As people age they are more likely to develop chronic conditions and will tend to be on multiple medications for long periods of time to manage those conditions. Some of these medications have side effects that are anticholinergic in nature. These side effects can impact different parts of the body including the central nervous system. As people enter their later years the permeability of the blood brain barrier increases, increasing their risk of these kinds of side effects.

No description available.

<p dir="ltr">Over 50% of ambulatory older adults administer at least one anticholinergic medication. Older adults may be more susceptible to the adverse effects of anticholinergic medications, and there is evidence showing an association between anticholinergic exposure and increased risk of dementia. The primary objective of this research is to assess the impact of one-year of prescriptions for strong anticholinergics, with a score of 2 or 3 on the Anticholinergic Cognitive Burden (ACB) Scale, on cognitive measures indicative of dementia, followed by a comparative assessment of the relative impact of medication classes with anticholinergic activity.</p><p dir="ltr">The study utilizes a retrospective observational design to evaluate the relationship between anticholinergic medication prescriptions and cognitive measures. We used one-year EMR prescription data gleaned from R2D2 and BrainSafe clinical trials’ participants prior to baseline for the exposure variable along with the cognitive measures captured at the baseline visit. Total Standardized Daily Dose (TSDD) was computed from prescription records to quantify exposure to strong anticholinergics. Generalized Linear Models and Least Square means with Tukey’s adjustment were computed to detect the relationship between anticholinergic TSDD and anticholinergic medication classes and cognitive measures in multiple models.</p>

Yes / Anticholinergic medicines are associated with adverse outcomes for older people. However, little is known about their use in frailty. The objectives were to (1) investigate the prevalence of anticholinergic prescribing for older patients, and (2) examine anticholinergic burden according to frailty status. Methods: Cross-sectional analysis of Welsh primary care data from the Secure Anonymised Information Linkage (SAIL) databank including patients aged ≥65 at their first GP consultation between 1st January and 31st December 2018. Frailty was identified using the electronic Frailty Index (eFI) and anticholinergic burden using the Anticholinergic Cognitive Burden (ACB) scale. Descriptive analysis and logistic regression were conducted to 1) describe the type and frequency of anticholinergics prescribed; 2) to estimate the association between frailty and cumulative ACB score (ACB-Sum). Results: In this study of 529,095 patients, 47.4% of patients receiving any prescription medications were prescribed at least one anticholinergic medicine. Adjusted regression analysis showed that patients with increasing frailty had higher odds of having an ACB-Sum of >3 compared to patients who were fit (mild frailty, adj OR 1.062 (95%CI 1.061–1.064), moderate frailty, adj OR 1.134 (95%CI 1.131–1.136), severe frailty, adj OR 1.208 (95%CI 1.203–1.213)). Conclusions: Anticholinergic prescribing was high in this older population. Older people with advancing frailty are exposed to the highest anticholinergic burden despite being the most vulnerable to the associated adverse effects. Older people with advancing frailty should be considered for medicines review to prevent overaccumulation of anticholinergic medications given the risks of functional and cognitive decline that frailty presents. / NIHR / Research Development Fund Publication Prize Award winner, May 2023.

Datura metel is a herbaceous plant found in almost all tropical parts of the world. It belongs to the family Solanaceae whose members, viz. Duboisia, Atropa, Hyoscyamus and Datura plants are known to produce tropane alkaloids- hyoscyamine and scopolamine which are most noted for their therapeutic use as anti-cholinergic agents. Since these alkaloids are produced in very low amounts in plants, alternative sources and methods of production for these alkaloids have been crucial in meeting the demands for these drugs. Endophytic fungi inhabiting a plant may have the potential to produce the same compounds as the host plants. The aim of the present study was to search for tropane alkaloid producing endophytic fungal isolates from Datura metel. Eighteen endophytic fungi were isolated from various tissues of Datura metel and screened for the presence of three tropane alkaloid biosynthetic genes- putrescine N-methyltransferase (PMT), tropinone reductase I (TRI) and hyoscyamine 6β-hydroxylase (H6H) using PCR-based screening approach. Six endophytic fungal isolates were found to possess the PMT, TR1 and H6H genes. The fungi were identified using molecular taxonomy as Col letotrichum boninense, Phomopsis sp., Fusarium solani, Col letotrichum incarnatum, Col letotrichum siamense and Col letotrichum gloeosporioides and the identity was confirmed using colony and spore morphology. The production of tropane alkaloids hyoscyamine and scopolamine by the fungi has been ascertained using various techniques like TLC, HPLC and ESI-MS/MS by comparison with the authentic reference standards. The amount of tropane alkaloids produced by all six fungi in liquid cultures was quantified using HPLC analysis. Among the six tropane alkaloid-producing fungi Col letotrichum incarnatum gave the highest yields of hyoscyamine and scopolamine which were 3.906 mg/L and 4.13 mg/L, respectively. With an aim to characterize the tropane alkaloid biosynthetic genes in these fungi, the PMT gene was isolated from five of the endophytic fungi- Col letotrichum boni-nense, Fusarium solani, Col letotrichum incarnatum, Col letotrichum siamense and Col-letotrichum gloeosporioides for the first time and the sequence analysis showed high ho-mology (98%) to the Datura metel PMT cDNA. The gene was found to be devoid of introns in the fungi. Further phylogenetic analysis of the full length PMT sequence from the fungi strongly supports the hypothesis of horizontal gene transfer between the host plant and endophytic fungi. For further in detail characterization of fungal PMT, the Col letotrichum boninense PMT gene was taken as a representative. CbPMT gene was cloned in pRSET A expres-sion vector and heterologously expressed in E. coli and biochemically characterized. For optimal yield of soluble protein upon heterologous expression different conditions such as IPTG concentration, temperature and time post induction were optimized. Optimal yield was obtained by inducing the culture by 0.25 mM IPTG once it had reached and O.D. of 0.6 and incubating at 37◦ C for 3 h. The recombinant CbPMT enzyme expressed as histidine tagged fusion protein was purified using Ni-NTA affinity chromatography. Gel elution studies were carried out to determine molecular weight of the protein and it was found that the protein exists as a homodimer in solution with some amount also present as a monomer. Catalytic activity of the purified recombinant enzyme was studied for its dependence on both substrates putrescine as well as S-adenosylmethionine (SAM). The Km and Vmax values for putrescine were found to be 464 µM and 18.55 nkat/mg, respectively, while those for S-adenosylmethionine were found to be 628 µM and 18.63 nkat/mg, respectively. Optimum temperature for activity was found to be 37◦ C and optimum pH range was found to be 8-9. Fluorescence spectroscopy was used to study the binding affinity of both the sub-strates to the enzyme. Fluorescence quenching data for each substrate was analysed by using a nonlinear regression curve fit and Kd values were found to be 0.309 mM for pu-trescine and 0.118 mM for SAM, respectively. Circular dichroism spectrum of the enzyme indicated a pattern typical for alpha helix in the secondary structure. Binding of either substrate led to increase in ellipticity of the protein. Fluorescence quenching studies with collisional quenchers- acrylamide, potassium iodide, and cesium chloride indicated that the native protein is folded in a conformation that allows tryptophan residues to be acces-sible for quenching. The fraction of tryptophan residues (fa ) accessible for quenching by acrylamide (1.06) was found to be higher than that for potassium iodide (0.54) while that cesium ions was the least (0.38). The neutral quencher acrylamide could access all the tryptophans meaning that none of tryptophans are completely buried inside hydrophobic cores. the differential accessibility to the charged quenchers, however, indicates that more of the tryptophans are surrounded by positively charged amino acids. The unfolding of the protein was studied with the aid of chaotropic agents guanidine-HCl and urea and thermodynamic parameters were determined. The denaturant m-values were found to be 2.313 kcal/mol/M for Gdn-HCl and 2.345 kcal/mol/M for urea respectively. The free energy of unfolding was estimated to be 2.635 kcal/mol for Gdn-HCl and 4.630 kcal/mol for urea. Since no reports are available about the thermodynamics of folding and unfolding of PMT from any plant source, this study contributes towards the understanding of protein stability. Although a lot of reports are available on the biochemical characterization of PMT from different plant sources, the crystal structure of PMT is not yet available. In the current work, homology based modelling studies on CbPMT were carried out to get some idea about the protein tertiary structure. Homology based modelling studies showed that a significant amount of protein is present as α-helices which are present on the surface while the β-sheets are present in the interior of the protein. Each monomer of the protein is capable of binding both the substrates and hence the dimerization property of the enzyme could be a purely structural one leading to more stability and solubility of the protein. In conclusion, this study has shown for the first time that endophytic fungi have significant potential to be used for tropane alkaloid production and six such fungal strains have been identified. Although the production of tropane alkaloids by endophytic fungi is not very high, it can be scaled up by over-expressing the biosynthetic gene putrescine N-methyltransferase in the highest producer- Col letotrichum incarnatum to further increase the yield. These endophytic fungi have significant potential to be applied in fermentation technology to meet the demands for these drugs economically.

Chronic obstructive pulmonary disease (COPD) is characterized by a non-fully reversible airflow limitation and a chronic inflammatory response accompanied by the development of emphysema. The β2-adrenoceptor agonists and anticholinergic agents are widely used in patients with COPD due to their bronchodilator properties. Today, many studies in vitro and in vivo in experimental animal models have shown that these bronchodilators also exert anti-inflammatory effects, but their protective roles against lung inflammation and the development of emphysema in patients with COPD remain to be determined. The imbalance between the activity of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) is considered to play a key role in the pathogenesis of COPD, especially in the development of pulmonary emphysema. The modulation of inflammatory responses and emphysema via the inhibition of the MMPs activity induced by the use of synthetic inhibitors of MMPs suggests that MMPs may be therapeutic targets for COPD patients. However, very few studies have demonstrated the regulation exerted by β2-adrenoceptor agonists and anticholinergic agents on the activity of MMPs. The combination of β2-adrenoceptor agonists with anticholinergic agents has been found to exert an additive and even synergistic bronchodilator effect, but nothing is known about their combination on the inflammatory pathogenesis and the development of emphysema. Thus, a better knowledge of the activities of β2-adrenoceptor agonists and anticholinergic agents on controlling pulmonary inflammation and emphysema in COPD could provide a new therapeutic approach in this area. The first goal of the present work was to investigate the effects of formoterol, a β2-adrenoceptor agonist and/or ipratropium bromide, an anticholinergic agent, on acute pulmonary inflammation induced by cadmium inhalation in rats. In addition, we examined whether the expected anti-inflammatory effects of formoterol and/or of ipratropium bromide were associated with a modulation of the gelatinase A (MMP-2), gelatinase B (MMP-9) and macrophage metalloelastase (MMP-12) activity. Compared with the data observed in rats exposed to a single dose of cadmium, the pre-administration of formoterol or ipratropium bromide inhibited the cadmium-induced increase in airway resistance. Formoterol significantly reduced the total cell, neutrophil and macrophage counts in bronchoalveolar lavage fluid (BALF), whereas, ipratropium bromide only reduced the neutrophil number. Both bronchodilators administrated alone attenuated significantly the lung lesions associated with parenchyma inflammatory cell influx and congestion observed in cadmium-group. The increased MMP-9 activity was significantly attenuated. A reduction of pulmonary edema was also detected by measuring the lung wet-to-dry weight ratio. However, no additive or synergistic effect was obtained when formoterol was administrated in combination with ipratropium bromide. In conclusion, formoterol and ipratropium bromide partially protect the lungs against inflammation by reducing the neutrophilic infiltration. This protective effect may be related to the reduction of MMP-9 activity which plays an important role in the acute inflammation. Up to now, the impact of a long-term administration of bronchodilators aiming to control the chronic inflammation and the development of emphysema in experimental animal models and in patients with COPD has been poorly investigated. In this context, it was rational to investigate whether the protective role of formoterol and ipratropium bromide identified in acute conditions persists in a rat model of subacute neutrophilic pulmonary inflammation with an enlargement of airspaces. In the second part of this study, we also intended to determine whether these anti-inflammatory effects are related to the modulation of imbalance between MMPs and TIMPs. Though ipratropium induced no effect on the subacute pulmonary inflammation and the airspace enlargement induced by repeated cadmium inhalations during 5 weeks in rats, formoterol elicited marked anti-inflammatory effects on the increase of total cell and neutrophil counts as well as the activity of MMP-9 mainly expressed in alveolar macrophages and epithelial cells. This drug also prevented the inflammatory infiltration in alveoli and in interstitial tissue and significantly inhibited the airspace enlargement as demonstrated by the significant decrease in the mean linear intercept (Lm). The combination of both bronchodilators at inefficient concentrations induced synergistic inhibitory effects on the total cell and neutrophil counts and on the cadmium-induced increased Lm associated with a reduction of MMP-9 activity in BALF. These data suggest that formoterol alone or combined with ipratropium could protect lungs against subacute pulmonary inflammation and the airspace enlargement by inhibiting neutrophilic infiltration via the reduction of MMP-9 activity. To the best of our knowledge, this is the first report which reveals the anti-inflammatory effects of β2-adrenoceptor agonists and anticholinergic agents in an animal model which mimics the main features of COPD. The data obtained in this work contribute to identify new therapeutic targets in COPD for drugs currently used in clinical practice./ La broncho-pneumopathie chronique obstructive (BPCO) est caractérisée essentiellement par une limitation du débit aérien qui n'est pas entièrement réversible et une inflammation chronique pulmonaire accompagnée dun développement demphysème. Les agonistes β2-adrénergiques et les anticholinergiques sont largement utilisés chez les patients atteints de BPCO en raison de leurs propriétés bronchodilatatrices. Aujourdhui, de nombreuses études expérimentales in vitro et in vivo, utilisant des modèles animaux, ont montré que ces bronchodilatateurs exerçaient également des effets anti-inflammatoires. Leur rôle protecteur contre linflammation pulmonaire et le développement d'emphysème chez des patients souffrant de BPCO reste à déterminer. Le déséquilibre entre les métalloprotéinases de la matrice (MMPs) et leurs inhibiteurs tissulaires (TIMPs) est considéré comme un mécanisme clé dans lévolution de la maladie et surtout dans le développement d'emphysème pulmonaire. La modulation des réactions inflammatoires et de lemphysème obtenue grâce à la réduction de lactivité des MMPs induite par des inhibiteurs synthétiques suggère que les MMPs pourraient être des cibles thérapeutiques importantes dans le traitement de la BPCO. Mais jusquà ce jour, très peu détudes ont été consacrées à la régulation de lactivité des MMPs par les agonistes β2-adrénergiques et les anticholinergiques. Lassociation dun agoniste β2-adrénergique avec un anticholinergique donne lieu à une amplification des effets bronchodilatateurs, mais il nest pas certain que leur combinaison débouche sur des effets additifs ou synergiques sur le plan dun meilleur contrôle de la réaction inflammatoire. Ainsi, une meilleure connaissance des activités des agonistes β2-adrénergiques et des anticholinergiques visant au contrôle de l'inflammation pulmonaire et de l'emphysème dans la BPCO pourrait fournir une nouvelle approche thérapeutique dans ce domaine. Lobjectif de la première partie de ce travail était donc d'étudier les effets du formotérol, un agoniste β2-adrénergique et / ou du bromure d'ipratropium, un anticholinergique, sur l'inflammation pulmonaire aiguë provoquée par linhalation de cadmium chez le rat. En outre, nous voulions aussi vérifier si ces effets anti-inflammatoires étaient associés à une modulation de lactivité de la gélatinase A (MMP-2), de la gélatinase B (MMP-9) et de la métallo-élastase du macrophage (MMP-12). Par rapport aux effets observés chez des rats exposés à une dose de cadmium, ladministration préventive de formotérol ou de bromure dipratropium a atténué laugmentation de la résistance des voies aériennes. Le formotérol a induit une diminution significative du nombre de cellules totales, des neutrophiles et des macrophages dans le liquide de lavage broncho-alvéolaire (BALF). Par contre, le bromure dipratropium na entraîné quune diminution du nombre de neutrophiles. Les lésions pulmonaires caractérisées par de la congestion et une réaction inflammatoire du parenchyme ont été significativement inhibées par ces deux bronchodilatateurs administrés séparément. Lélévation remarquable de lactivité de MMP-9 dans le BALF a été significativement atténuée par le prétraitement au formotérol ou au bromure dipratropium. Il en est de même pour ldème pulmonaire évalué par le biais du rapport entre le poids humide et le poids sec du parenchyme. Lorsque les deux principes actifs ont été combinés et administrés préventivement à laction du cadmium, aucun effet synergique ou additif na été constaté. En conclusion, le formotérol et le bromure dipratropium préviennent partiellement linflammation pulmonaire aiguë en réduisant linfiltration neutrophilique du parenchyme pulmonaire faisant suite à une exposition aiguë au cadmium. Cet effet protecteur pourrait être lié à une réduction de lactivité de MMP-9 qui joue un rôle pro-inflammatoire important dans linflammation aiguë. Jusquici, les effets potentiels des bronchodilatateurs contre linflammation chronique et lévolution de lemphysème pulmonaire chez des animaux et chez les patients atteints de BPCO restent mal connus. Il nous restait donc à vérifier si les effets protecteurs du formotérol et du bromure dipratropium révélés par nos premières études au cours desquelles les rats ont été exposés de manière aiguë au cadmium persistent dans un modèle dinflammation pulmonaire subaiguë accompagnée dun élargissement des espaces aériens. Nous voulions également déterminer si ces effets étaient liés à la modulation du déséquilibre entre les MMP-2/9/12 et les TIMP-1/2. Bien que le bromure dipratropium nait aucun effet sur linflammation subaiguë pulmonaire et lélargissement des espaces aériens induits par des inhalations répétées de cadmium chez le rat, le prétraitement par du formotérol a, quant à lui, inhibé significativement laugmentation du nombre de cellules totales et des neutrophiles ainsi que de lactivité de MMP-9 exprimée principalement dans les macrophages et les cellules épithéliales alvéolaires. En outre, une atténuation importante des lésions pulmonaires caractérisées par un élargissement des espaces aériens les plus distaux et une infiltration de cellules inflammatoires dans les alvéoles et le tissu ont été observées. La combinaison des deux bronchodilatateurs, à des concentrations pourtant inefficaces, a provoqué un effet synergique sur la plupart des paramètres étudiés, en particulier sur linfiltration par les neutrophiles et lactivité de MMP-9 dans le BALF. Ce travail suggère que le formotérol, seul ou combiné avec le bromure dipratropium, pourrait protéger partiellement les poumons contre linflammation pulmonaire et lélargissement des espaces aériens en réduisant l'infiltration neutrophilique éventuellement via l'inhibition de lactivité de MMP-9. A notre connaissance, il sagit du premier rapport montrant les effets anti-inflammatoires des agonistes β2-adrénergiques et des anticholinergiques dans un modèle animal mimant les principales caractéristiques physiopathologiques de la BPCO. Les données obtenues dans ce travail pourraient contribuer à identifier de nouvelles cibles thérapeutiques pour cette maladie.

Abstract With the growing proportion of older people and increasing use of drugs in this population, it is important to study how drugs affect oral health among older people. The aim of this thesis was to study whether sedative load, which represents cumulative exposure to drugs with sedative properties, is associated with oral health among community-dwelling older people. The focus was on a dry mouth, oral health behavior, dental caries, and infection in the periodontium. In addition, sedative load and anticholinergic burden were compared. The present study population was a subpopulation from an intervention study “Geriatric Multidisciplinary Strategy for Good Care of the Elderly”. The study population consisted of 159 community-dwelling, dentate, and non-smoking people aged 75 or older from the city of Kuopio, Finland. Data were collected with interviews, geriatric assessments, and clinical oral examinations. Sedative load was determined by using a previously published method. The study showed that participants with a sedative load were more likely to have dental caries, but not periodontitis, when compared with participants without a sedative load. Sedative load was associated with decreased stimulated salivary secretion and less strongly with unstimulated salivary secretion but not with xerostomia. The results also showed that sedative load was associated with poor or insufficient oral health behavior. Anticholinergic burden was associated with low unstimulated salivary secretion and xerostomia, but not with low stimulated salivary secretion. In conclusion, cumulative exposure to drugs with sedative properties was associated with insufficient oral self-care and poor oral health. The results from this study emphasize the fact that older people using drugs with sedative properties require thorough prophylaxis measures and regular dental check-ups because of their high risk of having poor oral health. / Tiivistelmä Väestön iäkkäiden henkilöiden osuuden kasvaessa ja heidän lääkkeiden käytön lisääntyessä on tärkeää tutkia, miten lääkkeet vaikuttavat ikääntyneiden suun terveyteen. Tutkimuksen tarkoituksena oli selvittää lääkityksestä aiheutuvan sedatiivikuorman (sedative load) vaikutuksia suun terveyteen kotona asuvilla iäkkäillä henkilöillä. Eritoten tutkimuskohteena oli sedatiivikuorman yhteys kuivaan suuhun, suun terveyskäyttäytymiseen, kariekseen sekä hampaiden tukikudosten sairauteen. Lisäksi tutkittiin antikolinergisen kuorman yhteyttä kuivaan suuhun ja tuloksia verrattiin sedatiivikuormaan. Tutkimuspopulaatio oli osa geriatrista Hyvän Hoidon Strategia -interventiotutkimusta (HHS). Populaatio koostui 159 kotona asuvasta 75-vuotiaasta tai sitä vanhemmasta hampaallisesta, ei-tupakoivasta kuopiolaisesta. Tutkimusmateriaali kerättiin haastattelulla, geriatrisella tutkimuksella sekä kliinisellä suun tutkimuksella. Sedatiivikuorma laskettiin käyttäen aiemmin kehitettyä mallia, jossa määritetään kokonaislääkityksestä aiheutuva sedatiivikuorma. Tutkimus osoitti, että osallistujilla, joilla oli sedatiivikuormaa, oli keskimäärin enemmän kariesta muttei hampaiden tukikudoksen sairautta verrattuna henkilöihin, joilla ei ollut sedatiivikuormaa. Tulokset osoittivat myös, että sedatiivikuorma oli yhteydessä alentuneeseen stimuloidun syljeneritykseen ja vähemmässä määrin alentuneeseen leposyljeneritykseen, mutta ei kuivan suun tunteeseen. Antikolinerginen kuorma oli yhteydessä alentuneeseen leposyljeneritykseen ja kuivan suun tunteeseen, mutta ei alentuneeseen stimuloidun syljeneritykseen. Sedatiivikuorma oli yhteydessä puutteelliseen suun terveyskäyttäytymiseen, kuten vähäiseen hammastahnan käyttöön ja suureen plakkimäärään. Johtopäätöksenä voidaan todeta, että altistuminen väsyttäville lääkkeille on yhteydessä puutteelliseen omahoitoon ja huonoon suun terveyteen. Tämän tutkimuksen tulokset korostavat väsyttäviä lääkkeitä käyttävien ikääntyneiden tarvitsevan perusteellisia ennaltaehkäiseviä toimia sekä säännöllisiä suun tutkimuksia, koska heillä on suurentunut riski huonoon suun terveyteen.

Asthma is a chronic inflammatory airway disease, and its treatment is frequently challenging despite detailed national and international guidelines. While basic antiinflammatory therapy usually consists of inhaled corticosteroids in doses adapted to the asthma severity, add-on treatment with bronchodilators is essential in more severe asthma. Only recently, the long-acting anticholinergic tiotropium was introduced into the GINA guidelines. This review reports on the studies that have been performed with tiotropium in adult asthmatic patients. Following early proof-of-concept studies, several studies with tiotropium as an add-on therapy to inhaled corticosteroids (ICS), with or without a long-acting beta agonist (LABA), demonstrated convincing clinical benefit for patients. Important lung function parameters and quality of life scores significantly improved shortly after onset of the add-on therapy with tiotropium, and some studies even demonstrated non-inferiority against salmeterol. All studies reported an excellent safety profile of tiotropium. The still growing body of tiotropium studies, both in adults and children, will help to identify the position of tiotropium in future asthma guidelines and might also indicate which patients benefit most from an add-on therapy with tiotropium.