Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis.

BACKGROUND: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers. METHODS: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach. RESULTS: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics. CONCLUSIONS: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. CLINICAL TRIAL REGISTRATION: Dutch Cochrane Center 5359.

Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers.

BACKGROUND: Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. METHODS: Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. RESULTS: The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. CONCLUSIONS: We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

Field evaluation of a novel preservation medium to transport sputum specimens for molecular detection of Mycobacterium tuberculosis in a rural African setting.

OBJECTIVES: To assess the performance of an innovative method of transporting sputum to centralised facilities for molecular detection of Mycobacterium tuberculosis: using a swab to inoculate sputum in a transport medium, PrimeStore(®) Molecular Transport Medium (PS-MTM). METHODS: Two sputum specimens were obtained from suspected patients with tuberculosis (TB) at rural healthcare facilities in South Africa. A swab was taken from each specimen and placed into PS-MTM, prior to it being processed by either liquid culture or Xpert MTB/RIF assay (Xpert). RESULTS: A total of 141 patients (including 47 with laboratory-confirmed TB) were included in this analysis. M. tuberculosis was detected at 29% by culture and 29% by Xpert, whereas 31% tested positive by IS6110 real-time PCR of PS-MTM from the culture and 36% from the Xpert-paired specimen. Concordance between the method under evaluation with culture was 82% (McNemar, P = 0.55) and 84% (McNemar, P = 0.05) for Xpert. Stratified by culture result, the detection rate by IS6110 real-time PCR of PS-MTM was similar to Xpert for patients with positive culture (P = 0.32), but significantly higher if culture was negative (P = 0.008). CONCLUSIONS: These results suggest that swab collection of sputum into PS-MTM for transport is a promising method for diagnosis of TB in rural healthcare settings, thereby potentially improving the options available for molecular diagnosis of TB in countries incapable of applying decentralised high-tech molecular testing.

Antibiotic Prescriptions in Hospitalized Patients with an Exacerbation COPD and a Proven Influenza or RS Virus Infection.

Background: COPD exacerbations (AE-COPD) add up to over 200,000 hospitalization days annually in the Netherlands. Viral respiratory infections play a role in about half of COPD exacerbations. Although the prevalence of bacterial superinfection is estimated 10-40% in admitted AE-COPD patients with an influenza infection, the majority is treated with antibiotics. Current national and international guidelines provide limited guidance regarding antibiotic use in hospitalized patients with an AE-COPD with proven viral respiratory pathogens. Study Goal: We aimed to investigate antibiotic prescription in hospitalized patients with a COPD exacerbation and an influenza- or RS virus infection. Patients and methods: We performed a retrospective cohort study in patients admitted with an AE-COPD and influenza- or RS virus infection. We compared clinical characteristics of patients with and without antibiotic treatment on admission and estimated adequacy of antibiotic prescriptions. Results: We included 134 patients. Seventy-nine (59%) received antibiotics on admission. Chest X-ray infiltrates and plasma CRP level (≥50 mg/L) were correlated with the prescription of antibiotics. Outcomes, such as number of hospitalized days and mortality, were not significantly different between the groups with and without antibiotic treatment. Antibiotic treatment was considered "probably adequate" in 52/79 (65.8%) patients; "not necessary" in 12/79 patients (15.2%) and "probably not necessary" in another 15/79 patients (19.0%). Conclusion: Prescription of antibiotics in hospitalized COPD patients is common practice despite a proven viral infection on admission. A significant antibiotic reduction of 34.2% in these patients seems feasible. Future guidelines should include recommendations regarding antibiotic stewardship in hospitalized patients with AE-COPD with a proven viral respiratory infection.

Retinal oximetry with a prototype handheld oximeter during hyperoxia.

PURPOSE: Retinal oximetry measures oxygen saturation in retinal vessels. With the introduction of a mobile handheld prototype oximeter, this technique will become available for a broader patient population including bedridden patients and newborn babies. The objective is to determine the sensitivity of this handheld oximeter in room air and during isocapnic hyperoxia. A comparison is made between the handheld oximeter and the Oxymap T1. METHODS: Thirteen young healthy subjects with a mean age of 25 ± 2 years were recruited at the Leiden University Medical Center. Retinal oximetry images were acquired during normoxia and during isocapnic hyperoxia for both the prototype oximeter and the OxymapT1. Isocapnic hyperoxia was induced with the dynamic end-tidal forcing technique. For both oximeters, the oxygen saturation and vessel width were measured with Oxymap Analyzer software. The hyperoxic state was verified with blood gas analysis. RESULTS: The mean oxygen saturation measured with the handheld oximeter in arterioles was 91.3% ± 3.9% during normoxia and 94.6% ± 3.9% during hyperoxia (p = 0.001). Oxygen saturation in venules was 56.3% ± 9.8% during normoxia and 82.2 ± 7.4% during hyperoxia (p < 0.001). For the Oxymap T1, the mean oxygen saturation for arterioles was 94.0% ± 2.6% during normoxia and 95.4%±3.2% during hyperoxia (p = 0.004). For the venules, the oxygen saturation was during normoxia 58.9%±3.2% and 84.3 ± 4.0% during hyperoxia (p < 0.001). CONCLUSION: The handheld retinal oximeter is sensitive to the changes in inhaled oxygen concentration. A small increase in oxygen saturation was measured in the arterioles and a larger increase in the venules. The handheld oximeter gives similar values as the 'gold standard' Oxymap T1 oximeter.

Handheld Retinal Oximetry in Healthy Young Adults.

PURPOSE: The objective of this study was to measure the relative retinal oxygen saturation with a prototype, mobile handheld oximeter in upright and supine position and to compare these measurements to the gold standard Oxymap T1 retinal oximeter in upright position. A handheld oximeter is needed for measurements of infants with retinopathy of prematurity as well as acutely injured and bedridden adults. METHODS: Healthy volunteers (age 18-35) were recruited at the Leiden University Medical Center. Retinal images were acquired with the handheld oximeter and the Oxymap T1. Both cameras are dual-wavelength oximeters and acquire images with wavelengths of 570 and 600 nm. Retinal oxygen saturation values were determined for both the handheld camera and the Oxymap T1. RESULTS: Twenty-one subjects (age 25 ± 2 years) were included. In upright position, the oxygen saturation for the arterioles was 92.2% to 4.9% vs. 95.5% ± 4.2% and for the venules 57.9% ± 10.2% vs. 57.7% ± 6.4% for the handheld camera and Oxymap T1, respectively. The oxygen saturation was higher in the arterioles than the venules for both cameras (P < 0.05). In supine position, measured with the handheld oximeter, the oxygen saturation in the arterioles was 92.3% ± 5.8% and 59.2% ± 6.1% in the venules. CONCLUSIONS: Performance of the prototype, mobile handheld oximeter Corimap camera compares well with the Oxymap T1, with a slightly larger standard deviation in oxygen saturation measurements, both in upright and supine patients. TRANSLATION RELEVANCE: To date, to our knowledge, no oximeters are available for handheld use and for measurement in supine position in infants and bedridden adults. Here we tested such an oximeter and show that its performance compares well with that of the gold standard Oxymap T1 in healthy adults.

Ketamine for cancer pain: what is the evidence?

PURPOSE OF REVIEW: In this review, we assess the benefit of ketamine in the treatment of terminal cancer pain that is refractory to opioid treatment and/or complicated by neuropathy. RECENT FINDINGS: While randomized controlled trials consistently show lack of clinical efficacy of ketamine in treating cancer pain, a large number of open-label studies and case series show benefit. SUMMARY: Ketamine is an N-methyl-D-aspartate receptor antagonist that at low-dose has effective analgesic properties. In cancer pain, ketamine is usually prescribed as adjuvant to opioid therapy when pain becomes opioid resistant or when neuropathic pain symptoms dominate the clinical picture. A literature search revealed four randomized controlled trials that examined the benefit of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None showed clinically relevant benefit in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as adjuvant analgesic in cancer pain. These findings contrast the benefit from ketamine observed in a large number of open-label studies and (retrospective) case series. We relate the opposite outcomes to methodological issues. The complete picture is such that there is still insufficient evidence to state with certainty that ketamine is not effective in cancer pain.

Ketamine for pain.

The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine's lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.