Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV''s induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.     

Disability and quality of life in individuals with postpolio syndrome

Purpose : The purpose of the study is to investigate disability and quality of life in individuals with the characteristic symptoms of postpolio syndrome. Method : Disability is assessed by means of the self-report activities of daily living instrument, and quality of life by means of Kaasa's questionnaire and the quality of life profile. Results : The 39 subjects have on average lived with polio sequelae for 52 years. Their main difficulties are with moving, lifting and carrying. This means restricted mobility, sedentary activities and a need to prioritize. Half of them feel that polio has lessened their possibilities in life, and a quarter have still not accepted the limitations polio has involved. Nevertheless the majority report a high level of psychosocial well-being, and almost a quarter say that living with polio has meant personal development and strength. We found a significant correlation between on the one hand disability with regard to ambulation, arm strength and finger strength on the self-report ADL, and on the other hand the number of negative problems on the quality of life profile (0.33-0.45). Conclusion : The latter instrument needs further testing before its validity can be determined with certainty.     

Thyrotropin modulates EGF receptor function in porcine thyroid follicle cells

Porcine thyroid follicle cells in monolayer cultures were shown to contain one single class of high-affinity EGF receptors with Kd = 4.5 X 10(-10) M and approximately 20 000-25 000 receptors per cell. Suspension cultures of aggregated follicle cells, exposed to TSH for 3 days, showed a 3-fold increase in [125I]EGF binding. Scatchard analysis demonstrated that this was due to an increase in receptor number. Other cAMP-elevating agents (cholera toxin, dibutyryl cAMP, forskolin) induced a similar effect. In suspension cultures, preincubation with TSH or cholera toxin for 2 days reduced the subsequent [3H]thymidine incorporation. This inhibition was overcome by a low concentration of EGF (0.1 ng/ml). At higher concentrations of EGF (1-10 ng/ml) the incorporation of [3H]thymidine was potentiated 2-3-fold in cultures preexposed to TSH or cholera toxin. The results demonstrate the presence of a high-affinity EGF receptor in porcine thyroid follicle cells. Receptor expression, as well as responsiveness to the mitogenic action of EGF, is modulated in vitro by TSH, through a cAMP-dependent process.     

I-labelling of an internally Se-labelled monoclonal antibody—Biodistribution in tumour-bearing nude mice

A monoclonal antibody, C215, was first internally labelled with ⁷⁵Se-methionine and then labelled with ¹²⁵I. The biodistribution of the dual-labelled [¹²⁵I][⁷⁵Se]C215 was studied in tumour-bearing nude mice killed 3 days after injection. The biodistribution of the dual-labelled [¹²⁵I][⁷⁵Se]C215 was compared with the biodistribution of single-labelled [¹³¹I]C215 and [⁷⁵Se]C215. Iodine-labelled antibodies seem to be damaged during iodination, affecting the disappearance rate and tumour uptake. There were no signs of dehalogenation of circulating antibodies or antibodies taken up in the tumour.     

Closing patellar tendon defects after anterior cruciate ligament reconstruction: absence of any benefit

The most common graft in anterior cruciate ligament (ACL) surgery involves using the central one-third of the patellar tendon. Knowledge concerning the postoperative disability after harvesting the patellar tendon is, however, limited. The aim of this study was to evaluate the impact patellar tendon suture and bone grafting of the patellar bone defect might have in terms of functional outcome and patellofemoral pain after harvesting the bone-tendon-bone graft, compared with leaving the harvested site non-sutured and non-grafted. Sixty patients, scheduled for arthroscopically assisted ACL reconstruction, were randomly allocated to two groups. In group I, suture of the patellar tendon and bone grafting of the patellar defect were performed. In group II, the tendon gap and the patellar defect were left open. Preoperatively, there was no significant difference between the groups when comparing objective knee stability, as measured with a KT-1000 laxity meter, Lysholm score, Tegner activity level, IKDC score, or patellofemoral pain score. Both groups had a significantly improved Lysholm score at the 2-year follow-up, without any difference between them. Tegner's activity level was significantly lower at follow-up, compared with the pre-injury level in both groups. The patellofemoral pain score improved significantly after the reconstruction, without any difference between the groups. Ultrasonography did not reveal any difference between the groups in terms of healing of the tendon gap. This study revealed no differences in donor site morbidity, functional outcome, patellofemoral pain score or knee joint stability between the two treatment groups. The conclusion is that suture of the patellar tendon and bone grafting of the patellar defect do not improve the functional results or reduce donor site morbidity after arthroscopically assisted ACL. Received: 17 December 1996 Accepted: 30 July 1997     

Long-Term Morbidity and Mortality After a Clinically Diagnosed Vertebral Fracture in the Elderly—a 12- and 22-Year Follow-up of 257 Patients

The objective of this study was to analyze the long-term morbidity and mortality in patients with a clinically diagnosed vertebral fracture. Seventy men with a mean age of 70 years (range 50–91 years) and 187 women with a mean age of 72 years (range 50–96 years) were radiographically diagnosed as having a vertebral fracture in the thoracic or lumbar spine at the Malmö University Hospital (Sweden) during 1979. At the time of a follow-up examination 12 years later, 56 of the 76 patients who were still alive participated in an investigation that evaluated back pain and subjective health status by a questionnaire. Forty-four of these subjects also participated in a further radiologic examination of the spine. Serving as controls were age- and gender-matched subjects from the Malmö cohort of the European Vertebral Osteoporosis Study (EVOS). A mortality analysis was also conducted, covering 22 years following the baseline fracture. There were more female patients, who, in comparison with the controls, 12 years after the diagnosis, had had back pain during the year preceding the follow-up (72% vs 33%, P < 0.001), had current back pain (42% vs. 19%, P = 0.006), and had a subjectively impaired health status (44% vs. 17%, P < 0.001). The corresponding differences in men reached only a borderline significance, for both back pain during the year preceding the follow-up (60% vs. 28%, P = 0.07) and current back pain (40% vs. 15%, P = 0.09), whereas there was no difference in subjective health status. The incidence of new vertebral fractures in individuals with a clinically diagnosed vertebral fracture during the following 12 years was in men 25 per 1,000 person-years and in women 49 per 1000 person-years. There were more women with a new vertebral fracture at the 12-year follow-up examination who, in comparison with women without a new fracture, had had back pain during the year preceding the follow-up examination (90% vs. 50%, age-adjusted P = 0.02) and had current back pain (65% vs. 21%, age-adjusted P = 0.03). Women with a new vertebral fracture at the 12-year follow-up examination had a higher subsequent mortality rate in the next 10 years [age-adjusted hazard ratio 2.8 (95% CI 1.0–7.9)] as compared with women without. The mortality rate during the 22 years following the diagnosis among the male patients was 111.7 per 1,000 person-years as compared with 73.4 per 1,000 person-years among the male population at risk. The mortality rate among the female patients was 95.1 per 1,000 person-years as compared with 62.0 per 1,000 person-years among the female population at risk. We conclude that a clinically diagnosed thoracic or lumbar vertebral fracture in the elderly can be regarded as a risk factor for subsequent, long-term morbidity, especially in women, and for mortality in both genders.