Factors Associated with Therapeutic Adherence in Multiple Sclerosis in Spain.

Purpose: Adherence to disease-modifying therapies (DMTs) in multiple sclerosis (MS) is a complex and multidimensional phenomenon. Identifying the predictors of therapeutic adherence in MS will guide the design of interventions to improve health outcomes. Our aim was to assess the degree of adherence to pharmacological treatments, assess the relationship between patient-related factors and pharmacological adherence and to identify predictors of adherence to pharmacological treatments in patients with MS in Spain. Patients and Methods: A cross-sectional nationwide study was carried out in Spain between December 2020 and September 2021. The web-based evaluation protocol consisted of a self-questionnaire survey designed ad hoc and the application of validated questionnaires to assess adherence, as well as beliefs about medication and quality of life. Predictor variables of adherence to MS treatment were assessed using multivariate analysis. Results: A total of 152 patients with MS participated (mean age: 44 years; 64% were female; and 78% had relapsing-remitting MS). Seventy-three percent of the patients reported being adherent to their pharmacological treatment for MS. Forgetfulness was the most common cause of non-adherence. Necessity beliefs and concerns beliefs were not statistically associated with adherence. The adherent group shows statistically significant better levels of quality of life in the cognitive function subscale than the non-adherent participants (p=0.040). Role limitations-emotional, emotional well-being and overall quality of life were not significantly associated with adherence. Predictors with a statistical association with adherence to treatment were years of education (OR=0.79; 95% CI: 0.65-0.96; p=0.020) and intravenous treatment (OR=3.17; 95% CI: 1.07-9.45; p=0.038). Conclusion: We found an adequate adherence to pharmacological treatment. Low education and intravenous treatment were significant predictors of adherence to DMTs.

Potential antipsoriatic effect of chondroitin sulfate through inhibition of NF-κB and STAT3 in human keratinocytes.

Chondroitin sulfate (CS) is a natural glycosaminoglycan, formed by the 1-3 linkage of d-glucuronic acid to N-acetylgalactosamine, present in the extracellular matrix. It is used as a slow acting disease modifying agent in the treatment of osteoarthritis, and part of its beneficial effects are due to its antiinflammatory properties that result from an inhibitory effect on NF-κB signaling pathway. This ability raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature. In addition, psoriasis is characterized by an upregulation of STAT3 signaling pathway that is related to the epidermal hyperplasia. In the present study we report the pharmacological modulation of the NF-κB and STAT3 signaling pathways by CS in normal human keratinocytes. CS inhibited NF-κB activation and the release of some of the key psoriatic cytokines such as TNFα, IL-8, IL-6 and CCL27. Moreover, it impaired STAT3 translocation to the nucleus and significantly reduced STAT3 transcriptional activity by a mechanism that was independent from STAT3 phosphorylation. Our results confirm the interest of CS as a candidate for future drug research in the therapeutics of psoriasis given the need of more effective and safer oral medications for these patients.

Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the Beers criteria / Prescripción potencialmente inapropiada en ancianos institucionalizados en España: los criterios STOPP-START comparados con los criterios de Beers

Objective: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people. Methods: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more) by pharmacists in a nursing home in the Lleida region (Spain). Results: The mean patients’ age was 84 (SD=8) years, with an average of 5 drugs per resident (total prescriptions: 416 medicines). The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%), but omissions corresponding to the cardiovascular system implied 23% of patients. Conclusion: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP) is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists’ review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homes (AU)

Objetivo: Este estudio está orientado a identificar la prescripción potencialmente inapropiada usando los criterios de Beers y STOPP. Las omisiones de prescripciones se detectan en esta población geriátrica aplicando los criterios START. Se compara la utilidad de estos criterios en ancianos institucionalizados. Métodos: Estudio descriptivo de revisión de la medicación y las historias clínicas por farmacéuticos, de 81 pacientes (con 65 o más años) ingresados en una residencia en la provincia de Lleida (España). Resultados: La media de edad de los pacientes fue de 84 años (DE=8), con cinco medicamentos de promedio de tratamiento por residente (prescripciones totales: 416 medicamentos). Los criterios de Beers detectaron el uso de medicación potencialmente inapropiada en el 25% de los pacientes. Los criterios STOPP identificaron una posible medicación inapropiada en el 48% de los pacientes. La mayor frecuencia de uso de medicamentos potencialmente inapropiados para ambos criterios correspondió a las benzodiacepinas de larga duración y los AINE. Los criterios START detectaron 58 prescripciones potencialmente omitidas en el 44% de los pacientes. Entre ellas, la ausencia de suplementos de Calcio-vitamina D en osteoporosis fue la regla más frecuentemente implicada (15% de los pacientes); sin embargo, las omisiones relacionadas con el sistema cardiovascular asociadas a elevado riesgo cardiovascular son las que implicaron hasta un 23% de pacientes. Conclusión: La aplicación de los criterios STOPPSTART ha detectado una elevada proporción de prescripciones potencialmente inapropiadas en pacientes ancianos en una residencia sanitaria en España, con una significativa correlación positiva entre el número de medicamentos prescritos al paciente y el número de prescripciones potencialmente inapropiadas. Los criterios STOPP identificaron más medicación potencialmente inapropiada que los criterios de Beers. Las omisiones detectadas por los criterios START son relevantes y requiere una intervención. La revisión de la medicación por un farmacéutico puede ayudar a identificar potenciales prescripciones inapropiadas y, con un abordaje interdisciplinario, en colaboración con los médicos se podría mejorar la prescripción en pacientes ancianos de residencias geriátricas (AU)

Prostaglandin D2 regulates joint inflammation and destruction in murine collagen-induced arthritis.

OBJECTIVE: Prostaglandin D2 (PGD2) may exert proinflammatory or antiinflammatory effects in different biologic systems. Although this prostanoid and the enzymes responsible for its synthesis are up-regulated by interleukin-1ß (IL-1ß) in human chondrocytes in vitro, the role of PGD2 in arthritis remains unclear. This study was undertaken to investigate the role of PGD2 in the inflammatory response and in joint destruction during the development of collagen-induced arthritis (CIA) in mice. METHODS: PGD2 and cytokine levels in mice with CIA were determined by enzyme-linked immunosorbent assay. Expression of hematopoietic PGD synthase (h-PGDS), lipocalin-type PGD synthase (l-PGDS), and DP1 and DP2 receptors was analyzed by immunohistochemical methods. PGE2 levels were determined by radioimmunoassay. RESULTS: The arthritic process up-regulated the expression of h-PGDS, l-PGDS, DP1, and DP2 in articular tissue. PGD2 was produced in the joint during the early phase of arthritis, and serum PGD2 levels increased progressively throughout the arthritic process, reaching a maximum during the late stages of CIA. Treatment of arthritic mice with the DP1 antagonist MK0524 soon after the onset of disease increased the incidence and severity of CIA as well as the local levels of IL-1ß, CXCL-1, and PGE2, whereas IL-10 levels were reduced. The administration of the DP2 antagonist CAY10595 did not modify the severity of arthritis. The injection of PGD2 into the paw, as well as the administration of the DP1 agonist BW245C, significantly lowered the incidence of CIA, the inflammatory response, and joint damage. CONCLUSION: Our findings indicate that PGD2 is produced in articular tissue during the development of CIA and plays an antiinflammatory role, acting through the DP1 receptor.

Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the Beers criteria.

OBJECTIVE: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people. METHODS: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more) by pharmacists in a nursing home in the Lleida region (Spain). RESULTS: The mean patients''age was 84 (SD=8) years, with an average of 5 drugs per resident (total prescriptions: 416 medicines). The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%), but omissions corresponding to the cardiovascular system implied 23% of patients. CONCLUSIONS: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP) is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists' review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homes.

Blood pressure reduction in hypertensive patients after withdrawal of effervescent medication.

BACKGROUND: Raised blood pressure associated with the sodium excipient content of soluble or effervescent analgesic has been previously reported. However, the influence of other anions associated with sodium on blood pressure is still controversial. METHODS: Observational study of elderly hypertensive patients with uncontrolled blood pressure treated with effervescent paracetamol (3 g/day) for osteoarthritis. Blood pressure was measured before and after (4 weeks or more) switching paracetamol from an effervescent format to a tablet form in 34 patients. Blood pressure was recorded by community pharmacists during a pharmacotherapeutic follow-up service. RESULTS: Sodium intake in an effervescent form was 74 mmol/day (mainly associated with sodium bicarbonate and carbonate excipients). Initial blood pressure was high (range: 153-168 mmHg systolic and 92-99 mmHg diastolic). Switching to paracetamol tablets (no sodium content) was associated with both lowered systolic pressure of 13.1 mmHg (95%CI: 11.9-14.3, p < 0.0001) and a moderate reduction of diastolic pressure of 2.5 mmHg (95%CI: 2.1-2.9, p < 0.0001). No changes in medication in the study period took place, and weight and lifestyles remained stable. A detailed review of pharmacotherapy and lifestyle reveals no other causes for blood pressure to lower. CONCLUSIONS: A relationship of causality between the intake of high sodium excipients and high blood pressure in elderly hypertensive individuals, without chloride ions, was found. Clinicians should be aware of possible raised blood pressure when effervescent formulations are prescribed to hypertensive patients.

Antidepressant utilization in primary care in a Spanish region: impact of generic and reference-based pricing policy (2000-2004).

OBJECTIVE: To describe the evolution of antidepressant use in primary care in the Valencian region (Spain) from 2000 to 2004 and to analyze the effects of reference-based price and generic drugs introduction on drug utilization and cost saving. METHODS: Retrospective observational study in primary care using sales data collected from antidepressant group (N06A), corresponding to the period 2000-2004. Defined daily dose (DDD)/1000 inhabitants per day were obtained as consumption data. Cost and cost/DDD rate evolution was related to reference price system implantation. RESULTS: Antidepressant utilization progressively increased by 44.0% from 30.3 DDDs/1000 per day in 2000 to 43.5% in 2004. Selective serotonin reuptake inhibitors (SSRIs) comprised 77% of the total consumption where paroxetine, sertraline and fluoxetine were the most used drugs in 2004. The proportion of relative use and cost of fluoxetine declined after a reference price and the introduction of generic competitors were put into effect in 1999; cost/DDD was reduced by 1.8. Third-generation antidepressants showed a fast rising rate i.e. venlafaxine utilization multiplied by 2.2; this drug with the higher cost/DDD was not subjected to the reference price system. Reduction in citalopram utilization was related to a replacement by its recently marketed enantiomer escitalopram. CONCLUSIONS: In 2004, reference price policy and the implementation of generic drugs reduced the antidepressant cost by DDD. However, antidepressant expenditure increased since 2000 due to a continued growth in consumption (SSRIs and novel agents) and a displacement of prescriptions to drugs that were not included in the reference price policy.

A novel indazolo-triazolo-benzotriazepine exerts anti-inflammatory effects by inhibition of cyclooxygenase-2 activity and nitric oxide synthase-2 expression.

We have studied the anti-inflammatory activity of (6-(p-bromophenyl)amino-7-(p-chlorophenyl)indazolo[2',3':1,5]-1,2,4-triazolo[4,3-a]-1,3,5-benzotriazepine (ITB), prepared by solid-phase synthesis. This novel compound reduced the production of nitrite and PGE(2) in RAW 264.7 macrophages stimulated with lipopolysaccharide in a concentration-dependent manner. The first effect was dependent on inhibition of nitric oxide synthase-2 (NOS-2) protein expression although ITB did not modify nuclear factor-kappa B (NF-kappa B)-DNA binding. In addition, this compound inhibited cyclooxygenase-2 (COX-2) activity, which was also observed in aspirin-treated human monocytes. The anti-inflammatory effects of ITB were demonstrated in the carrageenan-induced mouse paw oedema, where this compound inhibited swelling and PGE(2) levels in inflamed paws but not in stomachs, in contrast to the dual COX-1/COX-2 inhibitor indomethacin. Inhibition of COX-2 activity and NOS-2 protein expression was confirmed in vivo using the zymosan-injected mouse air pouch model. These results suggest that synthesis of fused indazolo bis(guanidines) is a useful approach in the search for new anti-inflammatory agents.

Synthesis and evaluation of 2-tosylamino and 2-tosyliminopyrimidine derivatives as inhibitors of some leukocyte functions.

We have studied the potential anti-inflammatory effects of 20 2-tosylamino and 2-tosyliminopyrimidine new derivatives in human neutrophils. We have evaluated their interference with some leukocyte functions and 5-lipoxygenase activity. All the compounds reduced neutrophil degranulation process at concentrations in the microM range. Besides, compounds with a phenolic substitution inhibited leukotriene B(4) biosynthesis in neutrophils and decreased the cell-free 5-lipoxygenase activity. This study demonstrates that 2-tosylamino and 2-tosyliminopyrimidine derivatives can reduce the activation of neutrophil cells which may have relevance for the modulation of the inflammatory response.

A new ditriazine inhibitor of NF-kappaB modulates chronic inflammation and angiogenesis.

We have previously shown that a ditriazine derivative 4,10-dichloropyrido[5,6:4,5]thieno[3,2- d':3,2- d]-1, 2, 3-ditriazine (DTD) modulates acute inflammation in murine models by inhibition of leukocyte functions and expression of inducible enzymes including nitric oxide synthase and cyclooxygenase-2 (COX-2). In the present work, we have demonstrated the anti-inflammatory effect of DTD after oral administration in the rat adjuvant-induced arthritis, by reduction of interleukin-1beta and tumour necrosis factor-alpha levels and COX-2 expression in the inflamed tissues. These mediators were also significantly decreased by DTD treatment in the angiogenesis-dependent murine air pouch granuloma model, where this agent exerted anti-inflammatory and antiangiogenic effects. In vitro experiments indicated that DTD is an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway of cellular activation in macrophages, in parallel with the regulation of cytokine release. Our results suggest that the anti-inflammatory and antiangiogenic properties of DTD can be related to the inhibition of cytokine and PGE(2) production by interfering with NF-kappaB activation. This compound thus offers a therapeutic potential for the treatment of chronic inflammatory diseases with an angiogenic component, such as rheumatoid arthritis.

Nitric oxide-scavenging properties of some chalcone derivatives.

The implication of NO in many inflammatory diseases has been well documented. We have previously reported that some chalcone derivatives can control the iNOS pathway in inflammatory processes. In the present study, we have assessed the NO-scavenging capacity of three chalcone derivatives (CH8, CH11, and CH12) in a competitive assay with HbO(2), a well-known physiologically relevant NO scavenger. Our data identify these chalcones as new NO scavengers. The estimated second-order rate constants (k(s)) for the reaction of the three derivatives with NO is in the same range as the value obtained for HbO(2), with CH11 exerting the greatest effect. These results suggest an additional action of these compounds on NO regulation.

A pyrroloquinazoline derivative with anti-inflammatory and analgesic activity by dual inhibition of cyclo-oxygenase-2 and 5-lipoxygenase.

In a previous study, we reported a new pyrroloquinazoline derivative, 3-(4'-acetoxy-3',5'-dimethoxy)benzylidene-1,2-dihydropyrrolo[2,1-b]quinazoline-9-one (PQ), which inhibited human purified 5-lipoxygenase activity and prostaglandin E2 release in lipopolysaccharide-stimulated RAW 264.7 cells. In the present work, we show that PQ inhibits cyclo-oxygenase-2 activity in intact cell assays (human monocytes) and purified enzyme preparations (ovine isoenzymes) without affecting cyclo-oxygenase-1 activity. This behaviour was confirmed in vivo by using the zymosan-injected mouse air pouch model, where PQ caused a marked reduction in cell migration and leukotriene B4 levels at 4 h, as well as inhibition of prostaglandin E2 levels without affecting cyclo-oxygenase-2 expression at 24 h after zymosan stimulation. In addition, oral administration of this compound significantly reduced carrageenan-induced mouse paw oedema and phenyl-p-benzoquinone-induced writhings in mice. These results indicate that oral PQ exerts analgesic and anti-inflammatory effects, which are related to dual inhibition of cyclo-oxygenase-2 and 5-lipoxygenase activities.