Development of a Multimodal, Physiotherapist-Led, Vocational Intervention for People with Inflammatory Arthritis and Reduced Work Ability: A Mixed-Methods Design Study.

PURPOSE: Work ability of people with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) is reduced, but underexamined as a clinical treatment target. The evidence on vocational interventions indicates that delivery by a single healthcare professional (HCP) may be beneficial. Physiotherapist (PT)-led interventions have potential because PTs are most commonly consulted by RA/axSpA patients in the Netherlands. The aim was to develop a PT-led, vocational intervention for people with RA/axSpA and reduced work ability. METHODS: Mixed-methods design based on the Medical Research Council (MRC) framework for developing and evaluating complex interventions, combining a rapid literature review and six group meetings with: patient representatives (n = 6 and 10), PTs (n = 12), (occupational) HCPs (n = 9), researchers (n = 6) and a feasibility test in patients (n = 4) and PTs (n = 4). RESULTS: An intervention was developed and evaluated. Patient representatives emphasized the importance of PTs' expertise in rheumatic diseases and work ability. The potential for PTs to support patients was confirmed by PTs and HCPs. The feasibility test confirmed adequate feasibility and underlined necessity of training PTs in delivery. The final intervention comprised work-focussed modalities integrated into conventional PT treatment (10-21 sessions over 12 months), including a personalized work-roadmap to guide patients to other professionals, exercise therapy, patient education and optional modalities. CONCLUSION: A mixed-methods design with stakeholder involvement produced a PT-led, vocational intervention for people with RA/axSpA and reduced work ability, tested for feasibility and ready for effectiveness evaluation.

[ADAPTHERA-Statewide cross-sectoral care network for patients with early rheumatoid arthritis shows sustained remission in standard care]. / ADAPTHERA ­ Landesweit transsektorales Versorgungsnetzwerk für Patienten mit früher rheumatoider Arthritis zeigt anhaltende Remissionen in der Regelversorgung.

BACKGROUND/OBJECTIVE: The majority of patients in Germany miss out on the necessity of early diagnosis and initiation of therapy for rheumatoid arthritis (RA) caused by considerable structural deficits in the health care system. The challenge is to reconcile the individual demand for the best possible therapy result with a sustainable expenditure of resources. METHODS: The cross-sectoral regional care network ADAPTHERA aims to improve early RA diagnosis and treatment in Rhineland-Palatinate. The retrospective triage analyses of suspected early onset RA patients was performed by tracing the selection process of all available enquiries (n = 1045). For analysis of the clinical course of the disease, a subset comprising 143 patients with a minimum observation time of 12 months (5 consecutive visits) was available. Clinical and laboratory parameters were collected quarter yearly, self-administered questionnaires were filled out and the treatment was adapted if necessary. RESULTS: A total of 454 patients were included. The mean waiting time was 23.9 (SD = 18) days. The mean observation period in the subcohort was 29.2 (SD = 12.7) months, with about 50% of the patients presenting within 3 months. Almost 75% of the patients were in remission after 2 years. A sustained remission could be described for 74.8% (6 months) and 53.5% (12 months), respectively. Especially patients with rapid remission induction benefited in terms of longer remissions (p = 0.03). A very early stage of the disease (VERA) was associated with a rarely necessary biologic therapy (p = 0.022). DISCUSSION: The approach of a supply network is not a panacea, but it might improve healthcare for patients with early onset RA. In order to minimize resource utilization, a pinpoint referral and accurate triage of potential cases are crucial.

[The regional network ADAPTHERA : Rheumatology care through coordinated cooperation: comprehensive, trans-sectoral, covering all health insurance. Initial results]. / Das landesweite Netzwerk ADAPTHERA : Erste Ergebnisse einer flächendeckenden, krankenkassenübergreifenden und transsektoralen rheumatologischen Versorgung.

The aim of the rheumatology network ADAPTHERA ("risk-adapted rheumatology therapy") is to achieve a comprehensive improvement in rheumatology care by coordinating treatment in a regional, trans-sectoral network. Accompanying biomedical research projects, training concepts, and the construction of a rheumatology register (gathering data and biomaterials) should furthermore ensure the stable and sustainable optimisation of care. In the pilot phase (2012-2015) the focus of the ADAPTHERA network, required as a "regional key project" within the framework of the Initiative on Health Economy of Rheinland-Palatinate (RL-P), Germany, was placed on the optimisation of the early diagnosis of rheumatoid arthritis, where it is well-known that there is a significant care deficit.Through the intensive, stable, and coordinated cooperation of all health care partners in the field of rheumatology (registered general practitioners and orthopaedic specialists, registered core rheumatologists as well as the Association of Rheumatology of RL-P) a unique regional, comprehensive offer with verifiable care optimisation has been established in RL-P. The network is supported by outstanding collaboration with the Association of Statutory Health Insurance Physicians and the self-help organisation Rheumatology League.The aims that were established at the start of the project will be achieved by the end of the pilot phase:- significant improvement in the early diagnosis of rheumatoid arthritis (an average of 23.7 days until diagnosis by rheumatologists)- access covering all health insurance (regardless of the particular scheme the patients belong to)- comprehensive (verifiable participation of general practitioners from all over RL-P)- data and biomaterials collection, established as a basis for biomarker research, and a rheumatology register for RL-P.

Photo-physical properties of 2-(1-ethynylpyrene)-adenosine: influence of hydrogen bonding on excited state properties.

The photo-physical properties of 2-(1-ethynylpyrene)-adenosine (PyA), a fluorescent probe for RNA dynamics, were examined by solvation studies. The excited-state dynamics display the influence of the vicinity on the spectral features. Combining improved transient absorption and streak camera measurements along with a new analysis method provide a detailed molecular picture of the photophysics. After intramolecular vibrational energy redistribution (IVR), two distinct states are observed. Solvent class (protic/aprotic) and permittivity strongly affect the properties of these states and their population ratio. As a result their emission spectrum is altered, while the fluorescence quantum yield and the overall lifetime remain nearly unchanged. Consequently, the hitherto existing model of the photophysics is herein refined and extended. The findings can serve as basis for improving the information content of measurements with PyA as a label in RNA.

Effect evaluation of a self-management program for dutch workers with a chronic somatic disease: a randomized controlled trial.

PURPOSE: The objective of this study is to investigate the effect of a Self-Management Program for workers with a chronic disease. This program is based on the Chronic Disease Self-Management Program of Stanford University, modified for workers with a chronic somatic disease. METHODS: In a randomized controlled trial, the effectiveness of a Self-Management Program was evaluated. Participants were randomly assigned to the experimental group (n = 57) and the control group (n = 47). The experimental group received an intervention, the control group received care as usual. Primary outcome measures were self-efficacy at work and the attitude towards self-management at work. Secondary outcomes were the SF-12 health survey questionnaire, job satisfaction and intention to change job. The results were measured at baseline, after the intervention and 8 months after the intervention. RESULTS: The attitude towards self-management at work (enjoyment) improved after 8 months for the intervention group (p = 0.030). No other outcome variable differed significantly. As an interaction effect, it was found that low educated workers developed a better physical health quality (SF-12) in the intervention group compared with the control group. The attitude towards self-management at work (importance) improved in the intervention group for older and female workers and the attitude toward enjoying self-management at work improved for female workers only. CONCLUSION: The results show that low educated workers, older workers and women benefit significantly more from the training than higher educated workers, younger workers and men.

Effectiveness and cost-effectiveness of a multimodal, physiotherapist-led, vocational intervention in people with inflammatory arthritis: study protocol of the Physiotherapy WORKs trial.

BACKGROUND: Although reduced work ability is a substantial problem among people with inflammatory arthritis (IA), work ability is an underexposed area in clinical practice. Evidence on vocational interventions in IA is limited, but favourable results of delivery by a physiotherapist (PT) warrant the need for further research. Therefore, we aim to evaluate the (cost-)effectiveness of a multimodal, PT-led, vocational intervention in (self-)employed people with IA compared to usual care. METHODS: This randomized controlled trial will include 140 people with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) who are (self-)employed and have reduced work ability (Work Ability Index - Single Item Scale (WAS) ≤ 7/10) and/or RA/axSpA related sick leave (≤ 6 months). Participants will be randomized 1:1 to the intervention or control condition (usual care). The intervention, delivered by primary care PTs, will be personalized to each patient, consisting of 10 to 21 sessions over 12 months. The intervention will be multimodal, comprising of 1) exercise therapy and a physical activity plan, 2) education/self-management support, 3) work-roadmap to guide participants in finding relevant other care, with optionally 4) online self-management course and 5) workplace examination. Assessments will be performed at baseline and after 3, 6, and 12 months. The primary outcome measure of effectiveness is work ability, as measured with the WAS at 12 months. For the cost-effectiveness analysis, the EuroQol (EQ-5D-5L), self-reported healthcare use, sick leave and productivity while at work will be used to estimate the trial based cost-utility from a societal perspective. A process evaluation, including assessments of adherence and treatment fidelity, will be undertaken using the registrations of the PTs and semi-structured interviews at 12 months follow-up in a random sample of the intervention group. DISCUSSION: The results of this study will provide insights in the (cost-)effectiveness of a multimodal, PT-led, vocational intervention in people with IA and a reduced work ability. TRIAL REGISTRATION: This study is registered in the International Clinical Trial Registry Platform (ICTRP) under number NL9343.

The fluoride cleavable 2-(cyanoethoxy)methyl (CEM) group as reversible 3'-O-terminator for DNA sequencing-by-synthesis - synthesis, incorporation, and cleavage.

A new and promising sequencing technology called sequencing-by-synthesis (SBS) enables fast determination of DNA sequences. 2'-Deoxynucleotides containing the (2-cyanoethoxy)methyl (CEM) group at the 3'-O-position are potential reversible terminators for the SBS technology. Herein we describe the synthesis, the incorporation by several polymerases, and the cleavage of this 3'-O-blocking group using 3'-O-CEM-thymidinyl-5'-O-triphosphate 7 as an example.

A new typology of work schedules: Evidence from a cross-sectional study among nurses working in residential elder care.

BACKGROUND: Work schedules contribute substantially to the health and well-being of nurses. Too broad typologies are used in research that do not meet the current variety in work schedules. OBJECTIVE: To develop a new typology for nurses' work schedules based on five requirements and to validate the typology. METHODS: This study is based on a questionnaire returned by 498 nurses (response 51%) including questions regarding nurses' work schedule, socio-demographic, and family characteristics and their appraisal of the work schedule. Frequencies of the different schedules were computed to determine the typology. To validate the typology, differences between the types were tested with ANOVAs, Chi2 and Kruskal-Wallis tests. RESULTS: Five main types can be distinguished based on predetermined requirements and frequencies, namely: (1) fixed early shift, (2) rotating two shift pattern without night shift, (3) rotating three shift pattern, (4) fixed and rotating two shift pattern including night shift, and (5) fixed normal day or afternoon shifts. Nurses in these types of work schedule differed significantly with respect to hours worked, days off between shifts, age, education, years in the job, commuting time, contribution to household income, satisfaction with work schedule and work schedule control. Especially nurses with type 3 schedules differed from other types. CONCLUSIONS: A typology of five main types of work schedules is proposed. Content validity of the typology is sufficient and the new typology seems useful for research on work-related aspects of nursing.

Thermodynamics of unfolding of the alpha-amylase inhibitor tendamistat. Correlations between accessible surface area and heat capacity.

Unfolding of the small alpha-amylase inhibitor tendamistat (74 residues, 2 disulfide bridges) has been characterized thermodynamically by high sensitivity scanning microcalorimetry. To link the stability parameters with structural information we use heat capacity group parameters and water accessible surface areas to calculate the change in heat capacity on unfolding of tendamistat. Our results show that both the group parameter and surface area approaches provide a reasonable, though not perfect, basis for delta Cp calculations. When using the experimentally determined temperature-independent heat capacity increase of 2.89 kJ mol-1 K-1 tendamistat exhibits convergence of thermodynamic parameters at about 140 degrees C, in agreement with recent predictions of the temperature at which the hydrophobic hydration is supposed to disappear. Despite the apparent support of this new view of the hydrophobic effect, there are inconsistencies in the interpretation of the thermodynamic parameters and these are addressed in the Discussion. The specific stability of tendamistat is similar to that of modified bovine pancreatic trypsin inhibitor, with only two of the native three disulfide bridges intact. This observation confirms our previous conclusion that disulfide bridges affect significantly the enthalpy and entropy of unfolding. The recent study by Doig & Williams provides additional convincing support for this conclusion. The predictive scheme proposed by these authors permits a fair estimate of the Gibbs free energy and enthalpy changes of these two proteins.

Native-like beta-structure in a trifluoroethanol-induced partially folded state of the all-beta-sheet protein tendamistat.

The effect of trifluoroethanol (TFE) on the structure of the all-beta-sheet protein tendamistat was investigated. At low concentrations TFE induces cooperative loss of the native tertiary structure leading to a partially folded state. The loss of specific side-chain interactions in the transition from the native state of the TFE-induced state is demonstrated by the disappearance of the CD bands in the aromatic region, a reduced chemical shift dispersion of the one-dimensional 1H NMR spectrum and a broad, uncooperative thermal unfolding transition of the partially folded state. An increased line-width of the NMR bands in the TFE state compared with the unfolded state suggests the presence of multiple, rapidly interconverting conformations. Hydrogen-exchange studies of amide proteins in the TFE state reveal the existence of defined hydrogen bonds at the same locations as in the native state, but with largely reduced stability. This suggests the presence of most of the native beta-sheet structure. These results are supported by Fourier transformed IR measurements, which show nearly the same amount of beta-structure in the TFE state and in the native state. Far UV CD spectroscopy suggests the induction of some alpha-helical structure upon addition of TFE, which appears to be located mainly in regions corresponding to loops or random structure in the native state and which seems to represent fluctuating conformations with preferred backbone angles rather than stable, hydrogen-bonded alpha-helices. These results show that stable non-local interactions, as they occur in beta-sheets, can form in the absence of specific side-chain interactions. The presence of a subset of the native long-range interactions and the absence of stable non-native interactions suggests that the observed partially folded state might represent an early intermediate on a hierarchical folding pathway of tendamistat.

Mechanism of protein stabilization by disulfide bridges: calorimetric unfolding studies on disulfide-deficient mutants of the alpha-amylase inhibitor tendamistat.

The present differential scanning calorimetry and circular dichroism studies on the mechanism of protein stabilization by disulfide bonds were concerned with two questions: is the increase in unfolding entropy upon removal of disulfide links sufficient for the explantation of the general stability decrease of disulfide-deficient mutants? Is it immaterial by which residue cysteine residues are replaced when disulfide bridges are to be opened? To answer these questions we investigated two disulfide bridge mutants of the alpha-amylase inhibitor Tendamistat where the large loop (C45A/C73A) or the small loop (C11A/C27A) had been opened by recombinant DNA techniques, and we compared the stability of the mutated proteins with that of wild-type Tendamistat published previously. To elucidate the significance of the nature of the group that replaces Cys we introduced in position 27 of the small loop four different amino acids instead of Cys: Ala, Leu, Ser and Thr. Surprisingly, opening of the small loop (17 residues) causes larger destabilization than opening of the large loop comprising 29 residues. The thermodynamic parameters at pH 7.0 are: wild-type: t1/2 = 81.6 degrees C, delta Hcal = 296 kJ mol-1, large loop mutant (C45A/C73A): t1/2 = 58.6 degrees C, delta Hcal = 225 kJ mol-1 and small loop mutant (C11A/C27A): t1/2 = 42.7 degrees C, delta Hcal = 135 kJ mol-1. This finding is at variance with the entropy hypothesis. The relative contributions to stability of enthalpic and entropic terms can be varied by a proper choice of substitutions. While the destabilization originating from C45A/C73A exchanges in the large loop turns out to be purely entropic, the stability decreases of the small loop mutants are caused by changes in both enthalpic and entropic terms. Leu or Ser in position 27 leads to an overall enthalpic destabilization. Thr in position 27 increases the transition enthalpy of this mutant to the value of the wild-type protein but increases at the same time the value of the transition entropy with the result of an overall entropic destabilization. Finally, in the C11A/C27A small loop mutant of lowest stability a very large enthalpic destabilization occurs, which is, however, partly counterbalanced by a reduction in the transition entropy. The preferential perturbation of the native state by the mutations is manifest in the increase of the native state heat capacity relative to that of the wild-type protein and the identity of the heat capacity of the unfolded state.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis and purification of fluorinated benzimidazole and benzene nucleoside-5'-triphosphates.

The expression "universal base" is very often used to express hybridization properties and recognition patterns of nucleosides. Their behaviour in biological applications, however, is of great interest regarding, e.g.,' their incorporation by polymerases. The 4,6-difluorobenzimidazole and the 2,4-difluorobenzene nucleoside analogues have proven to be universal bases that do not discriminate between the four natural nucleobases in RNA duplexes. Therefore, we synthesized the corresponding triphosphates to evaluate their behavior in polymerase catalyzed reactions and to investigate their ability to serve as substrates for the T7 RNA polymerase.

RNA recognition by fluor-aromatic substituted.

RNA exhibits a higher structural diversity than DNA and is an important molecule in the biology of life. It shows a number of secondary structures such as duplexes, hairpin loops, bulges, internal loops, etc. However, in natural RNA, bases are limited to the four predominant structures U, C, A, and G and so the number of compounds that can be used for investigation of parameters of base stacking, base pairing, and hydrogen bond is limited. We synthesized different fluoromodifications of RNA building blocks: 1'-deoxy-1'-phenyl-beta-D-ribofuranose (B), 1'-deoxy-1'-(4-fluorophenyl)-beta-D-ribofuranose (4 FB), 1'-deoxy-1'-(2,4-difluorophenyl)-beta-D-ribofuranose (2,4 DFB), 1'-deoxy- 1'-(2,4,5-trifluorophenyl)-beta-D-ribofuranose (2,4,5 TFB), 1'-deoxy- 1'-(2,4, 6-trifluorophenyl)-beta-D-ribofuranose, 1'-deoxy- 1'-(pentafluorophenyl)-beta-D-ribofuranose (PFB), 1'-deoxy-1'-(benzimidazol-1-yl)-beta-D-ribofuranose (BI), 1'-deoxy-1'-(4-fluoro-1H-benzimidazol-1-yl)-1-beta-ribofuranose (4 FBI), 1'-deoxy- 1'-(6-fluoro- 1H-benzimidazol-1-yl)-beta-D-ribofuranose (6FBI), 1'-deoxy- 1'-(4, 6-difluoro- 1H-benzimidazol- 1-yl)-beta-D-ribofuranose (4,6 DFBI), 1'-deoxy- 1'-(4-trifluoromnethyl- H-benzimidazol-1-yl)-beta-D-ribofuranose (4 TFM), 1'-deoxy-1'-(5-trifluoromnethyl-1H-benzimidazol-1-yl)-beta-D-ribofuranose (5 TFM), and 1'-deoxy-1'-(6-trifluoromethyl-1H-benzimidazol-1-yl)-beta-D-ribofuranose (6 TFM). These amidites were incorporated and tested in a defined A, U-rich RNA sequence (12-mer, 5-CUU UUCXUU CUU-3' paired with 3'-GAA AAG YAA GAA-5'). Only one position was modified, marked as X and Y, respectively. UV melting profiles of those oligonucleotides were measured.

Homo and heterodimers of ddI, d4T and AZT: influence of (5'-5') thiolcabonate-carbamate linkage on anti-HIV activity.

New homo and heterodimers of ddI, d4T and AZT with (5-5) thiolcarbonate-carbamate linkages have been prepared with the aim of testing them against wild type and NNRTI resistant HIV mutants. The prepared dimers showed a low activity in comparison to the parent drug.

Secretory synthesis of human interleukin-2 by Streptomyces lividans.

To study the ability of Streptomyces lividans to produce heterologous proteins by secretion, we directly fused DNA encoding the leader peptide of the alpha-amylase inhibitor, tendamistat, produced by Streptomyces tendae, with DNA encoding the mature part of interleukin-2 (IL-2). Such cloned fusion constructs are translated in S. lividans, in spite of the quite different codon usage. The active Il-2 is secreted into the culture broth, though the amounts are much less than that of the alpha-amylase inhibitor. The presence of IL-2 in the supernatants could be demonstrated both by an activity assay and by immunoblotting. In addition to the secreted form, three different species of Il-2 antibody immunoreactive proteins, with different Mrs, are either present in the cells or attached to the cells. This indicates that inefficient processing and translocation of the precursor is a major reason for the low activities found in the supernatant.

Primary structures of new 'iso-hirudins'.

Crude hirudin (12.7 U/micrograms), a complex mixture of polypeptides obtained from the leech, could be separated by microbore HPLC. A combination of amino acid analysis, N-terminal microsequencing and chemical as well as enzymatic fragmentation made the primary sequence of the new isohirudins Ia-IIIb' accessible. The biological activity determined in the thrombin inhibition test showed a comparable value for all of these compounds. The results presented address the question as to whether these isohirudins are true mutations from a family of genes or a family of leeches.

3'-O-methylated analogs of 2-5A as inhibitors of virus replication.

We have explored analogs of 2'-5'-linked andeylic acid trimer (2-5A): 3'-O-methylated 2-5A, 2'-end modified adenylate trimer with deoxyadenosine or araadenine, methyl phosphonate and methyl phosphorotriester analogs as potential antiviral agents. For the treatment of virus infections, 2-5A and its analogs may serve in lieu of interferon, however, the use of 2-5A has two serious limitations: it is presumed to be impermeable to most cells, and moreover, cellular enzymes rapidly degrade it. Methylated analogs of 2-5A core strongly inhibited virus growth when added directly to cells in culture. 2'-End modified adenylate trimer with araadenine also inhibited virus growth, however, neither 2-5A nor other analogs showed any significant antiviral activity. The inhibition of virus growth was not due to the toxic effect of these compounds on cell growth as they had no inhibitory effect on the growth of uninfected cells.

Cell type-specific tyrosine phosphorylation of IL-2 receptor beta chain in response to IL-2.

Functional activities of the IL-2 receptor (IL-2R) beta chain exogenously expressed on lymphoid and non-lymphoid cells were examined in terms of phosphorylation of IL-2R beta and cell growth. Lymphoid MOLT-4 and its transfectants expressing IL-2R beta either alone or with IL-2R alpha chain were found to be rapidly phosphorylated predominantly at tyrosine residues of IL-2R beta and to be affected in their growth in an IL-2-dependent manner. In contrast, IL-2 induced neither phosphorylation of IL-2R beta nor cell growth in non-lymphoid transfectants derived from COS7, HeLa and L929, even though they acquired the IL-2 binding ability when coexpressed as IL-2R beta and IL-2R alpha. These results suggest that IL-2 induces activation of a tyrosine kinase possibly associated with IL-2R beta in a cell type-specific manner.

Synthesis, structure, and reactivity of adenosine cyclic 3',5'-phosphate benzyl triesters.

A series of triesters of adenosine cyclic 3',5'-phosphate was synthesized by treatment of the free acid with various diazoalkanes (R=H, CH3, C6H5,0-NO2C6H4, p-NO2C6H4, p-CH3C6H4). The resulting diastereomeric mixtures were separated into their axial and equatorial components. Hydrolysis of the compounds was examined as well as photolysis of the photolabile o-nitrobenzyl ester. All compounds were then tested for their ability to activate the cAMP-dependent protein kinase and for their ability to serve as a substrate for the cAMP phosphodiesterase showing almost no effect on either enzyme. In a biological assay the benzyl triesters were able to penetrate into C 6 rat glioma cells and to induce the typical morphological alteration of the cell shape known for high cellular levels of cAMP. It was concluded that the benzyl triesters of cAMP are useful derivatives which can be efficiently and specifically converted to the parent nucleotide. Benzyl derivatives of biologically active phosphodiesters may provide a useful tool for study in biology and pharmacology.

Inotropic and electrophysiological effects of 8-substituted cyclic AMP analogues on guinea-pig papillary muscle.

The inotropic potencies of 8-substituted cyclic AMP analogues, applied as sodium salts and in form of benzyl esters, were determined in isolated guinea-pig papillary muscles contracting isometrically at a frequency of 0.2 Hz. Half-maximally effective concentrations, EC50, for the positive inotropic effect of 8-substituted cyclic AMP (sodium salt) increased in the order 8-(4-chloro-phenyl)thio-cyclic AMP, 8-tertiary-butyl-thio-cyclic AMP, 8-benzyl-seleno-cyclic AMP, 8-benzyl-thio-cyclic AMP, 8-methyl-thio-cyclic AMP, 8-bromo-cyclic AMP. Neutralization of the phosphate hydroxyl residue of 8-substituted cyclic AMP by a benzyl group yielded cyclic AMP benzyl esters (cAMP-O-Bn) which were 30 to 100 times more potent than the respective cyclic AMP salts. Cyclic AMP derivatives with a 8-(4-chloro-phenyl)thio- or a 8-tertiary butyl-thio substituent showed comparatively high inotropic potencies. The intrinsic activity was uniformely the same for all 8-substituted cyclic AMP derivatives and equalled that of isoprenaline. As measured by octanol/water partitioning (log P), the increase in lipophilicity of 8-substituted cyclic AMP by esterification with a benzyl group was 7000-fold for 8-bromo-cyclic AMP, 5000-fold for 8-methyl-thio-cyclic AMP, and approximately 1000-fold for the other derivatives. Within the series of benzyl esters, differences in lipophilicity were small. The positive inotropic effect of 8-substituted cyclic AMP analogues was accompanied by a shortening of contraction duration, mainly due to an abbreviation of relaxation time.(ABSTRACT TRUNCATED AT 250 WORDS)