Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase the absorption of perphenazine in rabbits

Objectives The sublingual administration route as well as solid dispersion formation with macrogol 8000 and complexation with β‐cyclodextrin (β‐CyD) were investigated as ways for improving the absorption of perphenazine, a poorly water‐soluble drug subjected to substantial first‐pass metabolism. Methods The absorption of perphenazine was studied in rabbits after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/β‐CyD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze‐drying (perphenazine/macrogol solid dispersion) or spray‐drying (perphenazine/β‐CyD complex). Key findings The value for area under the curve from 0 to 360 min (AUC_{0–360 min}) of perphenazine after peroral administration was only 8% of the AUC_{0–360 min} value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/β‐CyD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first‐pass metabolism; good sublingual absorption of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations. Conclusions With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo.     

Experimental and computational analysis of soft tissue stiffness in forearm using a manual indentation device

A hand held stiffness meter can be used to measure indentation stiffness of human soft tissues, sensitively altered, e.g., by pathological tissue swelling. Under indentation load, the relative contribution of each soft tissue component (i.e., skin, adipose tissue and muscle) to the biomechanical response is not known. In the present study, we evaluated the biomechanical role of different soft tissues in relaxed, physically stressed and oedemic human forearm. Soft tissue stiffness of the forearms of nine healthy human subjects was measured under four different test protocols: (1) forearm at rest, (2) forearm under isometric flexor loading, (3) forearm under isometric extensor loading, and (4) forearm under venous occlusion. In (2) and (3) the loading forces were monitored using a dynamometer, and in (4) the soft tissue swelling was induced by venous occlusion using a pressure cuff. At the site of indentation, thickness of different tissue layers (skin, adipose tissue and muscle) was measured using B-mode ultrasound imaging. Layered, hyperelastic finite element (FE) model of the indentation measurement was created and the model response was matched with that of the stiffness meter to determine the elastic modulus for each tissue in the model. Optimized values of the elastic modulus for skin and adipose tissue at rest were 210 kPa and 1.9 kPa, respectively. Further, significance of the variations in stiffness of different tissues on the indentation response was tested. Experimentally, indentation stiffness of the forearm increased during isometric extensor and flexor loads as well as under venous occlusion by 53, 91 and 15%, respectively. The FE model could reproduce the experimental responses primarily by the increased modulus of skin; 112% (446 kPa), 210% (651 kPa) and 21% (254 kPa) under flexor and extensor loading as well as during venous occlusion, respectively. The indentation response was 9–16 times more sensitive to changes in the mechanical properties of skin than those of adipose tissue and muscle. In conclusion, the present stiffness meter may be used to quantify in vivo mechanical properties of soft tissues in the forearm, sensitively modulated by soft tissue swelling and muscle loading.     

GSM mobile phone radiation suppresses brain glucose metabolism

We investigated the effects of mobile phone radiation on cerebral glucose metabolism using high-resolution positron emission tomography (PET) with the (18)F-deoxyglucose (FDG) tracer. A long half-life (109 minutes) of the (18)F isotope allowed a long, natural exposure condition outside the PET scanner. Thirteen young right-handed male subjects were exposed to a pulse-modulated 902.4 MHz Global System for Mobile Communications signal for 33 minutes, while performing a simple visual vigilance task. Temperature was also measured in the head region (forehead, eyes, cheeks, ear canals) during exposure. (18)F-deoxyglucose PET images acquired after the exposure showed that relative cerebral metabolic rate of glucose was significantly reduced in the temporoparietal junction and anterior temporal lobe of the right hemisphere ipsilateral to the exposure. Temperature rise was also observed on the exposed side of the head, but the magnitude was very small. The exposure did not affect task performance (reaction time, error rate). Our results show that short-term mobile phone exposure can locally suppress brain energy metabolism in humans.     

Effects of growth and exercise on composition, structural maturation and appearance of osteoarthritis in articular cartilage of hamsters

Articular cartilage composition and structure are maintained and remodeled by chondrocytes under the influence of loading. Exercise‐induced changes in the composition, structure, mechanical properties and tissue integrity of growing and aging hamster articular cartilage were investigated. Articular cartilage samples (n = 191) were harvested from the proximal tibiae of hamsters aged 1, 3, 6, 12 and 15 months. The hamsters were divided into runners and controls. The runners had free access to a running wheel between 1 and 3 months (runner groups 3‐, 12‐ and 15‐month‐old hamsters) or 1 and 6 months (runner group 6‐month‐old hamsters) of age. Control animals were subjected to a sedentary lifestyle. Mechanical indentation tests and depth‐wise compositional and structural analyses were performed for the cartilage samples. Furthermore, the integrity of articular cartilage was assessed using histological osteoarthritis grading. Exercise affected the collagen network organization after a 5‐month exercise period, especially in the middle and deep zones. However, no effect on the mechanical properties was detected after exercise. Before the age of 12 months, the runners showed less osteoarthritis than the controls, whereas at 15 months of age the situation was reversed. It is concluded that, in hamsters, physical exercise at a young age enhances cartilage maturation and alters the depth‐wise cartilage structure and composition. This may be considered beneficial. However, exercise at a young age demonstrated adverse effects on cartilage at a later age with a significant increase in the incidence of osteoarthritis.     

Crying behaviour in early infancy is associated with developmental outcome at two years of age in very low birth weight infants

AIM: To evaluate the association between infant fussing and crying and developmental outcome in very low birth weight (VLBW) infants. METHODS: Hundred and seventeen VLBW infants were followed up to 24 months of corrected age. The duration of fussing and crying and frequency of fuss/cry bouts were measured at term 6 weeks and 5 months of corrected age. Cognitive and motor development was assessed at 24 months of corrected age. RESULTS: The increased duration of combined fuss/cry at term associated with lower psychomotor developmental index (PDI), [regression coefficient (b)=-0.83, p=0.025]. Crying at term associated negatively with mental developmental index (MDI) (b=-0.91, p=0.040) and PDI (b=-1.10, p=0.015). The associations between fuss/cry and PDI, and crying and PDI persisted in multiple regression analysis (b=-0.89, p=0.030 and b=-1.23, p=0.018, respectively). Excessive fuss/cry (>or=180 min/day) at term associated with lower PDI (p=0.005) and at 6 weeks with lower MDI (p=0.024) and PDI (p=0.012). Increase in the frequency of fuss/cry bouts at 5 months associated with higher PDI in both simple (b=2.90, p=0.045) and in multiple regression analysis (b=3.60, p=0.019). CONCLUSIONS: In VLBW infants, longer duration of fussing and crying in very early infancy, but not at 5 months, is associated with less optimal development at 24 months of age.     

Mother-infant interaction is influenced by the amount of holding in preterm infants

OBJECTIVES: The aim of this study was to evaluate associations between infant crying, holding and mother-infant interaction. METHODS: The study groups included 30 firstborn Finnish preterm infants (<1501 g or <32 weeks), and their 36 full-term controls. Caregiver's holding and infant's crying behavior was assessed using Baby Day Diary at 5 months of corrected age. The quality of mother-infant interaction was assessed using PC-ERA at 6 and 12 months of corrected age. RESULTS: The results showed that longer duration of holding in home environment was associated with better quality of mother-infant interaction at 6 and 12 months of corrected age in preterm infants. Preterm infants cried more often and were held more than full-term infants. The frequency of crying was associated with the duration of holding in preterm infants. Mother-infant interaction was comparable between the groups of preterm and full-term infants. CONCLUSIONS: Our results underline the importance of caregiver's physical closeness for the quality of the mother-infant interaction in preterm infants. Prematurity itself does not necessary affect the quality of mother-infants interaction in a non-risk population.     

Dissolved organic matter modulating the uptake, biotransformation, and elimination rates of pyrene in Daphnia magna

In the current study, the toxicokinetics of pyrene in Daphnia magna was determined in detail, and the role of dissolved organic matter (DOM) in these processes was investigated. Uptake, biotransformation, parent compound and metabolite elimination rates (k(u), k(m), k(ep), k(em)), depuration rates, bioconcentration factors (BCFs), and biological half-lives were studied in one natural humic water, in two waters made from DOM isolates, and in DOM-free artificial fresh water. The daphnids were exposed to pyrene for 24 h and depurated for another 24 h. To analyze the data, the two-compartment model was used to obtain toxicokinetic parameters, and the depuration data were analyzed by linear regression. Extensive biotransformation of pyrene resulted in high metabolite concentration in the organisms (83% of total radioactivity) after 24 h exposure. Depuration of the parent compound seemed to be biphasic: at first, depuration was rapid, but after 4 to 10 h in uncontaminated water, the disappearance rate came close to zero. After a 24-h depuration time, 7.8% of the pyrene accumulated remained in the organism. Overall, the elimination of parent compound was faster than the elimination of metabolites, which might imply inefficient excretion of water-soluble biotransformation products from daphnids. The effect of DOM on accumulation of pyrene was seen in a decreased uptake rate, indicating lower bioavailability of the compound in waters that contain high-aromaticity DOM. In the same waters, DOM significantly accelerated pyrene biotransformation and overall elimination. Altogether, DOM appears to be able to affect toxicokinetics through mechanisms that are connected to interaction with the contaminant but also directly through interaction with biotransformation systems.     

The incidence of knee arthroplasty for primary osteoarthritis grows rapidly among baby boomers: A population‐based study in Finland

Objective

Total knee arthroplasty (TKA) is a commonly used treatment for severe primary knee osteoarthritis (OA) that is refractory to conservative treatment. Despite the presumed increase in the use of this treatment modality in younger patients, there are few published data concerning this. The aim of our study was to examine the changes in the age‐ and sex‐standardized incidence of TKA and unicondylar knee arthroplasty (UKA) in Finland during 1980–2006 and to identify factors that might affect the incidence during this period.

Methods

We obtained data on UKAs and TKAs from the Finnish Arthroplasty Registry and population data from Statistics Finland to analyze the incidence of UKAs and TKAs in Finland for the period 1980–2006. The effects of sex, age group, and hospital volume on the incidence of these procedures were also evaluated.

Results

The annual cumulative incidence of UKAs and TKAs has increased rapidly from 1980 to 2006 among 30–59‐year‐old inhabitants of Finland. For UKAs, the incidence increased from 0.2 per 100,000 inhabitants to 10 per 100,000, and for TKAs, the incidence increased from 0.5 per 100,000 to 65 per 100,000. The incidence remained higher among women during the entire study period. Most of the increase occurred among patients ages 50–59 years. The incidence grew more rapidly in low‐volume and intermediate‐volume hospitals.

Conclusion

We demonstrated a rapid increase in the incidence of arthroplasty among patients with primary knee OA in Finland, especially in those ages 50–59 years. There was no single explanatory factor behind this finding, although some of the growth might be due to the increased incidence noted in low‐ and intermediate‐volume hospitals.