Economic evaluation of a 2-dose hepatitis B vaccination regimen for adolescents.

OBJECTIVE: To investigate the economic implications of a 2-dose hepatitis B virus vaccination regimen compared with the current 3-dose vaccination regimen for adolescents in 3 settings: public schools, public health clinics, and private sector settings in the United States. METHODS: To measure resource utilization and costs associated with the administration of the 3-dose regimen and to assess vaccination compliance rates with this regimen, primary data were collected with the use of questionnaires tailored for each setting. Conservative modeling assumptions were used to derive 2-dose compliance rates from 3-dose compliance data. The results were incorporated into a decision analytic model, which was used to examine short-term and lifetime scenarios for an adolescent cohort receiving the 2-dose versus the 3-dose regimen. In the short-term analysis, the vaccination program costs were compared for the 2 regimens. In the lifetime analysis, the model also incorporated long-term disease costs for those individuals who contract hepatitis B. RESULTS: Predicted increases in compliance with a 2-dose vaccination regimen contributed to a higher probability of seroprotection in each setting. In the lifetime analysis, this positive impact of improved compliance resulted in a lower infection rate and greater cost-effectiveness for the 2-dose regimen in all settings, including private sector settings, where it cost an average of only $964 per year of life gained, and in public schools, costing an average of $1246 per year of life gained. In public health clinics, the 2-dose regimen had both lower expected lifetime costs and better clinical outcomes than the 3-dose regimen. In the short-term analysis, costs were higher for the 2-dose regimen, reflecting higher total vaccine acquisition costs without the long-term offset of cost savings from reduced infection. Sensitivity analyses identified cost per dose of vaccine and the probability of completing the regimens as the most sensitive model variables. CONCLUSIONS: Improved compliance with a 2-dose regimen would contribute to a higher probability of adolescents' achieving seroprotection. When the long-term consequences of hepatitis B virus infection are included, the 2-dose regimen would be cost-effective compared with the 3-dose regimen in all settings and cost saving in public health clinic settings.

Cost of treatment for onychomycosis. Data from a 9-month observational study.

OBJECTIVES: To estimate component and total costs of treatment and to examine differences in cost and cost effectiveness between oral antifungal medication and local therapy for patients with toenail onychomycosis. DESIGN: Prospective, observational study of patients with onychomycosis who visited dermatologists and podiatrists in the US. Physicians provided data on clinical management, disease severity, nail improvement and resource utilisation. Patients completed questionnaires on resource utilisation and symptoms at base-line, 4 and 9 months. To estimate costs, reported utilisation was multiplied by unit costs expressed in 1997 US dollars ($US) and derived in 2 ways: first, using Medicare fees; and second, using standard physician fees. RESULTS: After adjustment for key demographic and clinical variables, participants receiving oral medication had higher total costs based on standard fees ($US794 vs $US575) and medication costs ($US564 vs $US109), lower procedure costs ($US0 vs $US122) and physician visit costs ($US200 vs $US330), and greater clinical effectiveness as measured by global improvement rating (86 vs 35%) and Toenail Symptom Index (94 vs 49%). For participants receiving oral medication, 90% of total costs were incurred during the first 4 months of follow-up, whereas for those receiving local therapy, costs were more evenly distributed throughout the study period. Incremental cost-effectiveness analysis showed $US304 to $US491 per additional case improved with oral medication over a 9-month timeframe. Extrapolation of these results using 2 time-points (months 4 and 9) suggested that cost equivalence would be reached 17 to 21 months following the initiation of treatment. CONCLUSIONS: During 9 months of follow-up in patients with toenail onychomycosis, the use of oral antifungal medication resulted in superior patient outcomes, but at higher total cost compared with local therapy.

Relationship of first-year costs of treating localized prostate cancer to initial choice of therapy and stage at diagnosis: results from the CAPSURE database.

OBJECTIVES: To determine the relationship among the initial choice of therapy, stage at presentation, and first-year treatment costs in men with newly diagnosed localized prostate cancer. METHODS: First-year resource use and clinical data were collected for 235 subjects with newly diagnosed localized prostate cancer. The costs were estimated from the standard Medicare payment schedules. The relationship among the initial therapy, stage at presentation, and overall cost was examined for the entire cohort and in the subgroup of patients who underwent radical prostatectomy. In addition, the inpatient, outpatient, and medication cost components were evaluated separately to determine what influenced the changes in cost by stage. RESULTS: The mean first-year cost of treating localized prostate cancer in CaPSURE was $6375. When broken down by stage, the mean first-year cost for patients with Stage T1c was $5731, with T2a/b was $6426, and with Stage T2c was $6810 (P = 0.059). The initial treatment choice was significantly associated with the total first-year costs (P <0.001). The mean cost specifically for radical prostatectomy patients with Stage T1c disease was $6881, with T2a/b was $7216, and with T2c was $8027 (P = 0.004). The increases in the first-year cost with higher stage appeared to primarily be associated with increased inpatient resource use and the greater use of adjuvant hormonal therapy. CONCLUSIONS: The first-year costs of treating localized prostate cancer in CaPSURE are associated with the choice of primary and adjuvant therapy. This supports the notion that cost savings may be possible with earlier detection of disease or by minimizing the use of hormonal adjuvant therapy.

An economic assessment of Apligraf (Graftskin) for the treatment of hard-to-heal venous leg ulcers.

Several recent advances in wound care may offer promise for the treatment of hard-to-heal venous leg ulcers. One such treatment is Apligraf (Graftskin), a bilayered, living human skin construct. To assess the economic impact of Graftskin, a model was constructed to compare the annual medical costs and cost-effectiveness of treating hard-to-heal venous leg ulcers with Graftskin vs. compression therapy using Unna's boot. A semi-Markov model was used to describe the pattern of ulcer treatment, healing, and recurrence among patients with venous leg ulcers. Patients received 1 of 2 treatment regimens, Graftskin or Unna's boot, and were followed in the model for a 12-month period. The analysis was done from the perspective of a commercial health plan; therefore, only direct medical costs were included. Health care resource use included the primary therapeutic intervention, additional compression dressings, physician office visits, home health visits, laboratory tests and procedures, management of adverse events, and hospitalizations. The model estimated the annual medical cost of managing patients with hard-to-heal venous leg ulcers to be $20,041 for those treated with Graftskin and $27,493 for those treated with Unna's boot. In addition, treatment with Graftskin led to approximately 3 more months in the healed state per person per year than did treatment with Unna's boot. Because patients treated with Graftskin experienced improved healing compared with those treated with compression therapy using Unna's boot, they required fewer months of treatment for unhealed ulcers. As a result, the use of Graftskin for treating hard-to-heal venous leg ulcers resulted in lower overall treatment costs.

A neurobehavioral treatment for unilateral complex partial seizure disorders: a comparison of right- and left-hemisphere patients.

This study looked at the efficacy of a multi-disciplinary neurobehavioral approach for treating patients with complex partial seizure disorders. Patients with a seizure focus in either the left or right hemisphere were compared for overall effectiveness of this approach in achieving control of complex partial seizures. Patients in this study received short-term treatment based on a model of self-control developed by the Andrews/Reiter Epilepsy Research Program. This research selected all patients who met the lateralization criterion from among cases receiving short-term treatment between 1992 and 1996. Forty-four patients were identified, a group of 21 right-hemisphere subjects and a second group of 23 left-hemisphere subjects. These patients were treated in a short-term (5 consecutive days) treatment protocol and then released, with weekly phone contact for 6 months following treatment. They were then followed for an additional 19 months through the continued submission of their seizure logs and journals. Subjects in both groups kept seizure records throughout the study starting with a two-month baseline period. Other data collected allowed study of the interaction of emotional states with seizure occurrence. This project produced valuable and relevant information regarding neurobehavioral management interventions as an effective adjunctive or alternative treatment for obtaining seizure control in epilepsy patients. Overall, 79% of patients treated achieved seizure control. More than 64% identified a recognizable emotional state that triggered seizures. The emotional trigger was specific for either the right or left hemisphere.

The cost-effectiveness of octreotide acetate in the treatment of carcinoid syndrome and VIPoma.

Markov modeling was used to evaluate the cost-effectiveness of octreotide in treating carcinoid syndrome and VIPoma. For each condition, using octreotide was associated with doubled survival time. Octreotide was cost-effective for treating carcinoid tumor ($752 per additional year of life, two additional years on average), and cost saving for VIPoma.

Use of second treatment following definitive local therapy for prostate cancer: data from the caPSURE database.

PURPOSE: We compare secondary cancer treatment use in patients who underwent definitive local treatment for prostate cancer. MATERIALS AND METHODS: The rate of second cancer treatment was determined in patients who underwent radical prostatectomy (1,254), radiotherapy (499) or cryosurgery (141) using data from the CaPSURE database, a longitudinal disease registry of patients with prostate cancer. Second treatments started within 3 months after initial treatment were defined as adjuvant and those started more than 3 months were defined as nonadjuvant. Using a parametric regression model of survival analysis, second treatment rates were adjusted for differences in clinical and demographic characteristics, and duration of followup among groups. RESULTS: Of the patients 4% received a second adjuvant treatment and 17% received a second nonadjuvant treatment within 3 years of initial therapy. Adjusted rates of nonadjuvant second treatment were lowest after radical prostatectomy, and 34 and 88% higher after radiation and cryosurgery, respectively (p = 0.01). This finding was most evident in patients with pretreatment prostate specific antigen 10.0 ng./ml. or less, clinical stage T2N0M0 disease, or Gleason score 6 or less on diagnostic biopsy, and in those classified as low risk for recurrence based on a combination of these parameters (p = 0.004). CONCLUSIONS: Approximately 1 in 5 patients receive second cancer treatment within a mean of 3 years following initial local treatment for prostate cancer. Our data suggest that the likelihood of receiving second treatment was lowest in patients initially treated with radical prostatectomy.

Molecular mode of action of the antifungal beta-amino acid BAY 10-8888.

BAY 10-8888 is a cyclic beta-amino acid that is related to cispentacin and that has antifungal activity. Candida albicans cells accumulated BAY 10-8888 intracellularly to a concentration about 200 that in the medium when grown in media with a variety of nitrogen sources. In complex growth medium, BAY 10-8888 transport activity was markedly reduced and was paralleled by a decrease in its antifungal activity. Uptake of BAY 10-8888 was mediated by an H+-coupled amino acid transporter with specificity for branched-chain amino acids (isoleucine, leucine, and valine) and showed a KT (Michaelis constant of the transport reaction) of 0.95 mM and a Vmax of 18.9 nmol x min-1 x 10(7) cells-1. Similar to the transport of natural amino acids in Saccharomyces cerevisiae, the transport of BAY 10-8888 into the cell was unidirectional. Efflux occurred by diffusion and was not carrier mediated. Inside the cell BAY 10-8888 inhibited specifically isoleucyl-tRNA synthetase, resulting in inhibition of protein synthesis and cell growth. Intracellular isoleucine reversed BAY 10-8888-induced growth inhibition. BAY 10-8888 was not incorporated into proteins. BAY 10-8888 inhibited isoleucyl-tRNA synthetase with the same concentration dependency as protein biosynthesis in intact cells assuming 200-fold accumulation.

The functioning and well-being of patients with unrecognized anxiety disorders and major depressive disorder.

This study examines the degree to which untreated anxiety disorders and major depressive disorder, occurring either singly or in combination, reduce functioning and well-being among primary care patients. Adult patients were screened using the SCL-52 to identify those with clinically significant anxiety symptoms. They also completed the Rand Short-Form (SF-36) to measure self-reported patient functioning and well-being. Patients with untreated disorders were identified using the Q-DIS-III-R to diagnose six DIS-anxiety disorders (generalized anxiety disorder, post-traumatic stress disorder (PTSD), simple phobia, social phobia, panic/agoraphobia, obsessive/compulsive disorder) and major depression. Of 319 patients identified, 137 (43%) had a single disorder and 182 (57%) had multiple disorders. Regression models estimated the relative effects of these disorders on health status (SF-36) by comparing patients with the disorders to patients screened as being not-anxious. Estimates of these effects were consistent with available national norms. The estimated effect of each single disorder on all subscales for physical, social and emotional functioning was negative, often as much as a 20-30 point reduction on this 100-point scale. Major depression had the greatest negative impact, followed by PTSD and panic/ agoraphobia. For patients with multiple disorders, the presence of major depression was associated with the greatest reduction in functioning status. The impact of untreated anxiety disorders and major depressive disorder on functioning was comparable to, or greater than, the effects of medical conditions such as low back pain, arthritis, diabetes and heart disease.

Economic evaluation of pharmacist involvement in disease management in a community pharmacy setting.

This study evaluated the economic impact of patient-focused pharmacist intervention in the community retail setting in patients with hypertension, diabetes, asthma, and/or hypercholesterolemia. Specially trained pharmacists intervened by providing targeted patient education, performing systematic patient monitoring, offering feedback and behavior modification, and communicating regularly with patients' physicians to enable early intervention for drug-related problems. We evaluated prescription drug costs and total medical costs by comparing claims data from 188 patients enrolled in the program at three intervention pharmacies with data from 401 control patients at five nonparticipating pharmacies from the same retail chain. For all disease states, the average cost per prescription was significantly higher in the group receiving intervention than in the control group. Differences in total monthly prescription costs were significant only for patients with asthma, with higher monthly costs in the group receiving intervention. Substantial savings were demonstrated across all cost analyses for total monthly medical costs. Savings ranged from a conservative estimate of $143.95 per patient per month to $293.39 per patient per month when accounting for the possible influence of age, comorbid conditions, and disease severity. Our data indicate that pharmacist intervention in this community pharmacy-based disease management model substantially reduced monthly health care costs in patients with hypertension, hypercholesterolemia, diabetes, and asthma.

Leukotriene generation in patients with multiple injuries.

We determined the generation and metabolism of lipoxygenase products in isolated granulocyte fractions of patients with multiple trauma (n = 9) and compared the results with those of healthy volunteers (n = 8). The supernatants of stimulated cells were analyzed by high-performance liquid chromatography. During the first week after injury a significantly reduced capacity to generate LTB4 and an increased metabolism of LTB4 into omega-oxidated products (20-OH-LTB4 and 20-COOH-LTB4) were observed after stimulation of the granulocytes with Ca ionophore. The depressed leukotriene production could be partly abrogated by the addition of arachidonic acid. These findings are comparable with alterations previously described in severely burned patients with postburn sepsis. Additionally, an elevated production of LTC4 by peripheral granulocyte fractions was observed in two patients suffering from adult respiratory distress syndrome (ARDS) as well as an increased number of eosinophils during the time of lung dysfunction. Analysis of bronchoalveolar lavage in patients with multiple trauma (11 patients with ARDS and 11 patients without ARDS) by a specific radio-immunoassay confirmed an elevated production of cysteinyl-leukotrienes.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictive factors for controlling seizures using a behavioural approach.

A behavioural approach using EEG biofeedback for controlling complex-partial seizures has been successful at the Andrews/Reiter Epilepsy Research Program. Records for a random sample of 83 patients with uncontrolled seizures, one third of those receiving care between 1980 and 1985, document that 69 (83%) achieved control by completion of the programme. Additional data about initial age of seizure onset, number of years seizures had been uncontrolled and seizure frequency when treatment started were collected to determine whether these factors predicted seizure control. Only frequency was significantly related to whether seizures were controlled when treatment ended. Further study using discriminant analysis showed that earlier onset age and higher seizure frequency were associated with a significantly greater number of treatment sessions required. Thus, these two factors predicted difficulty in controlling seizures, as measured by number of sessions, although onset age did not predict whether control was eventually achieved. Since even the subgroup achieving the lowest rate of control (i.e., patients having daily seizures when treatment started) had 67% success, these results suggest that a behavioural approach can be useful for many people with currently uncontrolled complex-partial seizures regardless of their characteristics on factors examined in this study.

Endotoxin-neutralizing capacity of soluble CD14.

Luminol-enhanced chemiluminescence was used to determine the effect of soluble CD14 (sCD14) on the endotoxin-inducible generation of reactive oxygen species in human monocytes. It was necessary to mediate lipopolysaccharide (LPS) monocyte-activating capability by serum factors (LPS-binding proteins). sCD14 reduced LPS-inducible monocyte activation in a dose-dependent manner, even in the case of CD14- monocytes, obtained from a patient with paroxysmal nocturnal haemoglobinuria. These monocytes could be activated by opsonized LPS via other receptors. Using anti-mouse Ig-coated microbeads, it was demonstrated in FACS analysis that sCD14 mediates the binding of a mouse monoclonal anti-CD14 antibody (RoMo 1) to a complex of LPS/FITC (fluoroisothiocyanate) and a LPS-binding protein. The release of sCD14 from cultured monocytes was measured using LPS, TNF alpha (tumour necrosis factor), IL1, 4 and 6 (interleukin-1, -4 and -6) and IFN gamma (interferon-gamma) as stimulators. Addition of LPS and TNF alpha led to a dose-dependent increase in sCD14-levels in the culture supernatant, whereas IL1, IL6 and IFN gamma had no significant effect. IL4 dose-dependently depressed spontaneous sCD14 release. It is possible that elevated sCD14-serum levels in polytraumatized patients indicate a natural protective mechanism against excessive monocyte mediator production. Therefore, sCD14 may be a new therapeutic concept in endotoxic shock prevention.

[LTB4-metabolism and histamine liberation by granulocytes in the disease pattern of cystic fibrosis (CF)]. / LTB4-Metabolismus und Histaminfreisetzung durch Granulozyten im Krankheitsbild der zystischen Fibrose (CF).

We determined the generation and liberation of LTB4 in peripheral granulocytes and the histamine release from basophils in patients suffering from cystic fibrosis (CF, median 17.2 years of age, n = 12). We compared the data with an age matched group of healthy donors (n = 12). All patients suffered from an exacerbation of a chronic pulmonary infection caused by P. aeruginosa. Peripheral granulocytes were stimulated at different days before, during and after antiinfectious treatment with Ca-Ionophore, opsonized zymosan and arachidonic acid. The granulocytes from patients with CF as compared to the control group showed an increased omega-Oxidation of the synthesized LTB4 into 20-COOH- and 20-OH-LTB4 after stimulation with Ca-Ionophore and opsonized zymosan (Ca-Ionophore: ratio of LTB4 versus omega-oxidated products (CF): 0.77 +/- 0.007 mean +/- S.E.M., n = 12, control group: 1.07 +/- 0.1, n = 12, p less than 0.01). Stimulation of the cells with Ca-Ionophore combined with arachidonic acid led to a significantly increased formation of lipoxygenase products in the patient group. No significant differences in the basophil counts were determined between both populations. However, the absolute histamine content per basophil was elevated in the CF group (2.4 +/- 0.3 versus 1.6 +/- 0.2 mean +/- S.E.M., n = 12/12, p less than 0.04). Stimulation of basophils with Ca-Ionophore and anti-IgE leads to a significant higher release of histamine per basophil in CF patients (Ca-Ionophore: 2.6 +/- 0.2 versus 1.3 +/- 0.8 pg/basophil, mean +/- S.E.M., p less than 0.05). These data indicate that basophils in CF may have a greater potential to release mediators. During the antiinfectious treatment a normalization of the altered pattern was observed. Within the CF-groups a strong correlation between the release of LTB4, its metabolites, the histamine release per basophil, the total histamine content and clinical (e.g. pO2 FEV1) and laboratory findings (e.g. IgE and IgG levels, CRP) was established. Our data suggest that the inflammatory process in patients with CF is associated with an alteration of the lipoxygenase pathway and histamine releasability of granulocyte subpopulations which correlates with the clinical signs of inflammation.

Analysis of leukotriene B4 metabolism in human promyelocytic HL-60 cells.

We previously reported that human alveolar macrophages rapidly metabolize the chemotactic active lipid mediator leukotriene B4 (LTB4) into the dihydro-LTB4 by reduction of one of the conjugated double bonds. We herein report that human HL-60 cells (a myeloid precursor which can be differentiated into granulocyte- as well as monocyte-like cells by dimethyl sulphoxide or phorbol myristate acetate) express a highly active LTB4 reductase in the undifferentiated state. Differentiation by dimethyl sulphoxide (1.3%) along the granulocyte lineage, as confirmed by light microscopy, conversion of NitroBlue Tetrazolium into formazan, failed to induce a substantial capacity for omega-oxidation of LTB4; this reaction is exclusively found in mature granulocytes. Studies with the cell homogenate of undifferentiated HL-60 cells indicated that the activity of the enzyme depends on the presence of NADPH, Ca2+ and Mg2+, with a pH optimum of 7.5 at 37 degrees C. The enzyme was not released into the supernatant after stimulation of HL-60 cells with phorbol myristate acetate (100 ng) or Ca2+ ionophore (7.5 microM). Subcellular fractionation revealed evidence that the LTB4 reductase is located within the membrane fraction. Purification of the enzyme by gel filtration and gel electrophoresis suggests an apparent molecular mass of 40 kDa.

Metabolism of leukotriene B4 via reduction into dihydro-leukotriene B4 in human monocytes, alveolar macrophages, and U-937 cells.

The biological effects of leukotriene B4 (LTB4) within the microenvironment are controlled by rapid inactivation. In this regard human granulocytes convert LTB4 into omega-oxidated products (20-OH-LTB4 and 20-COOH-LTB4); moreover, we recently described the formation of unpolar metabolites of LTB4 in human tonsillar and lung macrophages. By means of high performance liquid chromatography (HPLC) we identified the main metabolite of LTB4 as dihydro-LTB4 (5,12-dihydroxyeicosatrienoic acid). Studies on a lymphocyte (74-78%), monocyte (19-22%), and basophil (less than 4%) containing cell fraction isolated from peripheral blood as well as peripheral monocytes purified by elutriation centrifugation revealed evidence that these cells metabolize LTB4 to a very low degree if incubated immediately after isolation. However, after culture for 24-72 h these cells showed a strongly increased capacity to metabolize LTB4. The pattern of metabolites in this cell fraction was identical to bronchoalveolar macrophages (purity greater than 95%). Similarly, the LTB4-reductase was expressed in differentiated human monocytic U-937 cells almost 5-7 h after the addition of dimethylsulfoxide (1.3%) or phorbol-myristate-acetate (16 nM). The expression of this pathway was blocked in the presence of cycloheximide (10 micrograms/ml) whereas actinomycin (3.8 micrograms/ml) had no effects. Dihydro-LTB4 was further metabolized by granulocytes probably via omega-oxidation; therefore, several metabolites could be detected by radioactive high performance liquid chromatography (HPLC) after incubation of bronchoalveolar cells consisting of macrophages and granulocytes with 3H-LTB4. Our data provide evidence for a unique role of macrophages to control the level of LTB4 by generation as well as metabolism into dihydro-LTB4.

Serum CD14 levels in polytraumatized and severely burned patients.

Recently it has been demonstrated that the CD14 molecule which is expressed on monocytes and macrophages serves as a receptor for lipopolysaccharide (LPS) bound to LPS-binding protein (LBP) and thus mediates LPS-induced tumour necrosis factor (TNF) production. Here we report that CD14 is found as a soluble (s) molecule in serum. In healthy volunteers sCD14 levels (mean +/- s.e.m.) were 3.7 +/- 0.05 micrograms/ml (n = 30, 25-50 years of age) as determined by ELISA (detection limit 20 ng/ml serum) using two monoclonal antibodies in a sandwich technique. In polytraumatized patients (n = 16) significantly decreased levels (1.7 +/- 0.3) were detected immediately after the trauma, which increased to 4.9 +/- 0.3 micrograms/ml within the first 6 days post trauma. sCD14 remained elevated during the first 14 days post trauma in patients with the most severe injuries (injury severity score greater than 45 points), whereas a return to normal levels was observed in patients with an injury score of less than 45 points. In addition, the levels of the high-density lipoproteins that partially inactivate free endotoxin are significantly decreased post trauma. No correlation between parameters of inflammation (C3a and neopterin levels, leucocyte counts, amount of band cells), liver function and sCD14 levels was established. Comparable to polytraumatized patients, increased sCD14 serum levels were observed in five patients with burn trauma (burned area greater than 35%) within the second week post trauma when clinical signs of septicaemia were evident.

[Post-traumatic alveolar changes in lung contusion]. / Posttraumatische alveoläre Veränderungen nach Lungenkontusion.

Bronchoalveolar lavage (BAL) specimens taken from nine patients with lung contusion following multiple trauma were compared with specimens from different control groups. Early interstitial and intra-alveolar reactions are PMN degranulation, mediator release and high protein leakage. The alveolar reactions are similar in extent to the reaction found in post-traumatic ARDS.

Interaction of progesterone derivatives with the digitalis target enzyme: impact of glycosidation on inhibitory potency.

As a function of the structural modification of the steroid nucleus, the inhibitory interaction of 11 progesterone derivatives with human Na/K-ATPase (Na+/K(+)-transporting ATPase, EC 3.6.1.37), through C3-O-rhamnosylation, is either much decreased or weakly up to strongly increased, so that the rhamnosyl residue contributes to the complementary Gibbs energy of interaction, at the most, the same Gibbs energy increment as realized in ouabain. After C3 beta-O-rhamnosylation, the activity of some progesterone derivatives considerably surpasses that of 3 beta-O-rhamnosyl-chlormadinolacetate, which has been known to elicit positive inotropy in cats. The progesterone derivatives (aglycons and glycosides), that have been analysed more closely, produce their effects by the same molecular mechanism of interaction with Na/K-ATPase as characteristic for digitalis aglycons and glycosides. The results promise to pave the way for the identification of the chemical nature of endogenous digitalis and for the design of novel inotropic drugs.