Mortality and Hospitalizations Among Patients Enrolled in an Interprofessional Medication Management Program.

BACKGROUND: Measures for improving medication safety in outpatient care are often complex and involve medication reviews. Over the period 2016-2022 (with a preceeding one-year pilot phase), an interprofessional medication management program- the Medicines Initiative Saxony-Thuringia (Arzneimittelinitiative Sachsen-Thüringen, ARMIN)-was implemented in two German federal states. More than 5000 patients received a medication review by the end of 2019 by a team composed of physicians and pharmacists and were provided with joint, continuous care thereafter. METHODS: In the framework of a retrospectively registered cohort study, the mortality and hospitalizations of this population (5033 patients) were studied using routine data from a statutory health insurer (observation period 2015-2019) and compared with those of a control group (10 039 patients) determined from the routine data by propensity score matching. Mortality was compared by survival analysis (Cox regression), and hospitalization rates were compared in terms of event probabilities within two years of enrollment in the medication management program. Robustness was tested in multiple sensitivity analyses. RESULTS: Over the observation period, 9.3% of the ARMIN participants and 12.9% of persons in the control group died (hazard ratio of the adjusted Cox regression, 0.84; 95% confidence interval [0.76; 0.94], P = 0.001). In the first two years after inclusion, the ARMIN participants were hospitalized just as often as the persons in the control group (52.4% versus 53.4%; odds ratio from the adjusted model, 1.04 [0.96; 1.11], P = 0.347). The effects were consistent in sensitivity analyses. CONCLUSION: In this retrospective cohort study, participation in the ARMIN program was associated with a lower risk of death. Exploratory analyses provide clues to the potential origin of this association.

[Medication reviews in community pharmacies: An approach to external quality assessment]. / Medikationsanalysen in öffentlichen Apotheken: Konzept zur externen Qualitätsüberprüfung.

BACKGROUND: A medication review aims at the optimization of medication use, the detection of drug-related problems (DRPs) and the recommendation of interventions. As part of the pilot project "Arzneimittelinitiative Sachsen-Thüringen" (ARMIN) and caused by the introduction of several training programs, numerous public pharmacies in Germany currently offer medication reviews for patients. However, a standardized method for external quality control has so far not been established. METHODS: A round robin test for medication reviews was designed in written form by five pharmacists with expertise in different areas (Drug information service ARMIN, Saxonian Chamber of pharmacists, public pharmacy, hospital pharmacy), based on the recommendations of the guideline for medication reviews of the German Federal Chamber of Pharmacists (Bundesapothekerkammer). On the basis of a fictitious case study the participants were asked to check a patient's medication data for the presence of DRPs, propose possible solutions and generate a medication plan. The solutions were assessed by two pharmacists of the drug information service ARMIN on the basis of a best practice solution that had been consented in the study group beforehand. RESULTS: 102 pharmacists and 13 pharmacy students in internship took part in the round robin test. On average, participants achieved a score of 7,62 out of 9 for recognizing DRPs and recommending solutions and a score of 0,79 out of 1 for generating a correct medication plan. 106 participants (92%) met the requirements for successful participation (recognizing the three most relevant DRPs and at least one further DRP as well as generating an adequate medication plan). The implementation of the approach described here proved to be practicable The State Directorate of Saxony accepted the round robin test as a measure for external quality assessment in accordance with legal requirements. CONCLUSIONS: Due to the nationwide introduction of medication reviews as a pharmaceutical service in June 2022, medication reviews performed by German community pharmacies will gain in importance in the coming years. This is why quality assurance is necessary. Since the participants' performance in medication analysis becomes comparable by completing the round robin test, this instrument appears to be potentially suitable for the external quality assessment of medications reviews nationwide.

Attitudes of non-participating general practitioners and community pharmacists towards interprofessional medication management in primary care: an interview study.

BACKGROUND: Interprofessional medication management in primary care is a recognized strategy for improving medication safety, but it is poorly implemented in Germany. As a pilot project, ARMIN [Arzneimittelinitiative Sachsen-Thüringen] was initiated in 2014 to establish better interprofessional medication management between general practitioners and community pharmacists. AIM: The aim of this study was to explore the views of non-participating general practitioners and community pharmacists towards interprofessional medication management within ARMIN and to identify barriers to participation. METHOD: This was an interview study comprising a series of semi-structured telephone interviews. In total, 36 general practitioners and 15 community pharmacists were interviewed in the period between March and June 2020. Data were analyzed using thematic analysis as an inductive approach and the consolidated framework for implementation research as a deductive approach. RESULTS: Many general practitioners and community pharmacists had a generally positive attitude towards interprofessional medication management. However, various barriers were identified and categorized into five major themes: (I) collaboration between general practitioners and community pharmacists, e.g. concerning general practitioners' professional sovereignty and pharmacists' fear of jeopardizing their relationship with general practitioners when interfering in therapy; (II) eligibility for participation, e.g., the fact that patients had to be insured with a specific statutory health insurance fund; (III) local circumstances, e.g. many pharmacists could not find a collaborating general practitioner (and vice versa). Moreover, patient demand was low, probably because patients were not aware of the program; (IV) information technology, e.g. concerning the lack of available software and data security concerns; and (V) cost-benefit ratio, e.g. the fact that potential benefits were outweighed by program-associated costs. CONCLUSION: The perceived discrepancy between positive attitudes and multiple prevalent barriers indicates considerable potential for further interprofessional collaboration between general practitioners and community pharmacists.

Patients' perception on generating medication plans in an interprofessional medication management program: a mixed-methods study.

A medication plan (MP) provides an overview of a patient's entire medication. In the interprofessional medication management program ARMIN (ARzneiMittelINitiative Sachsen-Thueringen), MPs are jointly generated by general practitioners (GPs) and community pharmacists (CPs). We aimed to assess patients' initial acceptance of the service, how they use the printed MP, and whether they perceived a benefit from it. This was evaluated with mixed-methods: a cross sectional written (quantitative) survey followed by semi-structured (qualitative) interviews. The data were analysed separately and compared. Qualitative data were analysed by thematic analysis. For the survey, 103 patients (mean 73 years) were involved. Benefits indicated were: improved communication between GPs and CPs, safer handling of the medication, and increased knowledge on dosages and indications. Ninety-six percent of the patients used their MP, 51% regularly. Regular use was significantly associated with older age, higher number of drugs, and need for assistance with the medication. Ten patients were interviewed. Results from interviews agreed with the results from the survey but revealed some additional aspects (e.g., patients reported an increased feeling of safety). Health-care professionals should consider providing MPs for their patients. This interprofessional cooperation also meets patient's need for safety in health issues.

Solid-Phase Synthesis of Megamolecules.

This paper presents a solid-phase strategy to efficiently assemble multiprotein scaffolds-known as megamolecules-without the need for protecting groups and with precisely defined nanoscale architectures. The megamolecules are assembled through sequential reactions of linkers that present irreversible inhibitors for enzymes and fusion proteins containing the enzyme domains. Here, a fusion protein containing an N-terminal cutinase and a C-terminal SnapTag domain react with an ethyl p-nitrophenyl phosphonate (pNPP) or a chloro-pyrimidine (CP) group, respectively, to give covalent products. By starting with resin beads that are functionalized with benzylguanine, a series of reactions lead to linear, branched, and dendritic structures that are released from the solid support by addition of TEV protease and that have sizes up to approximately 25 nm.

[Effect of acetylcholine and acetylcholinesterase on the activity of contractile vacuole of Amoeba proteus].

Acetylcholine (ACh, 1 microM) stimulates activity of the contractile vacuole of proteus. The effect of ACh is not mimicked by its analogs which are not hydrolyzed by acetylcholinesterase (AChE), i. e., carbacholine and 5-methylfurmethide. The effect of ACh is not sensitive to the blocking action of M-cholinolytics, atropine and mytolone, but is suppressed by N-cholinolytic, tubocurarine. The inhibitors of AChE, eserine (0.01 microM) and armine (0.1 microM), suppress the effect of ACh on amoeba contractile vacuole. ACh does not affect activation of contractile vacuole induced by arginine-vasopressin (1 microM), but it blocks such effect of opiate receptors agonist, dynorphin A1-13 (0.01 microM). This effect of ACh is also suppressed by the inhibitors of AChE. These results suggest that, in the above-described effects of ACh, AChE acts not as an antagonist, but rather as a synergist.

Mechanisms of cardiac muscle insensitivity to a novel acetylcholinesterase inhibitor C-547.

We compared the effects of the novel acetylcholinesterase (AChE) inhibitor C-547 on action potential configuration and sinus rhythm in the isolated right atrium preparation of rat with those of armin and neostigmine. Both armin (10(-7), 10(-6), and 10(-5) M) and neostigmine (10(-7), 10(-6), and 5 x 10(-6) M) produced a marked decrease in action potential duration and slowing of sinus rate. These effects were abolished by atropine and are attributable to the accumulation of acetylcholine in the myocardium. The novel selective AChE inhibitor C-547 (10(-9) to 10(-7) M), an alkylammonium derivative of 6-methyluracil, had no such effects. The inhibition constant of C-547 on cardiac AChE is 40-fold higher than that on extensor digitorum longus muscle AChE. These results suggest that C-547 might be employed to treat diseases such as myasthenia gravis or Alzheimer disease, without having unwanted effects on the heart.

[The use of probit-method for an estimation of toxic effects of combined toxicants at low concentration levels]. / Ispol'zovanie probit-metoda pri otsenke toksicheskikh éffektov kombinirovannogo deistviia toksikantov na nizkikh urovniakh vozdeistviia.

In the present report the result of investigation of combined operating of propyl clone of Arminum is esteemed at effect on different intensity levels (LD, ED, Relatively Safe Level of Compound), with three-orthocresylphosphate and chlorophose in experience on white mice. The tendency of more expressed potentiation of toxic effect is detected at low levels of toxicant effect. Based on the dates of literature and the mathirials of the inner investigation, the expediency of the count toxicometric and statistical parameters received by a probit-method at a 5% level responses of the bioanswer is routined at a quantitative assessment of effects of combined operating of xenobiotics on low levels of effect.

[Modulation of the intensity of the non-quantal transmitter release by nitric oxide (NO) at the neuromuscular junction]. / Moduliatsiia intensivnosti nekvantovoi sekretsii mediatora v nervno-myshechnom soedinenii krysy oksidom azota (NO).

In the rat diaphragm muscle, nitric oxide (NO)--sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP), as well as substrate for the NO synthesis L-arginine, decrease the level of hyperpolarization of the muscle fibre membrane after acetylcholine receptor blockade by the d-TC and irreversible acetylcholinesterase inhibition by armin (H-effect). Contrary to that, disruption of the NO synthesis in the muscle fibres by the NO-synthase inhibitor NG-nitrol-L-arginine methyl ester (L-NAME) results in enhancement of the H-effect both in vitro and in vivo. Inactivated SNP and inactive forms of arginine and NAME did not affect the H-effect magnitude. Haemoglobin, effectively binding the NO molecules, abolishes the suppressing effects of the SNP, SNAP and L-arginine upon the H-effect. The findings suggest that the NO could be acting as a modulator of nonquantal transmitter release at the mammalian neuromuscular junction.

[Protection of mice by carbamates cholinesterase inhibitors against poisoning by armin and its dependence on certain physico-chemical indicators]. / Zashchita myshei ingibitorami kholinésterazy iz klassa karbamatov ot otravleniia arminom i zavisimost' ot nekotorykh fiziko-khimicheskikh pokazatelei.

A series of aminostigmin derivatives with various substituents at nitrogen in the second position of the pyridine ring, has been tested. The efficacy of preventing the death of mice poisoned by armine in five of the seven substances correlates with the constant of the rate of carbamylation of acetylcholinesterase in the in vitro experiments and with the hydrophobic nature. It is suggested that the phenomenon of protection of animals against the toxic effect of organophosphorous compounds involves the "leaving portion" of the molecule of carbamates.

[The effect of armin on neuromuscular transmission in the frog against a background of hexadecamethonium action]. / Vliianie armina na nervno-myshechnuiu peredachu liagushki na fone deistviia geksadekametoniia.

Hexadecamethonium as well as its alkylating derivatives significantly decrease the effect of organophosphorous acetylcholinesterase inhibitor armine on the amplitude and duration of the EPPs. It seems possible that these substances prevent inhibition of acetylcholinesterase. This property of the substances seems to be due to a polymethelene chain with two nitrogens as the basic part of the molecule structure.

Alkylating derivative of hexadecamethonium protects muscle synaptic acetylcholinesterase against inhibition.

The action of the alkylating derivative of hexadecamethonium on frog neuromuscular transmission was studied with the help of intracellular microelectrodes. Treatment of frog m. cutaneous pectoris-n. pectoralis preparations with the alkylating derivative of hexadecamethonium (0.5 microM) for 30 min led to an irreversible decrease in the amplitude of the end-plate potentials by 2.5-fold without a change of their latency period or quantal content. Such treatment led also to a considerable reduction of the anticholinesterase effects of neostigmine and of the organophosphorus irreversible inhibitor, armine. Thus, when applied to intact nerve-muscle preparations, neostigmine (2 microM) or armine (1 microM) increased the amplitude of end-plate potentials by 80-90%, and the rise time and half-decay time by about 2- to 3-fold. However, after the nerve-muscle preparations were pretreated with the alkylating derivative of hexadecamethonium (0.5 microM, for 30 min), the amplitude of end-plate potentials increased by 20-25%, rise time by 15-20% and half-decay time by 40-50% only. Investigation of muscle acetylcholinesterase activity, using the Ellman technique, showed that the alkylating derivative of hexadecamethonium diminished the sensitivity of the muscle acetylcholinesterase to inhibition without exerting its own inhibitory action.

[Non-quantal secretion of a mediator as factor determining consequences of acetylcholinesterase inhibition]. / Nekvantovaia sekretsiia mediatora kak faktor, opredeliaiushchii posledstviia ingibirovaniia atsetilkholinésterazy.

The mechanism of shortening MEPC decay phase after initial prolongation due to acetylcholinesterase inhibition by armine and neostigmine was studied by use of two-electrode voltage-clamp at the mice diaphragm Factors which switch off non-quantal secretion of acetylcholine from the nerve (acute denervation in vitro, ouabain, high concentration of magnesium ions) only slightly reduced the prolongation of MEPC caused by AChE inhibition. So, postsynaptic potentiation of MEPC by nonquantal ACh is not significant immediately after AChE inhibition. At the same time these factors abolished the process of shortening MEPC decay phase. It is concluded, that desensitization of the postsynaptic membrane induced by nonquantal ACh is the main mechanism of the MEPC shortening and that this mechanism can compensate insufficient AChE activity.

[Post-intoxication hypothermia and processes of free radical lipid peroxidation in the rat brain and heart in organophosphorus cholinesterase inhibitor poisoning]. / Postintoksikatsionnaia gipotermiia i protsessy svobodnoradikal'nogo okisleniia lipidov v mozge i serdtse krys pri otravlenii fosfororganicheskimi ingibitorami kholinésteraz.

The activity of lipid peroxidation (LP) of the brain and myocardium as well as the intensity of the body hypothermia during 30 days after a single introduction of poisons at a dose < D50 were studied on the models of induced toxicosis in rats due to two organophosphorus compounds (malathion and armin). It has been established that the maximums of diene conjugates and Schiff's bases accumulation in the rat organs poisoned with malathion and the intensity of hypothermic response on days 14 and 21 after intoxication coincided. The similar elevated lipid peroxidation was associated with esophageal hypothermia on day 14 after armin administration. Therefore, because of hypothermia, the influence of organophosphorus compounds on lipids of the rat brain and heart in the post-intoxication period may include the free radical ways of their peroxidation.

[The effect of fenazepam on the humoral immune response in secondary immunodeficiency]. / Vliianie fenazepama na gumoral'nyi immunnyi otvet pri vtorichnom immunodefitsite.

A single administration of phenazepam (2.5 mg/kg) enhances the synthesis of antibodies after immunization with different vaccines. Phenazepam restores antibody formation in immunodeficiency induced by intoxication. The immunostimulating effect of phenazepam is linked with an increase in the capacity of macrophages for inducing humoral immune response and a rise in the number of antibody-producing cells in the spleen.

Non-quantal acetylcholine release after cholinesterase inhibition in vivo.

After anticholinesterase treatment in vivo, depolarization of the postsynaptic muscle fibre membrane by about 4 mV develops due to non-quantally released acetylcholine from the motor nerve terminal. This conclusion was supported by experiments with the curarization of diaphragm slices from anticholinesterase treated mice during intracellular microelectrode recordings.

[Effect of the quantal composition, membrane potential and cholinoreceptor density on the temporal flow of the end plate current in the rat under conditions of acetylcholinesterase inhibition]. / Vliianie kvantovogo sostava, membrannogo potentsiala i plotnosti kholinoretseptorov na vremennoe techenie tokov kontsevoi plastinki krysy v usloviiakh ingibirovaniia atsetilkholinésterazy.

The factors determining the decay of multiquantal end plate currents (EPC) were studied in the diaphragm muscle of rat by the comparison of EPC and miniature EPC (MEPC) amplitude--temporal characteristics. The decay of EPC (quantal content 25-100) was 1.2 times slower than the decay of MEPC when AChE was active. The AChE inhibition by armine or neostigmine made this difference 10-100 times higher. In most synapses the decay of multiquantal EPC can be approximated by a sum of two or three exponents. It depended on the quantal content and 3-exponential EPC could be transformed in 2-exponential and later to monoexponential ones if increasing concentration of magnesium ions. A slow component of EPCs (but not of MEPC) decay was highly sensitive to concentration of magnesium ions and had 3 times higher dependence of the membrane potential value than that one of MEPC. The irreversible blocking of receptors by alpha-bungarotoxin (alpha-BuTX) accelerated the decay of MEPC but the decay of multiquantal EPC changed in two phases: it was prolonged at the beginning of alpha-BuTX action followed by its acceleration, but never the time of the decay of EPC had achieved the apparent open time of ACh-activated ionic channels. It is suggested that during the multiquantal EPC generation not only the synchronization of opening but the kinetic of ACh-activated channels is changed, probably by blocking of this channels by high concentrations of endogenous ACh.