When poor solubility becomes an issue: From early stage to proof of concept

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.     

Das Verhalten der endexspiratorischen Atemgasdrucke,der O2-Aufnahme und CO2-Abgabe nach einfacher Apnoe im Wasser,an Land und apnoeischem Tauchen

Zusammenfassung Um zu untersuchen, wie ein Tauch- oder Atemanhalte-manöver den Sauerstoffverbrauch und die CO₂-Abgabe des Menschen beeinflußt, hielten 6 männliche Versuchspersonen 30, 60, 90, 120 und 165 sec ruhig an der Wasseroberfläche und an Land liegend den Atem an. In einer Vergleichsserie tauchten sie in 80 cm Tiefe gleich lange.Nach der Apnoe wurden der endexspiratorischeP _{O 2} undP _{CO 2}, und die Sauerstoffaufnahme und die CO₂-Abgabe pro Atemzug mit Hilfe eines Massenspektrometers und eines Pneumotachographen ermittelt.Es zeigte sich, daß die Sauerstoffschuld, die während der Apnoe eingegangen wird, beim Atemanhalten im Wasser bis zu 29%, an Land bis zu 38% unter der O₂-Schuld lag, die zu erwarten wäre, wenn die gemessene Ruheaufnahme angehalten hätte. Beim Tauchen sank die O₂-Schuld bis etwa 28% unter die erwartete Schuld. Der endexspiratorischeP _{O a} in der ersten Exspiration fiel mit Zunahme der Apnoezeit ab, lag jedoch bei gleich langen Apnoezeiten nach Tauchen signifikant unter dem Wert nach Atemanhalten.Die CO₂-Abgabe nach der Apnoe entsprach bis zu einer Apnoezeit von 90 sec etwa der in der Apnoe gebildeten Menge. Bei längeren Apnoezeiten trat eine deutliche CO₂-Retention ein. Beim Atemanhalten wurde bis zu 60% weniger CO₂ abgegeben als zu erwarten war.Der endexspiratorischeP _{CO 2} im ersten Exspirationsgas lag unabhängig von der Apnoezeit ziemlich konstant bei 45 mm Hg, die CO₂-Abgabe in der ersten Exspiration konstant bei etwa 150 ml ohne wesentlichen Unterschied zwischen Tauchen und Atemanhalten.     

Blood pressure and heart rate during rest-exercise and exercise-rest transitions

Summary The transients of mean arterial blood pressure ( ) and heart rate (f _c) during rest-exercise and exercise-rest transitions have been studied in six healthy sport students. After 5 min of rest in an upright position on a cycle ergometer they exercised for 15 min and remained seated for a further 5 min. The subjects exercised at four different constant intensities (40 W, 80 W, 120 W, 160 W) in random order separated by at least 24 h. The was determined by a noninvasive and continuous method. During the first minute of exercise, three phases of response could be distinguished, with the first two showing no clear relationship to intensity. Phase 1 consisted of simultaneous increases in bothf _c and BP during the first 6 s. In phase 2, decreased whilef _c continued to increase. During phase 3, andf _c approximated constant values or a linear increase. Both parameters showed no comparable intensity-independent reactions during the off-transients. In conclusion, during the first 15 s of rest-exercise transitions there seems to be a fast and uniform cardiovascular drive which overrode other influences onf _c.     

Challenges and opportunities in the design of age-appropriate drug products

The age appropriateness of a pharmaceutical product for older patient populations is most important in achieving ease of use, administration, and adherence as well as the therapeutic benefit of the drug. Drug development is a lengthy and risky investment accompanied by extensive regulatory requirements to meet all the safety, efficacy, and quality criteria of a pharmaceutical product. Older adults represent a very heterogeneous patient population with different needs compared to younger adults. Major areas that should be considered in the design of age-appropriate products (AAP) are age- and disease-related aspects such as (a) different dose strengths, (b) issues in handling, administering, and managing the drug product, (c) and complex medication regimens. The application of different technologies can meet these specific needs and should be considered at the very beginning of product development when setting the targeted quality product profile (TQPP) or later on during the product life-cycle management.     

Intraventricular dyssynchrony predicts mortality and morbidity after cardiac resynchronization therapy: a study using cardiovascular magnetic resonance tissue synchronization imaging.

OBJECTIVES: We aimed to assess a novel measure of left ventricular (LV) dyssynchrony, a cardiovascular magnetic resonance-tissue synchronization index (CMR-TSI), in patients with heart failure (HF). A further aim was to determine whether CMR-TSI predicts mortality and major cardiovascular events (MCE) after cardiac resynchronization therapy (CRT). BACKGROUND: Cardiac dyssynchrony is a predictor of mortality in patients with HF. The unparalleled spatial resolution of CMR may render CMR-TSI a predictor of clinical benefit after CRT. METHODS: In substudy A, CMR-TSI was assessed in 66 patients with HF (age 60.8 +/- 10.8 years, LV ejection fraction 23.9 +/- 12.1% [mean +/- SD]) and 20 age-matched control subjects. In substudy B, CMR-TSI was assessed in relation to clinical events in 77 patients with HF and with a QRS > or =120 ms undergoing CRT. RESULTS: In analysis A, CMR-TSI was higher in patients with HF and a QRS <120 ms (79.5 +/- 31.2 ms, p = 0.0003) and in those with a QRS > or =120 ms (105.9 +/- 55.8 ms, p < 0.0001) than in control subjects (21.2 +/- 8.1 ms). In analysis B, a CMR-TSI > or =110 ms emerged as an independent predictor of the composite end points of death or unplanned hospitalization for MCE (hazard ratio [HR] 2.45; 95% confidence interval [CI] 1.51 to 4.34, p = 0.0002) or death from any cause or unplanned hospitalization for HF (HR 2.15; 95% CI 1.23 to 4.14, p = 0.0060) as well as death from any cause (HR: 2.6; 95% CI 1.29 to 6.73, p = 0.0061) and cardiovascular death (HR 3.82; 95% CI 1.63 to 16.5, p = 0.0007) over a mean follow-up of 764 days. CONCLUSIONS: Myocardial dyssynchrony assessed by CMR-TSI is a powerful independent predictor of mortality and morbidity after CRT.     

Matrix composition regulates three-dimensional network formation by endothelial cells and mesenchymal stem cells in collagen/fibrin materials

Co-cultures of endothelial cells (EC) and mesenchymal stem cells (MSC) in three-dimensional (3D) protein hydrogels can be used to recapitulate aspects of vasculogenesis in vitro. MSC provide paracrine signals that stimulate EC to form vessel-like structures, which mature as the MSC transition to the role of mural cells. In this study, vessel-like network formation was studied using 3D collagen/fibrin (COL/FIB) matrices seeded with embedded EC and MSC and cultured for 7 days. The EC:MSC ratio was varied from 5:1, 3:2, 1:1, 2:3 and 1:5. The matrix composition was varied at COL/FIB compositions of 100/0 (pure COL), 60/40, 50/50, 40/60 and 0/100 (pure FIB). Vasculogenesis was markedly decreased in the highest EC:MSC ratio, relative to the other cell ratios. Network formation increased with increasing fibrin content in composite materials, although the 40/60 COL/FIB and pure fibrin materials exhibited the same degree of vasculogenesis. EC and MSC were co-localized in vessel-like structures after 7 days and total cell number increased by approximately 70%. Mechanical property measurements showed an inverse correlation between matrix stiffness and network formation. The effect of matrix stiffness was further investigated using gels made with varying total protein content and by crosslinking the matrix using the dialdehyde glyoxal. This systematic series of studies demonstrates that matrix composition regulates vasculogenesis in 3D protein hydrogels, and further suggests that this effect may be caused by matrix mechanical properties. These findings have relevance to the study of neovessel formation and the development of strategies to promote vascularization in transplanted tissues.     

The First 100 Consecutive,Robot-assisted,Intracorporeal Ileal Conduits: Evolution of Technique and 90-day Outcomes

Background

Robot-assisted radical cystectomy (RARC) has evolved over the last few years to become an acceptable alternative option to open radical cystectomy. Most series of RARC used an open approach to urinary diversion. Even though robot-assisted intracorporeal urinary diversion (RICUD) is the natural extension of RARC, few centers have reported their experiences with RICUD in general, and in particular, of robot-assisted intracorporeal ileal conduits (RICIC).

Objective

To report our experience with RICIC using the Marionette technique.

Design, setting, and participants

The first 100 consecutive patients who underwent RARC and RICIC, and had ≥3 mo of postoperative follow-up were included in this study. Patients were divided into four groups of 25 patients each to study the evolution of our surgical technique.

Intervention

RICIC.

Outcome measurements and statistical analysis

Intraoperative, pathologic, and 90-d postoperative outcomes for the four groups and the overall cohort were compared using the Fisher exact test (categorical variables) and the Kruskal-Wallis test (continuous variables). Continuous variables were reported as median (range) and categorical variables were specified as frequency (percentage).

Results and limitations

Overall operative and specific diversion times were 352 and 123 min, respectively. Estimated blood loss was 300 ml, lymph node yield was 24, and positive surgical margin rate was 4%. Length of hospital stay increased from 7 d for group 1 to 9 d for group 4. The overall 90-d complication rate was 81%; 19% of complications were high grade. Infections were the most common complications, representing 31% of all complications. There were no statistically significant intergroup differences except in diversion time, intraoperative transfusions, and length of stay.

Conclusions

RICIC diversion is safe, feasible, and reproducible. Larger series with longer follow-up are needed to validate the procedure and define its place in the minimally invasive urologic armamentarium. Quality of life studies need to be conducted to compare benefits of intracorporeal urinary diversion.     

How to Regulate Nonbiological Complex Drugs (NBCD) and Their Follow-on Versions: Points to Consider

The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the ‘families’ of liposomes, iron–carbohydrate (‘iron–sugar’) drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.     

Zum Mechanismus der Pulsfrequenzeinstellung durch den Stoffwechsel

Zusammenfassung An Hunden bewirkt die Reizung eines zentripetalen Ischiadicusstumpfes regelmäßig eine steile Zunahme der Pulsfrequenz, die sich mit einem overshoot auf einen neuen, konstanten Wert einstellt, den sie dann über die Dauer der Reizung beibehält. Das erste Pulsintervall nach Beginn der Reizung ist dabei immer schon verkürzt, die Latenzzeit also kürzer als ein Pulsintervall. Bei der Reizung steigt der Gesamtenergieumsatz geringfügig, wohl als Folge der erhöhten Herz- und Atemarbeit. Systolischer und diastolischer Blutdruck steigen bei weitgehend konstanter Blutdruckamplitude in etwa 6 sec auf einen höhern Wert an, der beibehalten wird, solange der Reiz dauert. Durchtrennung der Carotissinusnerven bewirkt einen steileren Anstieg des Blutdruckes, während die Pulsfrequenz nahezu ohne overshoot auf einen höheren Wert eingestellt wird. Die Ergebnisse werden im Zusammenhang mit der Frage diskutiert, wie Informationen über die Stoffwechselgröße vom Muskel zum Herzen gelangen können.

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Summary In dogs the electrical stimulation of the centripetal part of a cut ischiatic nerve caused a rise of the heart rate which reached a new level with an overshoot. This level remained unchanged during the whole stimulation period. The interval between the first two heart beats was shortened direktly after the onset of stimulation. The latent period is therefore shorter than the interval duration time. During the stimulation period the total metabolic rate of the dog is slightly higher than before, very probably as a consequence of the increased heart — and respiration work. The mean blood pressure rises with a constant pulse pressure within about 6 sec to a higher value then remaining constant during the whole stimulation period.The same stimulation caused after dissection of the two carotissinusnerves a sharper rise in bloodpressure and the heart rate reached a higher value than before, nearly without overshoot. The results are discussed in relation to the problem in which way informations from the muscles could be signalized to the heart.

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Influence of propofol on neuronal damage and apoptotic factors after incomplete cerebral ischemia and reperfusion in rats: a long-term observation

BACKGROUND: Propofol reduces neuronal damage from cerebral ischemia when investigated for less than 8 postischemic days. This study investigates the long-term effects of propofol on neuronal damage and apoptosis-related proteins after cerebral ischemia and reperfusion. METHODS: Male Sprague-Dawley rats were randomly assigned as follows: group 1 (n = 32, control): fentanyl and nitrous oxide-oxygen; group 2 (n = 32, propofol): propofol and oxygen-air. Ischemia (45 min) was induced by carotid artery occlusion and hemorrhagic hypotension. Pericranial temperature and arterial blood gases were maintained constant. After 1, 3, 7, and 28 postischemic days, brains were removed, frozen, and sliced. Hippocampal eosinophilic cells were counted. The amount of apoptosis-related proteins Bax, p53, Bcl-2, and Mdm-2 and neurons positive for activated caspase-3 were analyzed. RESULTS: In propofol-anesthetized rats, no eosinophilic neurons were detected, whereas in control animals, 16-54% of hippocampal neurons were eosinophilic (days 1-28). In control animals, the concentration of Bax was 70-200% higher after cerebral ischemia compared with that in animals receiving propofol over time. Bcl-2 was 50% lower in control animals compared with propofol-anesthetized rats during the first 3 days. In both groups, a maximal 3% of the hippocampal neurons were positive for activated caspase-3. CONCLUSIONS: These data show sustained neuroprotection with propofol. This relates to reduced eosinophilic and apoptotic injury. Activated caspase-3-dependent apoptotic pathways were not affected by propofol. This suggests the presence of activated caspase-3-independent apoptotic pathways.