The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.

Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti-inflammatory functions respectively. CRT induces pro-inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti-inflammatory cytokines, inhibits DC maturation and heightens T-regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat-me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long-term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease-relevant immune responses leading to a beneficial clinical outcome.

Indication-prescription study for the management of conjunctivitis in a Colombian population.

PURPOSE: Conjunctivitis is one of the most common ocular pathologies. Its treatment depends on its etiology, but an excessive use of antibiotics and corticosteroids, which in many cases are contraindicated, has been described. The objective was to describe the prescription patterns of medications used to treat conjunctivitis in a Colombian population. METHODS: This was a cross-sectional study on the pharmacological treatment of patients diagnosed with conjunctivitis between April 1, 2020, and March 31, 2021; based on a drug-dispensing database of approximately 8.5 million people affiliated with the Colombian Health System. Some sociodemographic and pharmacological variables and comorbidities were considered. A descriptive analysis was performed. RESULTS: A total of 8708 patients were identified; they had a median age of 44.7 years, and 59.3% were women. The most common causes of conjunctivitis were unspecified (53.1%) and allergic (37.4%). The most commonly used drug was olopatadine (26.1%), followed by dexamethasone with neomycin and polymyxin B (25.0%). A total of 97.0% of the patients received ophthalmic prescriptions, while 12.8% received systemic medications. Glucocorticoids (40.3%), antibiotics (37.7%) and antihistamines (31.7%) were the most commonly used groups of ophthalmic drugs. Glucocorticoids and ophthalmic antibiotics were the medications most frequently prescribed by general practitioners for the treatment of viral or bacterial conjunctivitis. CONCLUSIONS: Many patients with conjunctivitis are not being managed according to the recommendations of clinical practice guidelines, which highlights that the widespread use of antibiotics with ophthalmic glucocorticoids could be considered potentially inappropriate prescriptions in many cases.

Chronic pain and continuity of analgesic treatment during the COVID-19 pandemic.

INTRODUCTION: Chronic pain can trigger both physical and mental health complications. During the COVID-19 pandemic, patients with chronic diseases have had reduced access to some medications. OBJECTIVE: To determine the pharmacological management of patients with chronic pain and its continuity during the COVID-19 pandemic. METHODS: This was a retrospective longitudinal study of the continuity of analgesic use in patients with chronic pain between September 1, 2019 and February 28, 2021 based on a drug dispensing database. Survival analysis was performed until the discontinuation of chronic analgesics. RESULTS: A total of 12,701 patients who were being treated for chronic pain were identified. Their median age was 70.3 years, and 74.4% were women. The pain of rheumatological origin was the most frequent etiology (46.1%); the most used medications were nonopioid analgesics (78.9%), pain modulators (24.8%) and opioid analgesics (23.3%). A total of 76.1% of the patients experienced interruptions in their management during the study period. The median time to the first interruption of treatment was 5.0 months (95% CI: 4.8-5.2). Those who were treated for oncological pain experienced a greater number of interruptions in their management. CONCLUSIONS: The pharmacological management of patients with chronic pain is heterogeneous, and this real-world study showed that a high proportion of patients experienced an interruption of pain management during the 12 months following the onset of the COVID-19 pandemic.

Use of non-vitamin K antagonist oral anticoagulants in Colombia: A descriptive study using a national administrative healthcare database.

PURPOSE: We aimed to describe time-trends in the use of NOACs among a group of ambulatory patients with nonvalvular atrial fibrillation (NVAF) in Colombia and to describe treatment patterns and user characteristics. METHODS: Using the Audifarma S.A administrative healthcare database in Colombia, we identified 10 528 patients with NVAF aged at least 18 years between July 2009 and June 2017 with a first prescription (index date) for apixaban, dabigatran or rivaroxaban (index NOAC) and followed them for at least year (max, 8.0 years, mean 2.2 years). We described patient characteristics, NOAC use over time, and the dose of the first NOAC prescription. RESULTS: A total of 2153 (20.5%) patients started on apixaban, 3089 (29.3%) on dabigatran and 5286 (50.2%) on rivaroxaban. The incidence of new users of apixaban and rivaroxaban increased over study years while for dabigatran it decreased. Mean age at the index date was: 78.5 years (apixaban), 76.5 years (dabigatran), 76.0 years (rivaroxaban). The percentage of patients started NOAC therapy on the standard dose was: apixaban 38.0%, dabigatran 30.9%, rivaroxaban 56.9%. The percentage still prescribed their index NOAC at 6 months was apixaban 44.6%, dabigatran 51.4%, rivaroxaban 52.7%. Hypertension was the most common comorbidity (>80% in each NOAC cohort). CONCLUSION: During the last decade, the incidence of NOAC use in patients with NVAF affiliated with a private healthcare regime in Colombia has markedly increased. Future studies should evaluate whether the large number of patients with NVAF starting NOAC treatment on a reduced dose are done so appropriately.

Potentially inappropriate prescriptions of anticholinergic drugs in patients with benign prostatic hyperplasia.

BACKGROUND: Prostatic hyperplasia is frequent in the elderly, and it can be associated with urinary retention in patients who use cholinergic antagonists. The objective was to estimate the anticholinergic burden of drugs prescribed to patients diagnosed with benign prostatic hyperplasia. METHODS: A cross-sectional study using a population database to identify prescriptions of cholinergic antagonists drugs used in the management of benign prostatic hyperplasia. The anticholinergic burden was evaluated using the Anticholinergic Drug Scale. RESULTS: Three thousand seven hundred and sixty patients with benign prostatic hyperplasia were identified, with a mean age of 68.26 ± 10.46 years. Of these patients, 2961 (78.8%) received pharmacological treatment mainly with tamsulosin monotherapy (34.7%, n = 1026). Overall, 34.7% (n = 1303) of all patients were taking cholinergic antagonists. Patients aged 75-84 years (OR: 1.985, 95%CI: 1.063-3.709) and those 85 or older (OR: 2.52, 95%CI: 1.287-4.948) had a greater probability of having an anticholinergic burden score ≥3 points. Of the patients not receiving pharmacological treatment for benign prostatic hyperplasia, 35% (n = 280) were taking medications with anticholinergic properties. CONCLUSIONS: A high proportion of patients with benign prostatic hyperplasia were receiving medical management for the relief of symptoms, mostly via monotherapy. However, one-third of patients received some type of medication with anticholinergic properties, being much more frequent after 75 years.

Potentially Inappropriate Prescriptions for Anticholinergic Medications for Patients with Constipation.

INTRODUCTION: Constipation is a very common functional gastrointestinal disorder in the general population and can be primary or secondary. OBJECTIVE: The aim of this study was to estimate the anticholinergic burden of prescribed drugs in a population diagnosed with constipation in Colombia. METHODS: This was a cross-sectional study that used a population database of 6.5 million people to identify the prescription of cholinergic antagonists and drugs for the management of constipation in outpatient services. The anticholinergic burden was evaluated using the Anticholinergic Drug Scale. Potentially inappropriate prescriptions that increased the risk of constipation were identified. RESULTS: A total of 3,887 patients with constipation were identified; the identified patients had a mean age of 54.4 ± 21.9 years, and 69.4% were women. Eighty percent received at least one laxative, and the most prescribed laxative was bisacodyl (50.5%). Forty-one percent (n = 1,586) of all patients received drugs with cholinergic antagonist activity, in particular codeine (6.5%) and valproic acid (6.5%). Being over 30 years of age (odds ratio [OR]: 1.79; 95% confidence interval [CI]: 1.24-2.57), being treated in the cities of Manizales (OR: 2.20; 95% CI: 1.50-3.21) and Pereira (OR: 1.49; 95% CI: 1.07-2.09), and having hypothyroidism as a comorbidity (OR: 1.37; 95% CI: 1.08-1.73) were associated with a greater probability of receiving medications with an anticholinergic burden of 3 or more points. CONCLUSIONS: The majority of patients with constipation were women and were using laxatives to manage constipation. A large proportion of patients were prescribed at least one cholinergic antagonist drug, with an increased probability of use after 30 years of age.

Adherence to levothyroxine prescription in patients with hypothyroidism.

BACKGROUND: Hypothyroidism occurs in 1-2% of the general population, is associated with significant morbidity and requires continuous treatment with levothyroxine. AIM: To determine the effectiveness, adherence and safety of levothyroxine therapy in patients with hypothyroidism. MATERIAL AND METHODS: The Morisky-Green adherence test was applied, and effectiveness was determined by measuring thyroid-stimulating hormone (TSH) in 330 patients with with hypothyroidism; the mean age was 64+-15 years and 76% was women. RESULTS: Median TSH was 2.09 mIU/L (interquartile range: 1.16-3.61 mIU/L). Two hundred thirty-five (71%) patients had TSH levels in the euthyroid range, 64 (19%) in the hypothyroid range and 31 (9%) in the hyperthyroid range. Complete, moderate and lack of adherence with levothyroxine was reported in 283 (86%), 29 (9%) and 18 (5%) of patients, respectively. The presence of anemia (odds ratio (OR): 0.37, 95% confidence intervals (CI): 0.15-0.98) or the need of doses over 100 µg/day (OR: 0.47, 95%CI: 0.28-0.80) increased the probability of having an abnormal TSH level. CONCLUSIONS: In a large proportion of these patients, TSH levels were controlled, and most patients were adherent to levothyroxine therapy.

Potentially inappropriate prescriptions of anticholinergic medications in patients with closed-angle glaucoma.

PURPOSE: Glaucoma is the leading cause for blindness after cataracts worldwide. The aim was to identify anticholinergic drugs prescribed to patients diagnosed with closed-angle glaucoma in Colombia. METHODS: This cross-sectional study identified the prescribing patterns of cholinergic antagonists related to the increased intraocular pressure in patients diagnosed with closed-angle glaucoma from a Colombian database. The Anticholinergic Drug Scale was used to quantify the anticholinergic burden. RESULTS: We identified 1958 patients with closed-angle glaucoma, with a mean age of 70.5 ± 10.3 years, 72.9% of whom were women. Cholinergic antagonists were prescribed in at least 32.4% of cases. An age range between 75 and 84 years (odds ratio (OR) 2.35, 95% confidence interval (CI) 1.366-4.059) and being aged 85 years or older (OR 3.40, 95% CI 1.809-6.425) were associated with a greater probability of receiving an anticholinergic burden between 1 and 2 points. Females (OR 1.54, 95% CI 1.096-2.181) had a higher probability of receiving an anticholinergic burden ≥ 3 points. Interactions between antiglaucoma medications and anticholinergic treatments were identified in 32.1% of the patients. CONCLUSIONS: Most patients were prescribed multiple antiglaucoma medications, reflecting a large number of potentially inappropriate prescriptions, with anticholinergic drugs, related to the increased intraocular pressure.

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/ß 2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile.

AZD8871 is a novel muscarinic antagonist and ß 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the ß 2-adrenoceptor over the ß 1 and ß 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and ß 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats.

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

Potential prescribing omissions in patients with cardiovascular disease.

Aims Potential prescribing omissions (PPOs) of medications are a frequent form of inadequate prescription drug practices. The objective of this study was to identify PPOs in a sample of elderly patients with cardiovascular disease. Methods Quasi-experimental study. Data were collected from a population database. We included patients who were older than 65 years and had a diagnosis of hypertension, dyslipidaemia, diabetes mellitus, coronary heart disease, heart failure or atrial fibrillation in Colombia. PPOs were determined in a random sample of patients by the START-2 (Screening Tool to Alert doctors to Right Treatment) criteria. The impact of the PPO was determined after an educational intervention with the doctors who were responsible for treating said patients. Results A total of 630 patients, with a median age of 72 years (interquartile range: 68-78 years), were included; 56.2% were women. The most frequent diagnoses were arterial hypertension (94.1%, n = 593) and dyslipidaemia (56.5%, n = 356). We identified 100 patients (15.9%) with omissions equalling 139 PPOs, and the most common PPOs were due to a lack of angiotensin-converting enzyme inhibitors in patients associated with heart failure or coronary heart disease (n = 23, 16.5%) and a lack of statins (n = 20; 14.4%) and aspirin (n = 20; 14.4%) in coronary heart disease. Prescription adjustments were achieved in 35 patients (25.2%). Conclusions Potential prescribing omissions are common in elderly patients with cardiovascular disease. Educational interventions may contribute to a reduced PPO frequency and improve the quality of prescription drug administration.

Use of intravenous alprostadil in patients with severe critical ischemia of the lower limbs.

OBJECTIVES: To determine the indications for the use, potential benefits, and adverse reactions of alprostadil in a group of Colombian patients. METHODS: A retrospective cross-sectional study was conducted in patients diagnosed with critical limb ischemia who received alprostadil in five hospitals in Colombia between September 2011 and July 2017. We reviewed the clinical records of each patient to obtain the sociodemographic and pharmacological variables, clinical stages, complications, comorbidities, reported effectiveness and adverse reactions. RESULTS: Sixty-one patients treated with alprostadil were evaluated; 50.8% of patients were men, and the average age of 72.5 ± 10.7 years. A total of 86.9% of patients were hypertensive, and 65.6% were diabetic. A total of 77.0% presented ulceration, and this condition was considered as a diabetic foot in 57.4% of patients. A total of 81.9% of patients were classified as Fontaine stage 4; 60.7% received therapy as initially indicated, with an average of 19 days of alprostadil use. Regarding the therapy results, 58.0% of the patients with ulcers or trophic lesions showed improvement, 86.2% showed improvement of pain, and the limb was saved in 72.1% of patients. CONCLUSIONS: Critical limb ischemia was presented by patients with advanced age and high cardiovascular risk who were treated during severe and advanced stages where therapeutic options are limited. Treatment with alprostadil achieved satisfactory results with improvement in ulcers, pain, and limb salvage rates in this series of patients.

Drugs With Anticholinergic Potential and Risk of Falls With Hip Fracture in the Elderly Patients: A Case-Control Study.

BACKGROUND/OBJECTIVE: To determine the association between the use of anticholinergic drugs and the risk of falls with hip fracture in a population older than 60 years. METHODS: A case-control study in patients older than 60 years with a diagnosis of hip fracture. All drugs dispensed during the previous 30 days were identified. Sociodemographic, clinical, pharmacological (drugs according to the Anticholinergic Risk Scale [ARS]), and polypharmacy variables were analyzed. MEASUREMENTS: Falls with hip fracture and type of drug according to the ARS. RESULTS: A total of 300 patients with hip fracture and 600 controls were included. The mean age was 81.6 ± 8.9 years, with female predominance (71.3%). The use of drugs with moderate (odds ratio [OR]: 1.97, 95% confidence interval [CI]: 1.19-3.27) or high ARS scores (OR: 1.83, 95% CI: 1.13-2.96) increased the probability of fracture. CONCLUSIONS: There was an association between the use of drugs with anticholinergic properties and the probability of hip fracture in elderly patients and it was possible to establish the level of risk.

Association between the use of benzodiazepines and opioids with the risk of falls and hip fractures in older adults.

ABSTRACTBackground:To determine the association between the use of opioids and benzodiazepines and the risk of falls with hip fracture in populations older than 65 years in Colombia. METHODS: A case-control study with patients older than 65 years with diagnosis of hip fracture. Two controls were obtained per case. The drugs dispensed in the previous 30 days were identified. Sociodemographic, diagnostic, pharmacological (opioids and benzodiazepines), and polypharmacy variables were analyzed. A logistic regression model was used to analyze the risk of fall with hip fracture while using these drugs. RESULTS: We included 287 patients with hip fractures and 574 controls. There was a female predominance (72.1%) and a mean age of 82.4 ± 8.0 years. Of the patients, 12.7% had been prescribed with opioids and 4.2% with benzodiazepines in the previous month. The adjusted multivariate analysis found that using opioids (OR:4.49; 95%CI:2.72-7.42) and benzodiazepines (OR:3.73; 95%CI:1.60-8.70) in the month prior to the event was significantly associated with a greater probability of suffering a fall with hip fracture. CONCLUSIONS: People who are taking opioids and benzodiazepines have increased risk for hip fracture in Colombia. Strategies to educate physicians regarding the pharmacology of older adults should be strengthened.

Factors related to excessive polypharmacy (≥15 medications) in an outpatient population from Colombia.

AIMS: To determine the frequency of excessive polypharmacy (≥15 medications) in an outpatient population from Colombia and the variables associated with this condition. METHODS: A cross-sectional study using a systematised database of 6.2 million affiliates of the Colombian Health System. All patients treated uninterruptedly with 15 or more medications for 3 months (January-March 2017) were included. Sociodemographic, pharmacological, potential drug interactions, and prescribers' variables were identified. RESULTS: A total of 264 patients with prescriptions of ≥15 medications were identified; with an estimated prevalence of excessive polypharmacy of 108.4 per 100 000 people. The mean age was 67.7 ± 17.8 years and 60.6% were females. The mean number of medications per patient was 20.1 ± 4.5 and 48.9% (n = 129) had 20 or more. The most used were antiulcer medications (89.0%; n = 235), antihypertensives (85.6%; n = 226), analgesic/antipyretic (80.3%; n = 212), psychiatric/neurologic medications (78.5%; n = 207), statins (67.4%; n = 178), acetylsalicylic acid (59.5%; n = 157), and vitamins (57.2%; n = 151). On average, each patient had 21.0 ± 11.4 drug-drug interactions and were attended by 6.2 ± 3.1 physicians. Being treated by seven or more physicians (OR: 5.09; 95% CI: 1.64-15.79) increased the probability of receiving more than 20 medications. CONCLUSIONS: Drugs for treatment of chronic conditions prevailed, especially in elderly patients with multiple chronic conditions; however, some groups of medications without clear indications, such as antiulcer medications or vitamin supplements, also had extensive use. A main factor that increases the probability of polypharmacy greater than 20 drugs is care by seven or more physicians, which shows a fragmentation in patient care by the country's health system, without achieving co-ordination and integration between the different agents involved in medical care, also influenced by different physicians' practice patterns.

Prescription profile of pyridostigmine use in a population of patients with myasthenia gravis.

We determined the pyridostigmine prescription pattern in a population of patients with myasthenia gravis (MG). A descriptive cross-sectional study was conducted by using a prescription database of 3.5 million individuals from which patients who had been diagnosed with MG and for whom pyridostigmine had been prescribed were selected. A total of 306 outpatients with MG were found, and 258 were receiving pyridostigmine (mean age 53.0 ± 18.0 years). The calculated prevalence of MG was 86.7 cases per million persons. Monotherapy was used by 53.1% of the patients, prednisolone was used by 21.7%, and 30.2% used other immunomodulators. Medications for other comorbidities were taken by 74.8% of the patients, and 43.4% had prescriptions that could potentially trigger worsening symptoms. Pyridostigmine is being prescribed at doses close to the defined daily doses predominantly as monotherapy. A high proportion of patients were also prescribed a medication that could aggravate their condition, including some that can trigger a myasthenic crisis. Muscle Nerve 56: 1041-1046, 2017.

Tofacitinib ameliorates inflammation in a rat model of airway neutrophilia induced by inhaled LPS.

BACKGROUND AND PURPOSE: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model. EXPERIMENTAL APPROACH: Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o. KEY RESULTS: Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue. CONCLUSIONS AND IMPLICATIONS: In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.

Effectiveness and clinical inertia in patients with antidiabetic therapy.

AIMS: To establish the effectiveness of antidiabetic therapy and the frequency of clinical inertia in the management of type 2 diabetes mellitus in Colombia. METHODS: A cross-sectional study with follow-up of patients who had been treated for at least 1 year and were receiving medical consultation for antidiabetic treatment. Effectiveness was established when haemoglobin-A1c levels were <7% and when clinical inertia was reached, which was defined as no therapeutic modifications despite not achieving management controls. Sociodemographic, clinical and pharmacological variables were evaluated, and multivariate analyses were performed. RESULTS: In total, 363 patients with type 2 diabetes mellitus were evaluated, with a mean age of 62.0±12.2 years. A total of 1,016 consultations were evaluated, and the therapy was effective at the end of the follow-up in 57.9% of cases. Clinical inertia was found in 56.8% of patients who did not have metabolic control. The most frequently prescribed medications were metformin (84.0%), glibenclamide (23.4%) and insulin glargine (20.7%). Moreover, 57.6% of the patients were treated with two or more antidiabetic medications. Having metabolic control in the first consult of the follow-up was a protective factor against clinical inertia in the subsequent consultations (OR: 0.08; 95%CI: 0.04-0.15; P<.001). CONCLUSIONS: The effectiveness of treatment for patients with type 2 diabetes mellitus has increased in Colombia, and for the first time, clinical inertia was identifiable and quantifiable and found in similar proportions to other countries. Clinical inertia is a relevant condition given that it interferes with the possibility of controlling this pathology.

High prevalence of risk factors in elderly patients using drugs associated with acquired torsades de pointes chronically in Colombia.

AIMS: Medication is one of the main causes of long QT syndrome (LQTS) and torsades de pointes (TdP), and the older adult population is at particularly high risk. The aim of the present study was to describe the prescription patterns of drugs with a risk of TdP in the Colombian older adult population. METHODS: Patients older than 65 years who received medication with a risk of TdP during three consecutive months were selected. The medication was obtained and classified according to the QT Drug List from Crediblemeds.org. The data were analysed using SPSS-22. RESULTS: A total of 55 932 patients were chronically receiving QT-prolonging drugs; 61.9% (n = 34 ,632) were women and the mean age of the sample was 75.6 years. Drugs with a conditional risk were consumed by 95.2% of patients, 5.3% received drugs with a known risk and 2.9% received drugs with a possible risk. Two or more QT-prolonging drugs were consumed by 10.3% of the patients (n = 5786). Most of the sample (96.8%, n = 54 170) had at least one additional risk factor for LQTS, with a mean of 3.1 ± 0.9 risk factors. Patients receiving QT-prolonging drugs for psychiatric and neurological disease were at a higher risk of major polypharmacy [odds ratio (OR) 3.0; 95% confidence interval (CI) 2.80, 3.22) and of receiving high doses of QT-prolonging drugs (OR 3.8; 95% CI 3.52, 4.05). CONCLUSIONS: The widespread use of medication that causes TdP and the high prevalence of additional risks in the older adult population raise the need for accurate prediction of risk and constant patient monitoring. Patients taking psychiatric drugs are at a higher risk of TdP.

Comparison of the impact of human vs analogue insulins on glycosylated haemoglobin in a population with diabetes mellitus.

AIMS: To compare the effect on metabolic control of treatment with conventional and analogue insulins for patients with diabetes mellitus. METHODS: Retrospective cohort study held in cities of Colombia (Pereira and Manizales). People insured by the paid healthcare system, who were diagnosed with diabetes mellitus type 1 and 2, and treated with conventional and analogue insulin for at least 6 months prior to the start of the study were sampled and followed up for 18 months. Data were collected from clinical records for each patient. Treatment groups were compared according to the type of insulin received. RESULTS: A total of 313 patients were included; overall, 56.9% were women and the mean age was 57.3 years. No statistically significant difference was found in glycosylated haemoglobin reduction at 3, 6 and 18 months when comparing patients receiving glargine vs NPH insulin (P=.403) and NPH plus zinc crystalline insulin vs glargine plus glulisine (P=.514). The percentage of patients with metabolic control increased from 27.8% to 34.2% during follow-up with all types of insulin. CONCLUSIONS: Insulin analogues were not superior to human insulin for glycaemic control. A significant proportion of patients did not attain the treatment goals; therefore, it is necessary to implement measures to improve the monitoring and control of diabetes mellitus.