 277 nm. The method was validated in the linear range of 0.05-8 µg/ml with acceptable inter- and intra-assay precision, accuracy and stability. The method is simple and rapid and can be used to quantify this widely used antibiotic in the plasma of patients suffering from Peripheral Arterial Disease.

Factors affecting gentamicin penetration in lower extremity ischemic tissues with ulcers.

The aims of the study were to analyze the penetration of gentamicin in foot ulcers in patients with different severities of peripheral arterial disease (PAD) and to determine significant parameters affecting lower limb tissue concentrations. Patients undergoing debridement of a wound or an amputation procedure were included. All patients received a 120 mg or 240 mg intravenous dose of gentamicin prior to the procedure. Patients were classified according to the degree of PAD. Tissue and serum samples were collected at the time of intervention, and gentamicin concentrations were determined by fluorescence polarization immunoassay. Blood and tissue samples were taken from 61 patients, 41 males and 20 females with a mean age of 66 years. Nineteen patients had nil or borderline PAD, 9 patients had mild or moderate PAD, and 26 patients had severe PAD. Forty-eight patients had type 2 diabetes, 8 patients had type 1 diabetes, and 5 patients were nondiabetic. The concentration of gentamicin in peripheral skeletal muscle tissue was dependent on the serum concentration, degree of PAD, gender, and age. For patients with ischemic lower extremity wounds (patients with mild, moderate, and severe PAD), the concentration of gentamicin was significantly lower (P = .010) than the concentration in nonischemic wounds, and the concentration in female patients was also significantly lower than in male patients (P = .047). The concentration in peripheral subcutaneous tissue was 0.663 times the concentration in skeletal muscle tissue (P < .00001). Gentamicin showed greatest penetration in male patients without PAD. For patients with severe PAD, higher doses of gentamicin may be required to achieve the same effect.