Pharmacokinetics of Oxycodone and Paracetamol in the Elderly. Clinical Pharmacokinetic Study on Orthopaedic Surgical Patients and Healthy Volunteers

The proportion of elderly people over 65 years of age in Finland is expected to grow to over 25% by the 2025. It has been estimated that elderly people today consume nearly 40% of all drugs. Age brings about number of physiological changes that may affect the disposition, metabolism and excretion of drugs. The function of heart, lungs, liver and kidneys decreases even in healthy people, as they get older. The proportion of total body water decreases and the relative fat percentage increases. Also several other factors such as concurrent diseases, concomitant medication and nutritional factors have an effect on drug therapy in elderly. Age increases the risk of adverse drug reactions, which most often are dose-dependent. Despite all this there are not enough studies involving the elderly people and the elderly are most often excluded from clinical trials. Oxycodone is a strong opioid analgesic, which is used to treat moderate or severe pain. Paracetamol is a widely used nonopioid analgesic, which has become popular in the treatment of pain in many patient groups. In this series of studies the pharmacokinetics of oral and intravenous oxicodone as well as intravenous paracetamol in the elderly and young adult patients were investigated. Also a study investigating the interaction of oral antibiotic clarityhromycin, a known cytochrome P450 (CYP) 3A4 inhibitor, with oxycodone pharmacokinetics and pharmacodynamics in elderly and young healthy volunteers was carried out. The pharmacokinetics of oxycodone showed a clear age depency. Patients over 70 years had 50-80% higher mean exposure to oral oxycodone and a twofold greater plasma concentration than young adults 12 h after ingestion of the drug. Elderly patients had 40-80% greater exposure to intravenous oxycodone and patients over 80 years had over twofold greater plasma concentrations 8 h post dose than the young adults. The elderly patients had also greater exposure to intra venous paracetamol compared to young adults. Clarithromycin increased the exposure to oral oxycodone in both young and elderly volunteers. The elderly had marked interindividual variation in the pharmacokinetics and pharmacodynamics when clarithromycin was given concomitantly with oxycodone. Because the pharmacokinetics of oxycodone and intravenous paracetamol depend on the age of the subject, it is important to titrate the analgesic dose individually in the elderly.

Observations on the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clinical Studies on Healthy Volunteers and Intensive Care Patients

Patients treated in intensive care units require sedation and analgesia. However, sedative drugs also have potential adverse effects, and there is no single ideal sedativeanalgesic drug for these patients. Dexmedetomidine is an apha2-adrenoceptor agonist licenced for sedation of intensive care patients and patients undergoing surgery and other invasive procedures. Several routes of parenteral administration (intravenous, intramuscular, subcutaneous and intranasal) have been utilized. In the present series of studies, the pharmacokinetics and pharmacodynamics of intranasally administered dexmedetomidine as well as the gastrointestinal effects of intravenous dexmedetomidine were determined in healthy volunteers. Pharmacokinetics of dexmedetomidine during long lasting, high-dose infusions were characterized in intensive care patients. The bioavailability of intranasal dexmedetomidine was relatively good (65%), but interindividual variation was large. Dexmedetomidine significantly inhibited gastric emptying and gastrointestinal transit. In intensive care patients, the elimination half-life of dexmedetomidine was somewhat longer than reported for infusions of shorter duration and in less ill patients or healthy volunteers. Dexmedetomidine appeared to have linear pharmacokinetics up to the studied dose rate of 2.5 μg/kg/h. Dexmedetomidine clearance was decreasing with age and its volume of distribution was increased in hypoalbuminaemic patients, resulting in a longer elimination half-life and context-sensitive half-time. Intranasally administered dexmedetomidine was efficacious and well tolerated, making it appropriate for clinical situations requiring light sedation. The clinical significance of the gastrointestinal inhibitory effects of dexmedetomidine should be further evaluated in intensive care patients. The possibility of potentially altered potency and effect duration should be taken into account when administering dexmedetomidine to elderly or hypoalbuminaemic patients.

Free PAPP-A: a Novel Marker in Acute Coronary Syndrome Patients

In recent years, one important objective of cardiovascular research has been to find new markers that would improve the risk stratification and diagnosis of patients presenting with symptoms of acute coronary syndrome (ACS). Pregnancy-associated plasma protein A (PAPP-A) is a large metalloproteinase involved in insulin-like growth factor signalling. It is expressed in various tissues and seems to be involved in many physiological and pathological processes, such as folliculogenesis, bone formation, wound healing, pregnancy and atherosclerosis. The aim of this thesis was to investigate PAPP-A in ACS patients. Circulating concentrations of PAPP-A had been previously shown to be elevated in ACS. In this study it was revealed that the form of PAPP-A causing this elevation was the free noncomplexed PAPP-A. Thus, the form of PAPP-A in the circulation of ACS patients differed from the complexed PAPP-A form abundantly present in the circulation during pregnancy. A point-of-care method based on time-resolved immunofluorometric assays was developed, which enabled the rapid detection of free PAPP-A. The method was found to perform well with serum and heparin plasma samples as well as with heparinized whole blood samples. With this method the concentrations of free PAPP-A in healthy individuals were shown to be negligible. When the clinical performance of the method was evaluated with serum samples from ACS patients, it was shown that the free PAPP-A concentration in the admission sample was an independent predictor of myocardial infarction and death. Moreover, as a prognostic marker, free PAPP-A was revealed to be superior to total PAPPA, i.e. the combination of free and complexed PAPP-A, which has been measured by the other groups in this field. As heparin products are widely used as medication in ACS patients, the effect of heparin products on free PAPP-A molecule and circulating concentrations were also investigated in this study. It was shown that intravenous administration of low molecular weight or unfractionated heparin elicits a rapid release of free PAPP-A into the circulation in haemodialysis patients and patients undergoing angiography. Moreover, the interaction between PAPP-A and heparin was confirmed in gel filtration studies. Importantly, the patients included in the clinical evaluation of the free PAPP-A detection method developed had not received any heparin product medication before the admission sample and thus the results were not affected by the heparin effect. In conclusion, free PAPP-A was identified as a novel marker associated with ACS. The point-of-care methods developed enable rapid detection of this molecule which predicts adverse outcome when measured in the admission sample of ACS patients. However, the effect revealed of heparin products on circulating PAPP-A concentrations should be acknowledged when further studies are conducted related to free or total PAPP-A in ACS.

PET and MR imaging in Parkinson’s disease patients with cognitive impairment. A study of dopaminergic dysfunction, amyloid deposition, cortical hypometabolism and brain atrophy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by a severe loss of substantia nigra dopaminergic neurons leading to dopamine depletion in the striatum. PD affects movement, producing motor symptoms such as rigidity, tremor and bradykinesia. Non-motor symptoms include autonomic dysfunction, neurobehavioral problems and cognitive impairment, which may lead to dementia. The pathophysiological basis of cognitive impairment and dementia in PD is unclear. The aim of this thesis was to study the pathophysiological basis of cognitive impairment and dementia in PD. We evaluated the relation between frontostriatal dopaminergic dysfunction and the cognitive symptoms in PD patients with [18F]Fdopa PET. We also combined [C]PIB and [¹⁸F]FDG PET and magnetic resonance imaging in PD patients with and without dementia. In addition, we analysed subregional striatal [¹⁸F]Fdopa PET data to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. The impaired dopaminergic function of the frontostriatal regions was related to the impairment in cognitive functions, such as memory and cognitive processing in PD patients. PD patients with dementia showed an impaired glucose metabolism but not amyloid deposition in the cortical brain regions, and the hypometabolism was associated with the degree of cognitive impairment. PD patients had atrophy, both in the prefrontal cortex and in the hippocampus, and the hippocampal atrophy was related to impaired memory. A single 15-min scan 75 min after a tracer injection seemed to be sufficient for separating patients with PD from healthy controls in a clinical research environment. In conclusion, the occurrence of cognitive impairment and dementia in PD seems to be multifactorial and relates to changes, such as reduced dopaminergic activity, hypometabolism, brain atrophy and rarely to amyloid accumulation.

Asleep or not asleep? Evaluation of the Quality of Patients’ Sleep in Critical Care Nursing

Sleep is important for the recovery of a critically ill patient, as lack of sleep is known to influence negatively a person’s cardiovascular system, mood, orientation, and metabolic and immune function and thus, it may prolong patients’ intensive care unit (ICU) and hospital stay. Intubated and mechanically ventilated patients suffer from fragmented and light sleep. However, it is not known well how non-intubated patients sleep. The evaluation of the patients’ sleep may be compromised by their fatigue and still position with no indication if they are asleep or not. The purpose of this study was to evaluate ICU patients’ sleep evaluation methods, the quality of non-intubated patients’ sleep, and the sleep evaluations performed by ICU nurses. The aims were to develop recommendations of patients’ sleep evaluation for ICU nurses and to provide a description of the quality of non-intubated patients’ sleep. The literature review of ICU patients’ sleep evaluation methods was extended to the end of 2014. The evaluation of the quality of patients’ sleep was conducted with four data: A) the nurses’ narrative documentations of the quality of patients’ sleep (n=114), B) the nurses’ sleep evaluations (n=21) with a structured observation instrument C) the patients’ self-evaluations (n=114) with the Richards-Campbell Sleep Questionnaire, and D) polysomnographic evaluations of the quality of patients’ sleep (n=21). The correspondence of data A with data C (collected 4–8/2011), and data B with data D (collected 5–8/2009) were analysed. Content analysis was used for the nurses’ documentations and statistical analyses for all the other data. The quality of non-intubated patients’ sleep varied between individuals. In many patients, sleep was light, awakenings were frequent, and the amount of sleep was insufficient as compared to sleep in healthy people. However, some patients were able to sleep well. The patients evaluated the quality of their sleep on average neither high nor low. Sleep depth was evaluated to be the worst and the speed of falling asleep the best aspect of sleep, on a scale 0 (poor sleep) to 100 (good sleep). Nursing care was mostly performed while the patients were awake, and thus the disturbing effect was low. The instruments available for nurses to evaluate the quality of patients’ sleep were limited and measured mainly the quantity of sleep. Nurses’ structured observatory evaluations of the quality of patients’ sleep were correct for approximately two thirds of the cases, and only regarding total sleep time. Nurses’ narrative documentations of the patients’ sleep corresponded with patients’ self-evaluations in just over half of the cases. However, nurses documented several dimensions of sleep that are not included in the present sleep evaluation instruments. They could be classified according to the components of the nursing process: needs assessment, sleep assessment, intervention, and effect of intervention. Valid, more comprehensive sleep evaluation methods for nurses are needed to evaluate, document, improve and study patients’ quality of sleep.

Effect of bariatric surgery on adipose tissue distribution in severely obese patients

Background and aim: Bariatric surgery leads to sustain weight loss, improve metabolic and lipids profiles and ultimately leads to remission of type 2 diabetes (T2DM) in some obese individuals. The aim of the project is to evaluate the effect of bariatric on abdominal fat distribution in severely obese T2DM and non-T2DM obese patients. Study design and methods: A total of 23 morbidly obese subjects (mean ± SD body mass index 43.0 ± 3.6 kg/m2, age 46.5 ± 9.0 years) were recruited from the lager multicenter SLEEVEPASS studies (ClinicalTrials.gov/NCT00793143). 10 healthy age-matched non-obese individuals served as controls. The obese patients were studied before and 6 months after surgery. At baseline, there were 9 T2DMs and 14 non-diabetics. After surgery, there were 5 remitters and 4 nonremitters. Whole body magnetic resonance imaging including the abdominal regions was performed for the obese subjects before and 6 months after surgery and for the controls once. Abdominal fat were compartmentalized and analyzed. Results: At 6 months of follow-up, BMI in the obese decreased significantly (from 43 ± 4 to 33 ± 2 kg/m2, p < 0.001) with substantial improvement in whole body insulin sensitivity (from 12.2 ± 5.7 to 23.3 ± 8.1 µmol/kg/min, p < 0.001). Intraperitoneal fat mass decreased by 46% (from 3.4 ± 1.1 to 1.9± 1.0 kg, p < 0.001) more than the rest of the compartments. Abdominal visceral compartments in obese correlated with glycemic status independent of surgery. Pre-surgery posterior deep and intraperitoneal fat mass were better predictors of post-surgery glycemic status in obese. Remitters showed significant improvement in whole body insulin sensitivity (from 9.1 ± 2.1 to 20.9 ± 8.4 µmol/kg/min, p = 0.02), fasting glucose decreased significant only in nonremitters (from 7.1 ± 1.1 to 6.0 ± 0.8 mmol/l, p = 0.05) after surgery. There were no differences in extraperitoneal fat mass in remitters and superficial subcutaneous fat in non-remitters but all other compartments decreased significantly 6 months after the surgery Conclusion: Both deep subcutaneous and visceral fat are important contributors to glycemic status in obese subjects. Whereas visceral fat compartments are directly involved in T2DM, superficial subcutaneous may have offered protection against T2DM in obese subjects.