Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting

When Efexor (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n = 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.     

Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting

The prescribing of selective serotonin reuptake inhibitors for adolescents is extensive despite the fact that there are few pharmacokinetic (PK), efficacy, safety, or tolerability studies on this group. This study reports the PK findings from two trials in adolescents treated with citalopram (CIT) in naturalistic clinical settings: one retrospective and one prospective. The aim of our study was to describe serum concentrations of CIT, desmethylcitalopram (DCIT), and didesmethylcitalopram (DDCIT) (trough values in steady state) in adolescents in relation to daily dose and clinical information obtained from therapeutic drug monitoring request forms. Altogether, 44 patients younger than 21 years were scrutinized using this combined open-label approach.The main findings were that (1) there was a pronounced interindividual variability of serum CIT, DCIT, and DDCIT concentrations in all doses prescribed, in agreement with previous studies on adults; on correcting for dose, the coefficient of variance was about 50% for CIT, DCIT, and DDCIT; (2) the transformation of CIT to DCIT and of DCIT to DDCIT was similar within the dose range 20 to 60 mg/day; (3) there was a difference between the sexes on comparing the dose-corrected concentrations of CIT and DCIT, with girls presenting significantly higher values than boys; and (4) there was a strong dose-serum concentration relationship in three identified subgroups of adolescents: (a) nonsmokers (CIT, r(2) = 0.71; DCIT, r(2) = 0.81), (b) girls not taking oral contraceptives (CIT, r(2) = 0.75; DCIT, r(2) = 0.71,), and (c) girls in the last 14 days of the menstrual cycle (CIT, r(2) = 0.68; DCIT, r(2) = 0.64).In summary, the present study tentatively supports influences of sex, oral contraceptives, and smoking habits on the disposition of CIT in younger patients. Hence, future studies on CIT should assess these parameters.     

Susceptibility factors and DNA adducts in peripheral blood mononuclear cells of aluminium smelter workers exposed to polycyclic aromatic hydrocarbons

Formation of DNA adducts as a result of exposure to polycyclic aromatic hydrocarbons (PAH) was studied in 98 potroom workers from an aluminium smelting plant and in 55 blue-collar workers without occupational PAH exposure. DNA from peripheral blood mononuclear cells (PBMC) was used for quantitation of individual PAH-DNA adducts by 32P-postlabelling/high performance liquid chromatography (HPLC) analysis. Four individual DNA adducts (denoted A, B, C and D) were quantified in 141 of a total of 153 subjects. Genetic polymorphisms for cytochrome P-4501A1 ( CYP1A1), microsomal epoxide hydrolase, N-acetyltransferase 2, glutathione transferases M1, P1 and T1 ( GSTM1, GSTP1 and GSTT1, respectively) and NAD(P)H: quinone oxidoreductase 1 (NQO1) were analysed. For 52 subjects, analysis of mRNA inducibility of CYP1A1 was performed. No statistically significant differences in the levels of total or individual DNA adducts A, C and D were found between potroom workers and control subjects. All potroom workers and the subgroup of potroom workers who reported to never/sometimes use personal respiratory protection ( n=72) were found to have a significantly higher likelihood of having high levels of adduct B than control subjects [odds ratio (OR) =3.4 with 95% confidence interval (CI) of 1.3-9.2, and OR=4.2 with 95% CI 1.6-11.5, respectively]. In the subgroup, levels of adducts A and B were found to be significantly higher among workers with employment time of less than 6 months ( n=5). Also, the levels of the individual DNA adducts were to some extent modified by genetic polymorphisms in CYP1A1, GSTM1, GSTP1 and NQO1 and by CYP1A1 inducibility. In conclusion, levels of adduct B, identified by 32P-postlabelling/HPLC methodology as an indicator of PAH exposure in aluminium production, were modified by the use of respiratory protection, length of employment and genetic polymorphisms.     

Control of reaching movements in children and young adults with myelomeningocele

The aim of the present study was to analyze the ability to programme and execute reaching movements in individuals with myelomeningocele (MMC) and in a control group. Thirty-one participants (18 males, 13 females; mean age 12 years 11 months, SD 2 years 7 months, range 9 to 19 years) with MMC and 31 participants (matched for age and sex) without disabilities were investigated. Reaching was performed with and without visual feedback toward three targets displayed on a computer screen and data were collected using a digitizing tablet linked to a computer. The kinematics of reaching were analyzed and analysis of variance was used for statistical analysis. Results showed that both groups were able to programme reaching movements under both visual conditions. Although the execution of reaching was poor in the MMC group compared with the control individuals, as indicated by larger end-point errors (p=0.002), less straight movements (p=0.018), and shorter deceleration phases (p=0.004), movement time was not prolonged in the MMC group. Those with shunt treatment (n=21) had more difficulties when visual feedback was provided. Those with symptoms of early brainstem dysfunction (n=5) had shorter deceleration phases under both visual conditions.     

The Swedish version of the PACU‐Behavioural Pain Rating Scale: a reliable method of assessing postoperative pain?

One of the obstacles to effective pain management in the Post-Anaesthesia Care Unit (PACU) is the lack of systematic and comprehensive methods for assessing and treating postoperative pain. Nurses' intuitive knowledge of pain were verbalized and divided into four categories of pain behaviours in the PACU-Behavioural Pain Rating Scale. The aim of the present study was to test the reliability of the Swedish version by performing test-retest and interrater reliability in clinical conditions. Materials for this study were gathered through patient observations. The results showed poor agreement in the item restless, fair agreements in both items tense muscles and frowning and grimacing, while patients' sounds showed moderate agreement. Interrater reliability showed moderate agreement in the item restless, very good agreement in tense muscles and patient sounds, and good agreement in frowning and grimacing. A refined classification of the separate categories and a careful review of the category of behaviours is suggested. A more detailed manual for the categories needs to be developed to establish more acceptable reliability.     

Problems experienced during the first year of an acute traumatic hand injury - a prospective study

Background. Evidence‐based nursing of patients with acute traumatic hand injuries treated at the hand‐surgical clinic calls for knowledge about long‐term implications. Aims and objectives. The aim of the study was to investigate consequences of an acute traumatic hand injury during the first year after the accident. Specifically, the objectives were to investigate changes in the experience of physical and psychological problems over time, frequencies of remaining problems and the impact of the injury on work situation and life situation 1 year after the accident. Design. The study was prospective and followed the patients from the first weeks to 1 year after the accident. Method. Ninety‐one patients were assessed three times during the year. Each time the patients answered study‐specific questions, the Impact of Event Scale and the Hospital Anxiety and Depression Scale. Results. Problems experienced decreased during the first 3 months but tended to remain unchanged during the rest of the year. In the 1‐year follow‐up, the majority of the patients experienced slight or moderate functional limitations in the hand, one‐third had symptoms of trauma‐related distress and one out of seven had troublesome pain. Half of the patients who had returned to work reported a worse work situation and 16% were still on the sick list. One‐third of all patients considered their whole life situation to be worse as a result of the injury. Patients with amputations more often experienced a worse life situation. Blue‐collar workers reported functional limitations and a worse life situation more often than white‐collar workers. Conclusions. Patients with acute traumatic hand injuries requiring surgical treatment may experience problems, such as functional limitations, trauma‐related distress and troublesome pain, with long‐term implications for their work situation and life situation. Relevance to clinical practice. Caring for hand‐injured patients should include, not only surgical treatment and other actions for restoring the function of the hand, but also preventive action and follow‐up of trauma‐related distress and pain.     

Time-lapse recordings of human corneal epithelial healing

PURPOSE: The aim of this study was to design an experimental set-up for the study of human corneal epithelial wound healing in a controlled in vitro situation. METHODS: A time-lapse set-up was used. This allowed for pictures to be captured with a magnification ranging from x 80 to x 1800. Pictures were captured at 1-min intervals during the observation period, which lasted up to 4 days. Human corneal tissue was obtained from the Eye Bank or from surgery. A small, rounded lesion was produced in the corneal epithelium with a miniature drill. The specimens were placed in a mini-incubator; the camera focused on the epithelial lesion and continuously observed using the time-lapse set-up. RESULTS: The healing process of human corneal epithelium could be followed for several days. The initial healing response could be divided into a slow, a rapid and a consolidating phase. The first two phases lasted about 12 hours, and by then, epithelial cells covered the lesion. Depending on the origin of the tissue and the placement of the lesion, variations in the healing response could be seen. CONCLUSION: The time-lapse technique makes it possible to study epithelial wound healing over time at the cellular level. Data collected in this way can fill the gap between in vivo studies, where, by nature, human wound healing studies are restricted, and cell culture techniques, where cellular responses in many cases differ from the in vivo situation.