A Pharmacokinetic/Pharmacodynamic Approach to Predict the Cumulative Cortisol Suppression of Inhaled Corticosteroids

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16–21% was predicted for FP 250 g, FLU 500 g, and TCA 1000 g. For multiple dosing, a respective CCS of 28–33% was calculated for FLU 500 g bid, FP 250 g, bid, and TCA 1000 g bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.     

Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases.

For the diagnosis of CML and for monitoring of treatment response the detection of the t(9;22)(q34;q11) or the BCR-ABL rearrangement is necessary. Chromosome banding analysis (CA) is still the gold standard but other techniques like Southern blot, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are available. We analyzed 350 CML patients at different stages of disease in parallel with CA, interphase-FISH (IP-FISH), hypermetaphase-FISH (HM-FISH) and RT-PCR. In 20 cases with no Ph(+) metaphases in CA, HM-FISH detected 0.2 to 10% BCR-ABL(+)metaphases. After IP-FISH 107 samples were judged as negative. However, in 17 of these samples HM-FISH detected BCR-ABL(+) metaphases (0.3-11%), and in eight cases CA detected Ph(+) metaphases (2.5-25%). A comparison of IP-FISH performed on uncultivated cells vs cells cultivated for 48 h in 70 cases revealed a higher proportion of BCR-ABL+ cells in the cultivated samples. If nested PCR was negative, all other methods were negative in all cases too. In addition, 94 cases were evaluated using real-time PCR (LightCycler technology). The BCR-ABL/cABL ratio measured showed a high correlation with all other methods. Interestingly, a wide range in the BCR-ABL/ABL ratio was observed especially in patients who showed 100% Ph-positive metaphases in CA. In conclusion, CA, IP-FISH, HM-FISH and real-time PCR give reliable results but differences due to measurement of different target structures have to be kept in mind when using these data for definition of remission status.     

Plasma concentrations of fluticasone propionate and budesonide following inhalation: effect of induced bronchoconstriction

AIMS: To determine whether and to what extent bronchoconstriction affects plasma concentrations of fluticasone and budesonide following inhalation. METHODS: Twenty people with mild asthma inhaled 1000 microg fluticasone (Accuhaler) plus 800 microg budesonide (Turbohaler) on two visits. On one occasion, prior to drug inhalation, FEV(1) was decreased by at least 25% using inhaled methacholine. Plasma drug concentrations were measured for each drug over 5 h and area under the plasma concentration-time curve (AUC(0,5 h)) compared between visits. RESULTS: The mean difference in FEV(1) prior to drug inhalation on the 2 days was 33%. AUC(0,5 h) values for fluticasone and budesonide were lower by a median of 60% (IQR 36-75) and 29% (IQR 2-44), respectively, when administered following bronchoconstriction; the reduction was greater for fluticasone than for budesonide, P = 0.007. CONCLUSIONS: The lower plasma concentrations of fluticasone and, to a lesser extent, budesonide seen when the drugs were inhaled following induced bronchoconstriction, is likely to reflect variations that will occur with fluctuations in airway caliber in asthma.     

Methods used to assess pulmonary deposition and absorption of drugs

The assessment of pulmonary drug absorption and deposition is becoming increasingly important in drug development. Absorption information can be used to maximize pulmonary selectivity, to screen drug candidates and to help evaluate the bioequivalence of generic inhalation products. Several methods are available to investigate pulmonary drug absorption and deposition, ranging from in vitro experiments to in vivo pharmacokinetic and pharmacodynamic analyses. In combination, these methods can indicate the fate of an inhaled drug.     

Akute Leukämien des Erwachsenen

Background

The prognosis of adult patients with acute leukemia has continuously improved over the years due to the introduction of new diagnostic and therapeutic procedures and progress in the field of supportive therapy.

Methods

This article gives an overview of the currently available options and the clinical approach to the diagnostics and therapy of acute leukemia.

Results

The standardization as well as improvements in diagnostic procedures, in particular by immunocytological and genetic procedures, allow a more rapid determination of the exact diagnosis. In addition to age and performance status of patients, an established panel of cytogenetic and molecular markers allows an individual risk stratification for selecting the most appropriate therapeutic procedure for each patient. In acute myeloid leukemia (AML) younger patients with genetically determined intermediate and poor risk status benefit from allogeneic stem cell transplantation whereas patients in the low risk group are still primarily treated with conventional induction chemotherapy with anthracycline and cytarabine. The poor prognosis of elderly patients with AML has been improved by the development of stem cell transplantation procedures with reduced intensity conditioning and for patients not suitable for stem cell transplantation, the introduction of less toxic demethylating substances allows a substantial improvement in outcome and quality of life compared to cytoreductive therapy alone. The additional role of targeted therapies in AML is still under investigation. In adult patients with acute lymphoblastic leukemia (ALL), the standard systemic therapy still consists of complex cytotoxic regimens which have been modified from pediatric protocols. Biologically and genetically determined subgroups of ALL patients as well as poor responders, who can be identified by the detection of significant molecular determined residual disease (MRD) after standard therapy, benefit from allogeneic transplantation in first remission. In patients with bcr-abl positive ALL, the implementation of first and second generation tyrosine kinase inhibitors has led to rapidly rising response rates and less toxicity. Patients with relapsed ALL may benefit from new molecular options, e.g. bispecific antibodies. Additionally, improved standardization and supportive care, particularly due to the introduction of modern antimycotic agents, increase the treatment options and improve the prognosis of patients with acute leukemia.

Conclusion

The improved diagnostic and therapeutic options for patients with acute leukemia require a complex management. Currently only subgroups of patients benefit from molecular targeted therapeutic strategies. Due to this increasing complexity in the management, patients with acute leukemia should be treated in academic centers and within clinical trials.

     

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma

OBJECTIVE: Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit. DATA SOURCES: Published articles and data on file (Novartis Pharma AG, Genentech). RESULTS: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50 ng/ml (20.8 IU/ml) or less (target 25 ng/ml (10.4 IU/ml)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient's weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150-375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators. CONCLUSIONS: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.     

Psychological factors of familial alcoholism in American Indians and caucasians

Previous studies have reported on the familial transmission of alcoholism and its psychological concomitants. To date, investigators have not studied the familial factor and its relationship to transmission/risk in a group of American Indians (doubly at risk for alcoholism). In two related studies, we have assessed psychological adjustment and drinking behavior of (1) a group of Indians with one or more first-degree alcoholic relatives and a group of Indians without a history of familial alcoholism; and (2) Indians with a history of familial alcoholism compared to Caucasians with a history of familial alcoholism. Results indicate no psychological functioning differences between familial and nonfamilial Indians. However, the familial Indian group reported a style of drinking that more closely resembled that of an alcoholic group. Looking at these data cross-culturally, there are differences between Indians and Caucasians on psychological adjustment, as well as drinking behavior. These differences are present in spite of a shared familial history of alcoholism.     

Molecular response of CML patients treated with interferon-α monitored by quantitative Southern blot analysis

We analysed 459 samples from 206 chronic myeloid leukaemia (CML) patients at diagnosis and during or after treatment with interferon-α (IFN-α) by quantitative Southern blot analysis for BCR rearrangement. In a minority (2%) of Ph-positive patients, no BCR rearrangement was detectable due to breakpoints outside the major breakpoint cluster region (M-bcr) or possibly due to M-bcr deletions. Results from 235 samples were compared with the proportion of Ph-positive metaphases found in contemporaneous bone marrow specimens analysed by conventional cytogenetics. The rank correlation between both methods was 0.82 ( P <0.001). The proportion of CML cells in samples determined by Southern blot analysis (BCR ratio) was significantly different between cytogenetically-defined minor, partial, and complete response groups ( P <0.001). Empirically-derived cut-off points in the BCR ratio were introduced in order to define molecular response groups for comparison to standard cytogenetic response groups: a BCR ratio of 0% was defined as complete molecular response and ratios of 1–24%, 25–50%, and >50% were defined as partial, minor, and no molecular response, respectively. Using these cut-off points the concordance between both methods was 67% ( P <0.0001), a major cytogenetic response could be predicted or excluded in more than 90% of cases ( P <0.0001). Our findings demonstrated that quantitative Southern blot was as sensitive as cytogenetics and as peripheral blood samples are suitable for this technique it should be considered as the method of choice for routine monitoring IFN-α therapy in CML patients.