[SGLT2 inhibitors, also in frail older adults?] / SGLT2-remmers, ook bij kwetsbare ouderen?

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) have gained prominence in the treatment of diabetes mellitus type 2, heart failure, and chronic kidney disease. However, concerns arise for frail older adults, given their underrepresentation in trials and heightened susceptibility to adverse drug events. This review summarizes the clinical effects of SGLT2 inhibitors in older adults with frailty. SGLT2 inhibitors seem to exhibit consistent cardiovascular benefits irrespective of age. As such, these drugs can be beneficial for older adults with 'cardiovascular frailty': in other words, cardiovascular multimorbidity. However, in the current data there is a lack of focus on the broader definition of frailty, which also includes functional status and self-dependence. Also, some research suggest that adverse events, such as volume depletion and genitourinary infections, are more common in the frail older population. Therefore, until more data is available, SGLT2 inhibitors should be prescribed with caution in older adults living with frailty.

Towards a "prescribing license" for medical students: development and quality evaluation of an assessment for safe prescribing.

PURPOSE: This report describes the development and validation process of an assessment with national consensus in appropriate and safe pharmacotherapy. METHODS: A question-database on safe prescription based on literature of pharmacotherapy-related harm was developed by an expert group from Dutch medical faculties. Final-year medical students concluded a 2-year education program on appropriate and safe prescription by one of nine assessment variants of 40 multiple-choice questions each. An expert panel of professionals (n = 10) answered all database questions and rated questions on relevance. Questions were selected for revision based on lack of relevance or poor test and item characteristics. RESULTS: A total of 576 final-year medical students of the Radboud University was assessed. There was no significant difference in performance between students and content expert group (p = 0.7), probably due to learning behavior. Out of 165 questions, 59 were selected for revision. CONCLUSION: Joint national effort from a team of experts in prescription and pharmacotherapy is an appropriate way to achieve a valid and reliable last-year student drug prescription assessment.

Thermodynamic evaluation of the stability of the bone-seeking radiopharmaceutical [177Lu]Lu(III)-DOTP under simulated blood plasma conditions.

The stability and in vivo robustness of [(177)Lu]Lu-DOTP as a potential bone-targeting radiopharmaceutical was determined with the aid of thermodynamic blood plasma modeling simulations. Glass electrode potentiometry was employed to measure the stability constants of the complexes of Lu(3+) with DOTP. Similarly, the complexes of DOTP with a selection of the important physiological metal ions: Ca(2+), Mg(2+), and Cu(2+) were determined, representing the typical interactions that the ligand would encounter upon administration. This made possible the construction of a blood plasma model of DOTP, aiding in establishing the potential susceptibility of the radiopharmaceutical. The ligand binds predominantly to calcium in vivo, accounting for 59.6% of that initially introduced as a component of the Lu-DOTP complex. Furthermore, due to a preference of the DOTP to bind to Cu(2+) it causes mobilization of the ions in blood plasma, and would therefore indicate a deficiency if the ligand is administered at a concentration of 8.5 × 10(-5) mol dm(-3). The lutetium-ions are preferentially bound to DOTP, with as much as 98.1% of the Lu(3+) occupying the ligand under physiological conditions.

Targeted radiotherapy of bone malignancies.

The severe pain associated with many disorders affecting bone account for a large proportion of cases of patient morbidity, due to the encumbrance of mobility and therefore, compromised quality of life. Skeletal metastasis is one such condition, which generally complicates the treatment of the primary cancers such as that of the breast, prostate and lung - causing intense pain and eventually even mortality. This paper presents examples of various approaches explored and proposed in the ongoing search to identify better radiopharmaceuticals for the treatment of bone disorders such as metastases. The primary objective of these developments is to alleviate the debilitating pain commonly associated with bone lesions. The efficacy of a radiotherapeutic agent intended for the treatment of diseased bone is particularly dependent on the radiation dose to the tumor cells and on the extent to which suppression of bone marrow or other critical organs can be avoided. Therefore, the design rationale requires careful consideration of the choice radionuclide and especially ensuring that the drug selectively targets the lesion or tumor site. The options pursued include the use of radioisotopes with an intrinsic affinity for bone, such as (89)Sr or (223)Ra, or the design of bone-seeking ligands, such as phosphonates, to selectively deliver the radionuclide to the target, e.g. [(153)Sm]Sm-EDTMP. A combination of the above may too be possible, where the bone seeking ligand facilitates the selective accumulation of a radionuclide, which by itself is also bone homing. In terms of therapeutic application radionuclides with various decay modes are proposed, including beta (-) emitters: (153)Sm, (89)Sr, (186)Re, (188)Re, (32)P, (177)Lu and (170)Tm; alpha (α) emitters: (223)Ra and (225)Ra; and Auger or conversion electron emitter: (117)mSn. From a purely diagnostic perspective, the radioisotopes used for imaging include the well known photon emitting (99)mTc, and positron emitters (18)F and (68)Ga. The current status in the development and application of internal radiotherapy for the palliative treatment of bone pain will be discussed, summarizing the progress made and challenges encountered in the process to realizing an effective drug candidate.

[Frailty in the elderly]. / 'Frailty' bij ouderen.

Older people differ in their level of multimorbidity, functional dependence and need for assistance. Frailty is a recently constructed syndromatic entity used to characterize vulnerable older people with an increased risk of functional decline, institutionalization and death. This is illustrated by the case history of a 97-year-old woman. In addition to somatic multimorbidity, she suffered from fatigue, weight loss, diminished strength and mood, fear of falling and a decreased gait velocity, without a clear link to a disease. The term 'frailty' is useful in such cases and its application is quickly expanding. Frailty highlights the need to individualize and integrate guidelines for treatment, and to prevent adverse outcomes by choosing health care interventions fit for such frail elderly. However, in practice the frailty syndrome is defined by diverse sets of criteria. As frailty is used to predict different adverse outcomes, a single definition is not possible. Awareness of the advantages and pitfalls of the frailty concept may lead to fruitful clinical application.

Blood plasma model predictions for the proposed bone-seeking radiopharmaceutical [(117m)Sn]Sn(IV)-N,N',N'-trimethylenephosphonate-poly(ethyleneimine).

In an attempt to elucidate the in vivo stability of the prospective radiopharmaceutical [(117m)Sn]Sn(IV)-PEI-MP, where PEI-MP stands for N,N',N'-trimethylenephosphonate-polyethyleneimine, glass electrode potentiometry was used to determine the stability constants of the Sn(4+) ion as complexed with a variety of physiological amino acids. In addition, linear free energy relationship (LFER) correlation plots were used to extrapolate the constants of the major blood plasma ligands, based on data from Cu(2+), Pb(2+), and Zn(2+). In so doing, a thermodynamic model of blood plasma was established for Sn(4+) from which the complexation tendencies of Sn(4+) were predicted in the event of the intravenous administration of such a drug. It was found that the Sn(IV)-PEI-MP could succumb to competition by the glutamine amino acid, which forms more stable complex(es), whilst the PEI-MP gets taken up largely by Ca(2+). Also, this study shows the value of the in vitro experiments and modeling performed for radiopharmaceutical research and for attempts to reduce the number of animal experiments.

Hydroxyapatite chemisorption of N,N',N'-trimethylenephosphonate-poly(ethyleneimine) (PEI-MP) combined with Sn2+ or Sn4+.

To study the mechanism by which proposed bone-seeking radiopharmaceuticals consisting of tin (as l17mSn) and N,N',N'-trimethylenephosphonate-poly(ethyleneimine) (PEI-MP) are taken up and accumulated in bone tissue, the adsorption of Sn2+, Sn4+, and phosphonate polymer PEI-MP on hydroxyapatite was measured in vitro. Hydroxyapatite is the main mineral phase of bone; therefore, by determining the affinity of the metal ions and the ligand-and hence their complexes-for hydroxyapatite, the extent to which the radiopharmaceutical will be adsorbed can be predicted. The adsorption of the tin-phosphonate complexes and the two individual components to the solid phase was measured by inductively coupled plasma optical emission spectroscopy at physiological pH, at room temperature, and for a period of 48 h. The tin complexes and free ligand exhibited unique binding affinities. By varying the oxidation state of the metal ion (Sn2+, and Sn4+) and the size of the polyphosphonate ligand (using 10-30 and 30-50 kDa fractions), the adsorption characteristics of the individual components could be adapted. The tin-PEI-MP combination that showed the most favorable adsorption behavior was that of Sn2+ and PEI-MP(10-30 kDa), which had a maximum adsorption capacity of 2.21 +/- 0.14 micromol m(-2) and an affinity of 9.8 +/- 4.0 dm3 mmol(-1) with respect to the ligand and 2.30 +/- 0.07 micromol m(-2) and 26.6 +/- 6.1 dm3 mmol(-1) for the metal ion-as derived from the Langmuir adsorption model. The ligand showed enhanced adsorption when complexed with tin. This research provided a preliminary indication that the tin-PEI-MP combination could be favorable to other bone-seeking radiopharmaceuticals since the maximum adsorption capacities are comparable while PEI-MP offers the opportunity of using the enhanced permeability and retention effect for enhanced tumor accumulation.

Comparison of the predicted in vivo behaviour of the Sn(II)-APDDMP complex and the results as studied in a rodent model.

In a quest for more effective radiopharmaceuticals for pain palliation of metastatic bone cancer, this paper relates results obtained with ((117m)Sn labelled) Sn(II) complexed to the bone seeking bisphosphonate, N,N-dimethylenephosphonate-1-hydroxy-3-aminopropylidenediphosphonate (APDDMP). APDDMP is synthesised from the known bone cancer pain palliation agent 1-hydroxy-3-aminopropylidenediphosphonate (APD, Pamindronate). This work is performed to utilise the idea that the low bone marrow radio toxicity of (117m)Sn could afford a highly effective radiopharmaceutical in pain palliation but also in the curative treatment of bone metastasis. Complex-formation constants of APDDMP with the important blood plasma metal-ions, Ca(2+), Mg(2+), Zn(2+) as well as the added metal ion, Sn(2+) were measured by glass electrode potentiometry at 25 degrees C and I = 150 mM. Blood plasma models were constructed using the computer code ECCLES and the results compared with those gathered from tests on a rodent model. The ((117m)Sn-labelled) Sn(II)-APDDMP complex was found to have only some liver and bone uptake although a high trabecular to normal bone ratio was recorded. From the blood plasma model this was shown to be primarily due to the high affinity of APDDMP for Ca(II) causing some of the Sn(II)-APDDMP complex to dissociate. High kidney uptake and excretion as well as high bladder uptake was recorded which was shown to be due to the dissociation of the Sn(II)-APDDMP complex in blood plasma. Animal model observations could be explained by the blood plasma modelling.