Development of the Lie-to-Sit-to-Stand-to-Walk Transfer (LSSWT) test for early mobilization in older patients in geriatric rehabilitation

Background

Early discharge from a rehabilitation center is only possible, if patients are able to do basic transfers independently (e.g., get up from bed and walk to the toilet). Against this background, the Lie-to-Sit-to-Stand-to-Walk Transfer (LSSWT) test was developed in order to quantify complex transfer abilities in older adults. This study was to evaluate the reliability and validity of this instrument.

Material and methods

A total of 24?older patients (80.25±8.10?years) of a geriatric rehabilitation unit performed the LSSWT test. Expert ratings were used to measure criterion validity. The Timed Up &; Go test (TUG) was administered to assess construct validity. Furthermore, the time score of the LSSWT test was correlated with the Trunk Control Test (TCT), balance performance, the Chair Stand Test (CST) and gait speed. Intra- and interrater reliability were measured, conducting the LSSWT test on consecutive days.

Results

The coefficients of correlation between the LSSWT test and the expert ratings as well as the TUG test were r=?0.82 and r=0.83, respectively. Furthermore, the association with the TCT, balance, CST, and gait speed were r=?0.51, r=?0.45, r=0.47, and r=?0.72, respectively. The results of intrarater reliability and interrater reliability were ICC=0.96 and ICC=0.77, respectively.

Conclusion

The study shows that the LSSWT test is a valid measure for quantifying difficulties in transfer abilities of patients during geriatric rehabilitation. The good correlation between LSSWT test and TUG test indicates good construct validity, but also that the LSSWT test provides additional information. Interrater reliability was moderate; therefore, the training of the supervisors should be re-evaluated. Further research is needed to establish cut-off values for discharge decision and to analyze the use of the LSSWT test in different subgroups.     

Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic�Cpharmacodynamic analysis from the IELSG no. 20 trial

Background:

This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC_HD-MTX) in patients with primary central nervous system lymphoma (PCNSL).

Patients and methods:

We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUC_HD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling.

Results:

AUC_HD-MTX, the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC_HD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC_HD-MTX was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUC_HD-MTX and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 μmol l⁻¹ h⁻¹ increase in AUC_HD-MTX.

Conclusions:

Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis.     

The reaction of dental tissues to magnetic fields*

ABSTRACT The effects of cobalt samarium magnets on the dental tissues of dogs has been examined. After an exposure period of six months there was no evidence, clinically or microscopically, of tissue damage.     

Quantitative analysis of glycation sites on human serum albumin using 16O/18O-labeling and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

BackgroundOne of the long term complications of diabetes is the non-enzymatic addition of glucose to proteins in blood, such as human serum albumin (HSA), which leads to the formation of an Amadori product and advanced glycation end products (AGEs). This study uses ¹⁶O/¹⁸O-labeling and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to provide quantitative data on the extent of modification that occurs in the presence of glucose at various regions in the structure of minimally glycated HSA.MethodsNormal HSA, with no significant levels of glycation, was digested by various proteolytic enzymes in the presence of water, while a similar sample containing in vitro glycated HSA was digested in ¹⁸O-enriched water. These samples were then mixed and the ¹⁶O/¹⁸O ratios were measured for peptides in each digest. The values obtained for the ¹⁶O/¹⁸O ratios of the detected peptides for the mixed sample were used to determine the degree of modification that occurred in various regions of glycated HSA.ResultsPeptides containing arginines 114, 81, or 218 and lysines 413, 432, 159, 212, or 323 were found to have ¹⁶O/¹⁸O ratios greater than a cut off value of 2.0 (i.e., a cut off value based on results noted when using only normal HSA as a reference). A qualitative comparison of the ¹⁶O- and ¹⁸O-labeled digests indicated that lysines 525 and 439 also had significant degrees of modification. The modifications that occurred at these sites were variations of fructosyl–lysine and AGEs which included 1-alkyl-2-formyl-3,4-glycoyl-pyrole and pyrraline.ConclusionsPeptides containing arginine 218 and lysines 212, 413, 432, and 439 contained high levels of modification and are also present near the major drug binding sites on HSA. This result is clinically relevant because it suggests the glycation of HSA may alter its ability to bind various drugs and small solutes in blood.     

Prevention of docetaxel- or paclitaxel-associated taste alterations in cancer patients with oral glutamine: a randomized, placebo-controlled, double-blind study

Taste alteration (dysgeusia), an underrecognized toxicity associated with taxane-based chemotherapy (TaxCh), lacks standard treatment. We investigated prevention of dysgeusia with oral glutamine in patients undergoing first-time TaxCh. Adult patients were randomized to receive either 30 g/day glutamine or placebo (maltodextrin) from day 1 of TaxCh. Dysgeusia was measured daily with a visual analogue scale (VAS). On each chemotherapy cycle, objective (sour, sweet, salty, bitter) and subjective (four-category scale) taste and toxicity (National Cancer Institute Common Toxicity Criteria, v.3) were assessed. Stomatitis and zinc deficiency were treated. For primary outcomes, repeated dysgeusia scores were analyzed with a linear mixed model. Repeated data on each objective or subjective taste item were analyzed with a generalized estimating equation. Of 52 patients randomized, 41 completed treatment (median study duration, 74 days). At baseline, the glutamine (n = 21) and placebo (n = 20) groups were comparable for age (64 years), gender (32% men), tumor types, chemotherapy (docetaxel, 44%; paclitaxel, 56%), schedule (weekly, 78%; 3-weekly, 22%), treatment intention (15% adjuvant), dysgeusia (VAS, 11/100), and taste recognition (88%). Twenty-four patients had peripheral neuropathy grades 1-2; none had grade 3. Glutamine and placebo were not different for maximal dysgeusia and increase from baseline, with an insignificant linear time effect. Separate subgroup analyses for patients with baseline dysgeusia < or =11 or >11 did not alter the results. Objective or subjective taste tests were not different, neither were adverse events. Compared with placebo, oral glutamine did not prevent or decrease subjective taste disturbances or altered taste perception associated with TaxCh. The role of glutamine in supportive care of taxane-associated dysgeusia seems limited.     

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

Twenty-one adult patients were randomised to receive ghrelin on days 1 and 8 and placebo on days 4 and 11 or vice versa, given intravenously over a 60-min period before lunch: 10 received 2 microg kg(-1) (lower-dose) ghrelin; 11 received 8 microg kg(-1) (upper-dose) ghrelin. Active and total ghrelin, growth hormone (GH), and insulin-like growth factor 1 levels were monitored at baseline (4-5 days before day 1), during treatment days, and at end of study (day 17/18). Drug-related adverse events (assessed by NCI-CTC-toxicity criteria and cardiac examination) did not differ between ghrelin and placebo. No grade 3/4 toxicity or stimulation of tumour growth was observed. The peak increase of GH, a biological marker of ghrelin action, was 25 ng ml(-1) with lower-dose and 42 ng ml(-1) with upper-dose ghrelin. Morning fasting total ghrelin levels were higher (P<0.05) for upper-dose patients at end of study (3580 pg ml(-1)) than at baseline (990 pg ml(-1)). Insulin-like growth factor 1 levels did not change. At day 8, 81% of patients preferred ghrelin to placebo as against 63% at the end of study. Nutritional intake and eating-related symptoms, measured to explore preliminary efficacy, did not differ between ghrelin and placebo. Ghrelin is well tolerated and safe in patients with advanced cancer. For safety, tolerance, and patients' preference for treatment, no difference was observed between the lower- and upper-dose group.     

pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n =6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC_0–48h of 6.5 μg.h/mL and coefficient of variation (CV) of 116%) and much higher T_max, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC_0–48h of 27.1 μg.h/mL versus 17.7 μg.h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.     

Pharmacokinetics of 2-chloro-2′-deoxyadenosine administered subcutaneously or by continuous intravenous infusion

Purpose: Cladribine (2-chlorodeoxyadenosine, 2-CDA) is effective in the treatment of various lymphoproliferative disorders. In the standard protocol the compound is administered by continuous intravenous (i.v.) infusion. In order to allow outpatient therapy alternative modes of administration such as subcutaneous (s.c.) injection would be desirable. The aim of the present study was to compare the pharmacokinetics of 2-CDA after i.v. and s.c. administration. Patients and methods: Nine patients received 0.1 mg/kg 2-CDA per 24 h on one occasion by continuous i.v. infusion and on another occasion as a bolus subcutaneously. The concentrations of 2-CDA in the plasma and urine were determined by HPLC. Results: During i.v. infusion the concentration of 2-CDA in the plasma reached a plateau after 4–8 h, whereas with s.c. administration almost ten times higher peak concentrations were reached within 20 to 60 min. A two-compartment model was fitted to the data points whereby the goodness-of-fit statistics showed R ² values of >0.98. The calculated rate of elimination, k_elim, averaged 0.336 h⁻¹ with s.c. and 0.397 h⁻¹ with i.v. administration. The estimated volumes of distribution were 1.67 and 1.58 l/kg. The areas under the concentration time curves (608 ± 65 pmol · h/ml after s.c. administration vs 571 ± 50 pmol · h/ml during i.v. infusion) and the urinary excretion of 2-CDA in 24 h (4.75 ± 0.95 vs 3.55 ± 0.53 μmol/24 h) were similar in both groups, indicating identical bioavailability. Conclusions: Although the pharmacokinetic profile of 2-CDA administered s.c. differs substantially from the profile of a continuous i.v. infusion the areas under the plasma concentration time curves, the urinary excretion of unchanged drug and the estimated pharmacokinetic variables were similar with both modes of administration, indicating that the different time-courses of the plasma concentration did not influence the fraction metabolized or eliminated. Received: 3 November 1999 / Accepted: 3 March 2000     

Relationships among cell survival, O6-alkylguanine-DNA alkyltransferase activity, and reactivation of methylated adenovirus 5 and herpes simplex virus type 1 in human melanoma cell lines

O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea. These differences may be related to the effects observed with MTIC. A wide range of ATase activities was found in human melanoma biopsy material.