Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy

The skin retention and penetration characteristics of copper applied as glycyl-l-histidyl-l-lysine cuprate diacetate were evaluated in vitro in order to assess the potential for its transdermal delivery as anti-inflammatory agent. Flow-through diffusion cells with 1 cm2 exposure area were used under infinite dose conditions. 0.68% aq. Copper as a tripeptide was applied on isolated stratum corneum, on heat-separated epidermis and on dermatomed skin. Receptor fluid collected over 48 h in 4 h intervals was analyzed by inductively coupled plasma mass spectrometry for copper in tissues and receptor fluid. The permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10−4 cm/h; 136.2 ± 17.5 μg/cm2 copper permeated 1 cm2 of that tissue over 48 h, while 82 ± 8.1 μg/cm2 of copper were retained there as depot. Applied tansdermally as the tripeptide on human skin ex vivo, copper permeated the skin and was also retained in skin tissue in amounts potentially effective for the treatment of inflammatory diseases

New developments in the methodology available for the assessment of topical corticosteroid-induced skin blanching

Since the publication of the previous edition of this book there have been considerable developments and controversy in the field of topical corticosteroid bioequivalence assessment. There has been considerable discussion in the literature concerning the use of the Minolta chromameter for the measurement of corticosteroid-induced skin blanching, as it is believed this instrument would produce more objective results than the visual grading procedure. These efforts culminated in the release of a guidance document from the Food and Drug Administration (FDA) detailing the procedures to be followed for the determination of topical corticosteroid bioequivalence using the chromameter. Since the promulgation of this document there have been challenges on the validity and scientific merit of the documented procedures, and recently the FDA itself conceded that it may be necessary to redefine some of the protocol evaluations. This chapter attempts to redefine the current standing of the two methods of response assessment

Skin Permeability In Vivo: Comparison in Rat, Rabbit, Pig and Man

A comparative study was undertaken in rats, rabbits, miniature swine and man, in which the percutaneous absorption of the following compounds, labeled with 14C or 35S, were studied: haloprogin, N-acetylcysteine, cortisone, testosterone, caffeine and butter yellow. The amount of radioactivity excreted in urine for 5 days following application of the test compound to the skin was employed as the index for quantifying skin penetration. A special nonocclusive foam pad device for rabbits and miniature swine was developed to prevent artifacts resulting from transfer of drug to the urine by any route other than percutaneous absorption. The dose was 4 μg/cm2 of skin surface. The excretion data obtained from the topical studies were adjusted for recovery of radioactivity following intravenous administration of the radioactive drug. The results obtained in this study indicated that skin permeability decreases in the following order: rabbit, rat, pig and man. Overall, skin of miniature swine has the closest permeability characteristics to that of human skin with this series of compounds

Quality of life as subjective experience: Reframing of perception in patients with colon cancer undergoing radical resection with or without adjuvant chemotherapy

Purpose and background: We examined whether patients with colon cancer undergoing surgery with or without adjuvant chemotherapy change the internal standards on which they base their quality-of-life (QL) estimation, and, if they do so, whether this reframing alters interpretation of QL findings. These questions were addressed within a randomized clinical trial of the Swiss Group for Clinical Cancer Research (SAKK 40/93). Patients and methods: After radical resection of adenocar-cinoma of the colon (pT1-4pN>0M0 and pT3-4pN0M0) and perioperative chemotherapy, patients were randomized to three treatment arms: observation only (A), 5-FU 450 rag/m2plus Levamisol (B), or 5-FU 600 mg/m2 (C). QL was measured by linear analogue self-assessment indicators. Patients estimated their pre-surgery QL both before surgery and retrospectively thereafter, and their pre-adjuvant QL both at the beginning of randomly assigned chemotherapy or observation and retrospectively about two months later. Thereafter, current QL was assessed. Paired t-tests were used to test the hypotheses of no change. Results: Overall, 187 patients with at least one pair of corresponding questionnaires were analyzed. Patients estimated their pre-surgery QL after surgery significantly lower than before and their pre-adjuvant QL under treatment or observation also lower than at the beginning. In the adjuvant phase, in contradiction to our hypothesis, chemotherapy had almost no impact on these changes attributed to reframing. Conventionally assessed changes indicated an improvement in QL. Patients with treatment C reported less improvement in functional performance than those with B or those under observation (P = 0.04). Patients with treatment B indicated a greater worsening in nausea/vomiting than those with C, whereas patients with observation only showed an improvement (P = 0.0009). After adjustment of current QL scores under treatment or observation to patients' retrospective estimation, the treatment effects were diluted but the overall improvement was substantially amplified in most QL indicators. Conclusions: Patients with colon cancer substantially re-frame their perception in estimating QL both under radical resection and under adjuvant chemotherapy or observation. This effect is an integral part of patients' adaptation to disease and treatment. An understanding of this phenomenon is of particular relevance for patient care. Its role in evaluating QL endpoints in clinical trials needs further investigatio

Spondylodiscitis as the first manifestation of Whipple's disease -a removal worker with chronic low back pain

Whipple's disease is a rare systemic infectious disease caused by the actinobacterium Tropheryma whipplei. Spondylodiscitis is an extremely rare manifestation of the infection and has previously been described in only three case reports. We present a 55-year-old man with persistent lumbago and signs of systemic illness, but without any gastrointestinal symptoms or arthralgia. The signal response in the lumbar spine in magnetic resonance tomography, both native and after intravenous gadolinium administration, was compatible with spondylodiscitis at the L4/L5 level. Culture of a specimen obtained by radiographically guided disc puncture and repeated blood cultures remained sterile. Tropheryma whipplei was detected by PCR amplification in material obtained from the disc specimen, from a biopsy of the terminal ileum and from the stool. The histology of duodenum, terminal ileum, colon and disc material was normal and, in particular, showed no PAS-positive inclusions in macrophages. Long-term antibiotic treatment with sulphamethoxazole and trimethoprim was successful, with marked improvement of the low back pain and normalisation of the systemic inflammatory signs. The possibility of Whipple's disease must be suspected in the case of a ‘culture-negative' spondylodiscitis even if there are no gastrointestinal symptoms and no arthralgia presen

Covariates of corticotropin-releasing hormone (CRH) concentrations in cerebrospinal fluid (CSF) from healthy humans

BACKGROUND: Define covariates of cerebrospinal corticotropin-releasing hormone (CRH) levels in normal humans. CRH(CSF )was measured in 9 normal subjects as part of an intensive study of physiological responses stressors in chronic pain and fatigue states. CRH(CSF )was first correlated with demographic, vital sign, HPA axis, validated questionnaire domains, baseline and maximal responses to pain, exercise and other stressors. Significant factors were used for linear regression modeling. RESULTS: Highly significant correlations were found despite the small number of subjects. Three models were defined: (a) CRH(CSF )with blood glucose and sodium (explained variance = 0.979, adjusted R(2 )= 0.958, p = 0.02 by 2-tailed testing); (b) CRH(CSF )with resting respiratory and heart rates (R(2 )= 0.963, adjusted R(2 )= 0.939, p = 0.007); and (c) CRH(CSF )with SF-36 Vitality and Multidimensional Fatigue Inventory Physical Fatigue domains (R(2 )= 0.859, adjusted R(2 )= 0.789, p = 0.02). CONCLUSIONS: Low CRH(CSF )was predicted by lower glucose, respiratory and heart rates, and higher sodium and psychometric constructs of well being. Responses at peak exercise and to other acute stressors were not correlated. CRH(CSF )may have reflected an overall, or chronic, set-point for physiological responses, but did not predict the reserves available to respond to immediate stressors

The human skin-blanching assay as an indicator of topical corticosteroid bioavailability and potency: an update

The human skin-blanching (or vasoconstrictor) assay has evolved from initial observations that corticosteroids induce a pallor or whitening of the skin to which they are applied. McKenzie and Stoughton (1962) are generally recognized as having developed the first scientific bioassay for comparing corticosteroid potency. The extensive use of this bioassay to compare drug release from topical delivery systems has demonstrated numerous instances in which the topical bioavailability may vary greatly, dependent on the character of the delivery vehicle. It has become evident that simply incorporating an intrinsically potent drug into a formulation does not necessarily produce a clinically efficacious product

The human skin-blanching assay for comparing topical corticosteroid availability

The human skin blanching assay remains in widespread use as a reliable, qualitative, comparative indicator of topical corticosteroid availability and potency. The experimental refinements promulgated by certain researchers in this field have yielded a versatile bioassay for the accurate assessment of new drugs or delivery vehicles. With the increasing appearance of generic topical corticosteroid formulations which compete with trade-name equivalents, the vital importance of this assay in regulatory affairs and assessing bioequivalence has been re-emphasized. It is stressed that if the blanching assay is to be used in this sphere, then multiple-reading trials must be conducted; important registration or clinical decisions cannot be made with any validity from short-term assessments

Impact of 3-Cyanopropionic Acid Methyl Ester on the Electrochemical Performance of ZnMn₂O₄ as Negative Electrode for Li-Ion Batteries

Due to their high theoretical capacity, transition metal oxide compounds are promising electrode materials for lithium-ion batteries. However, one drawback is associated with relevant capacity fluctuations during cycling, widely observed in the literature. Such strong capacity variation can result in practical problems when positive and negative electrode materials have to be matched in a full cell. Herein, the study of ZnMn2O4 (ZMO) in a nonconventional electrolyte based on 3-cyanopropionic acid methyl ester (CPAME) solvent and LiPF6 salt is reported for the first time. Although ZMO in LiPF6/CPAME electrolyte displays a dramatic capacity decay during the first cycles, it shows promising cycling ability and a suppressed capacity fluctuation when vinylene carbonate (VC) is used as an additive to the CPAME-based electrolyte. To understand the nature of the solid electrolyte interphase (SEI), the electrochemical study is correlated to ex situ X-ray photoelectron spectroscopy (XPS)