Aerodynamic Properties and Drug Solubility of Dry Powders Prepared by Spray Drying: Clarithromycin Versus its Hydrochloride Salt

Aerodynamic Properties and Drug Solubility of Dry Powders Prepared by Spray Drying: Clarithromycin Versus its Hydrochloride Salt. Russo P, Manniello M.D., Simonetti A., Petrone A.M., Porta A., Del Gaudio P., Aquino R.P. Department of Pharmacy (DIFARMA), University of Salerno, Fisciano (SA) – Italy; ([email protected]). Introduction and Objectives. The antibiotic therapy for a direct administration to the lung in cystic fibrosis patients has to provide suitable drug availability, possibly in the lower respiratory tract characterized by the presence of thick secretions. Apart from deposition, systemic or local pharmacological activity of an inhalation product depends on drug dissolution into the biological fluids lining the lung. Therefore, one of the crucial step in the therapeutic management of the respiratory disease is the drug solubilization in this site of action. Clarithromycin (CLA; fig.1) is a broad spectrum and a well know macrolide antibiotic usually prescribed particularly for the treatment of respiratory infections, interestingly showing an additional anti-inflammatory effect (Pukhalsky et al., 2004); CLA is characterized by a very poor water solubility (0.33 mg/L). One of the common strategy, for increasing drug solubility in aqueous medium is represented by the production of dry powders in amorphous form using the spray drying technique (Yonemochi et al., 1999). Moreover, CLA has a dimethylamino group, which can be salified for solubility/dissolution improvement (fig.1). Hence, the aim of the present study was to obtain respirable powders of clarithromycin, while improving drug aqueous solubility. Powders were produced with CLA or CLA hydrochloride and characterized in terms of drug content, aerodynamic properties and drug solubility. Finally, in order to assess the effect of the spray-drying process on the antibiotic activity of the engineered particles, microbiological tests were performed. Materials and Methods. Several batches of micronized particles were prepared by spray drying different feed solutions; critical process parameters were solvent composition (isopropyl alcohol/water ratio), drug concentration and pH of the liquid feeds (table 1). Saturated solubility measurements were carried out keeping an excess amount of CLA raw material (RM), CLA spray-dried suspension and hydrochloride spray-dried in phosphate buffer (0.05 M, pH 6.75) at 37°C for 72h. After filtration, the solubility was measured by HPLC method and expressed in mg/ml. The results were reported as mean of three measurements and standard deviation. Particle size distribution of Raw Material and engineered particles was determined using a light-scattering laser granulometer, while particle morphology was assessed by scanning electron microscopy (SEM). The in vitro deposition of the micronized powders was evaluate by means of a Single-Stage Glass Impinger (SSGI; apparatus A; European Pharmacopoeia 8.0), using a proper device for the aerosolization. The antibacterial assay was carried out in MHB by microdilution method using 96-well microtiter plates. Briefly, 200 µl of 1X107 CFU/ml of P. aeruginosa ATCC 27853 were incubated at 37°C with different concentration of drug (4, 6 and 8 µg/ml). Results and Discussion. Morphology and aerodynamic properties of spray-dried particles were strongly dependent on organic solvent concentration as well as on pH of the liquid feeds processed, both influencing drug solubility. Adding clarithromycin to hydroalcoholic mixtures, alkaline feeds (pH~10.5; #1, #2, tab.1) in form of suspensions were obtained.   The resulting spray-dried powders showed good process yield, but unsatisfactory aerodynamic properties, due to a high particle size (tab. 1) and the presence of residual drug crystals mixed to spherical particles (fig.2; #2). With the aim to obtain clear feeds in form of solutions, we tested clarithromycin in its hydrochloride salt form, obtained lowering pH values of feed solutions (pH 6.5). Micronized salified powders showed higher process yield and very interesting FPF values, thanks to smaller and wrinkled particles (fig.2 #4, #6; tab.1). Moreover, water solubility of spray-dried powders was strongly influenced by clarithromycin form. Powders obtained from alkaline feed suspensions showed lower solubility in a phosphate buffer 0.05 M, pH 6.75 (fig.3, # 1). A substantial increase in drug solubility was obtained, at the same conditions, with powders dried from feed solution containing clarithromycin hydrochloride (fig.3 #9-#5). To verify the ability of the produced formulations to was performed. Three different drug concentrations were tested in a multi-well plate. Clarithromycin raw material (RM, line C, figure 4) and #1 (line D, figure 4) showed a lower activity against P. aeruginosa growth compared to #4, #5, #6, containing the hydrochloride form. This different behavior against P. aeruginosa may be due to the lower CLA solubility; at higher concentration, clarithromycin precipitates in RM and #1 wells, becoming unavailable for antibiotic purpose. Conclusions. Clarithromycin inhalable powders containing the drug in its hydrochloride form showed good aerodynamic properties and higher water solubility. Thanks to a fine-tuning of the process parameters and liquid feed composition, no excipients were necessary to obtain respirable powders. The spray drying process of CLA hydrochloride not only preserved antimicrobial activity, but also, increasing drug solubility, improved drug efficacy against P. aeruginosa. References. Pukhalsky, A. L., Shmarina, G. V., Kapranov, N. I., Kokarovtseva, S. N., Pukhalskaya, D., & Kashirskaja, N. J. (2004). Anti-inflammatory and immunomodulating effects of clarithromycin in patients with cystic fibrosis lung disease. Mediators Inflamm, 13(2), 111-117. doi: 10.1080/09629350410001688495 Yonemochi, E., Kitahara, S., Maeda, S., Yamamura, S., Oguchi, T., & Yamamoto, K. (1999). Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. Eur J Pharm Sci, 7(4), 331-338

Biohazard in air-conditioning systems installed in health facilities

The project "Biological hazard related to the operation of air-conditioning systems in sanitary environments in the province of Avellino" has had, as its main objective, the microbiological monitoring of the environments hospitals in order to evaluate the microbiological quality of the air, through procedures and criteria for sampling the environmental microbial flora. This procedure aims to assess and manage risks related to the hygiene of air treatment plants (UTA), which must be periodically subjected to checks, maintenance, cleaning and sanitisation in order to protect the health of Workers according to technical standards and national guidelines. Most important was the characterisation at the level of species and gender of the main microbiological contaminants present within the samples investigated. The entire trial was carried out on a temporal scale taking into account the frequency of the UTA maintenance activities and thus establishing the monitoring plan. In order to assess the effectiveness of the maintenance plan and the efficiency of the actions of sanitizations, withdrawals should be made at three different times or immediately after ordinary maintenance, halfway between the first and second Maintenance and immediately before the second maintenance. This way you can monitor the presence of different bacterial contaminants in time. The quantitative and qualitative analysis of bacteria, pathogens and not, in hospital environments aims to prevent the onset and spread of pathologies. In particular, the monitoring of air handling units is of fundamental importance since such plants can cause the diffusion of many pollutants, coming from outside or inside, resulting from residues of materials from Construction, from remnants of plant and animal origin (pigeons, mice, insects) or moulds and bacteria that can contaminate the water and the surfaces inside the aeraulic plants. The molecular-based taxonomic characterization of the most representative species in the test specimens has as its main purpose the identification of any "sentinel" markers as well as indicators of biohazard

SARS-CoV-2 vaccination modelling for safe surgery to save lives : data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.Peer reviewe

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements