[Incorporation of patient-reported outcomes into pharmacy and dermatology departments, in psoriasis and atopic dermatitis patients, as a tool to improve the healthcare quality and health outcomes]. / Incorporación de resultados informados por pacientes con psoriasis y dermatitis atópica en las consultas de atención farmacéutica y dermatología: herramienta que mejora la calidad asistencial y resultados en salud.

INTRODUCTION: Patient-reported outcomes (PROs) provide subjective information about their disease, treatment, and quality of life. OBJECTIVE: To introduce a new system of work coordinated between pharmacists and dermatologists, based on the collection and analysis of PROs to assess its clinical impact as well as patients satisfaction. METHOD: A prospective single-centre observational study was conducted under clinical conditions and included adult patients diagnosed with psoriasis (PS) and atopic dermatitis (AD) between April-2021 and February-2022. Pharmacists and dermatologists agreed on this systematic work. A REDCap® database was designed to facilitate data collection and the subsequent analysis. RESULTS: A total of 288 and 41 patients with PS and AD, respectively, were included. Those who started treatment showed significant improvement with a decrease in PROs and clinical parameters (p < 0.001). The pharmacist made 168 and 7 recommendations to dermatologists for PS and AD patients, respectively, of which 66.07% and 57.1% were accepted. The most common recommendations were «consult with rheumatologist¼ (20.83%), «extend drug regimen¼ (19.64%) and «consider change in treatment¼ (11.90%). Adverse events were reported in 55 and 17 patients with PS and AD, respectively. Of 103 patients, 75% were «very satisfied¼ and 20% «satisfied¼ with the system. CONCLUSIONS: This new working system helps to evaluate the short and long-term effectiveness of treatments and also to identify adverse events, alarm symptoms and co-morbidities in order to optimize therapies. Collaboration between pharmacists and dermatologists reduces decision-making time and patients appreciate better clinical care leading to higher patient satisfaction.

Real-world experience of palbociclib and ribociclib: novel oral therapy in metastatic breast cancer.

Background Palbociclib and ribociclib are novel oral agents in hormone receptor-positive metastatic breast cancer. Neutropenia is a common adverse event associated with these treatments and its clinical management often requires regimen changes, such as cycle delays and dose adjustments. Objective To provide a real-world experience of the effectiveness and toxicities associated with these drugs and to evaluate the impact of regimen changes in disease progression. Setting This study was performed at Hospital Universitario La Paz, in Spain. Methods Observational, retrospective study which included hormone receptor-positive metastatic breast cancer patients who initiated treatment with palbociclib or ribociclib between March 1st, 2018 and March 1st, 2019. Main outcome measure The primary effectiveness variable was progression-free survival. Safety evaluation was performed to determine neutropenia-incidence and severity, as well as its clinical management, including dose adjustments and treatment interruptions. Correlations between these regimen changes and effectiveness were also evaluated. Results Sixty-one patients were included, 33 treated with palbociclib and 28 with ribociclib. Palbociclib was mainly used as second line of treatment in the metastatic setting (81.8%) and ribociclib as first line (67.9%). The median progression-free survival was 12.76 months (95% CI 7.5 to not estimable) in palbociclib and not reached in ribociclib. After 12 months, the progression-free survival rate was 51.5% (95% CI 34-69) in palbociclib and 78.6% (95% CI 63-94.1) in ribociclib. Neutropenia was the most common adverse event with an incidence rate of 87.9% in palbociclib and 82.1% in ribociclib. Cycle delays were needed in more than half of the patients treated with palbociclib and ribociclib (63.6% and 64.3%). Dose adjustments were seen in 42.4% and 53.6% of the patients receiving palbociclib and ribociclib, respectively. Regimen changes did not involve statistically significant differences in 12-month PFS rates in the cohort investigated. Conclusion Palbociclib and ribociclib outcomes are comparable to those reached in the phase III trials, PALOMA-3 and MONALEESA-2, respectively, and cannot be compared as they were used in different treatment settings. The toxicity profile is favourable, being neutropenia the most common adverse event, easily managed with regimen changes. Further studies are needed to confirm the observed tendency of no detrimental impact on effectiveness of these regimen changes.

Hepatitis C virus (HCV) treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV-coinfected patients.

The efficacy of current hepatitis C therapy in HIV/HCV-coinfected patients is largely dependent on HCV genotype. The annual prevalence of HCV genotypes/subtypes and their influence on HCV clearance with antiviral treatment were examined in a dynamic cohort of HIV/HCV-coinfected patients followed up in Madrid since 2000. Patients entered the cohort at first visit and left the cohort when HCV clearance was achieved with HCV therapy or when follow-up was interrupted for any reason, including death. A total of 672 HIV/HCV-coinfected patients constituted the cohort. The mean follow-up time was 5.5 years, corresponding to 4108 patient-years. Mean age at entry was 37 years, and 73% were men and 86% were intravenous drug users. Overall distribution of HCV genotypes was as follows: 57.1% HCV-1 (1a: 29.2%, 1b: 20.4%, unknown: 7.6%), 1.3% HCV-2, 25.4% HCV-3 and 15.9% HCV-4. A total of 274 (40.8%) patients were treated with peginterferon-ribavirin, of whom 116 (42.3%) achieved HCV clearance following 1-3 courses of therapy. The proportion of HCV-1/4 rose from 71.7% in 2000 to 76.8% in 2008, whereas the proportion of HCV-2/3 fell from 28.1% in 2000 to 23.2% in 2008. The yearly prevalence increased for HCV-1 (R(2) : 0.92, b: 0.59, P < 0.001) and HCV-4 (R(2) : 0.77, b: 0.33, P < 0.005) and conversely diminished for HCV-3 (R(2) : 0.94, b: -0.82, P < 0.001). In summary, the prevalence of HCV-1 and HCV-4 has increased over the last decade in HIV/HCV-coinfected patients, whereas conversely it has declined for HCV-3, in association with the wider use of HCV therapy (41%) in this population.

Recommendations from SPNS/GEAM/SENBA/SENPE/AEDN/SEDCA/GESIDA on nutrition in the HIV-infected patient.

OBJECTIVE: to make recommendations on the approach to nutritional problems (malnutrition, cachexia, micronutrient deficiency, obesity, lipodystrophy) affecting HIV-infected patients. METHODS: these recommendations have been agreed upon by a group of expertes in the nutrition and care of HIV-infected patients, on behalf of the different groups involved in drafting them. Therefore, the latest advances in pathophysiology, epidemiology, and clinical care presented in studies published in medical journals or at scientific meetings were evaluated. RESULTS: there is no single method of evaluating nutrition, and diferent techniques--CT, MRI, and DXA--must be combined. The energy requirements of symptomatic patients increase by 20-30%. There is no evidence to support the increase in protein or fat intake. Micronutrient supplementation in only necessary in special circumstances (vitamin A in children and pregnant woman). Aerobic and resistance excercise is beneficial both for cardiovascular health and for improving lean mass and muscular strength. It is important to follow the rules of food safety at every stage in the chain. Therapeutic intervention in anorexia and cachexia must be tailored, by combining nutritional and pharmacological support (appetite stimulants, anabolic steroids, and, in some cases, testosterone). Artificial nutrition (oral supplementation, enteral or parenteral nutrition) is safe and efficacious, and improves nutritional status and response to therapy. In children, nutritional recommendations must be made early, and are a necessary component of therapy. CONCLUSION: appropriate nutritional evaluation and relevant therapeutic action are an essential part of the care of HIV-infected patients.

Overview of the pharmacogenetics of HIV therapy.

The administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, influencing antiviral activity as well as incidence of drug-related toxicities. The reasons for this large inter-individual variability in drug levels are multifactorial, and involve differences in metabolism related to gender, concomitant medications, drug compliance, underlying diseases and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the inter-individual variation in the body disposition of drugs. One of its main goals is to give grounds to individualized treatment. The majority of pharmacogenetic traits so far have involved drug metabolism. This is the case for the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid, which is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which allows splitting the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretroviral drugs have focussed on metabolizer enzymes at the liver and on transporter proteins on cell membranes. Herein, we review the most relevant metabolizer enzymes and protein transporters, along with the genetic polymorphisms, which seem to influence the pharmacokinetics of antiretroviral drugs, ultimately determining its efficacy and toxicity.

Clinical benefit of interventions driven by therapeutic drug monitoring.

BACKGROUND: Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. OBJECTIVE: To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. METHOD: S All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). R:A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. CONCLUSIONS: Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates.

[Opportunistic episodes in patients infected with the human immunodeficiency virus during the first 6 months of HAART]. / Episodios oportunistas en pacientes infectados por el virus de la inmunodeficiencia humana durante los primeros 6 meses de la terapia antirretroviral de gran actividad.

BACKGROUND: We aimed at analysing the incidence and characteristics of opportunistic events (OE) within a few months after starting highly active antiretroviral therapy (HAART) in HIV infected patients. PATIENTS AND METHOD: Retrospective study of HIV infected outclinic patients attended in a HIV/AIDS reference hospital in Madrid, who initiated HAART during the second semester of 1998, with a baseline CD4 cell count 250 x 10(6) cells/l. We recorded the incidence of OE within 6 months after beginning HAART and analysed virological and immunological parameters, sociodemographic variables and types of antiretroviral treatment. RESULTS: The study included 269 patients. Twenty-one (7.8%) OE were recorded. At the onset of HAART, the mean CD4 cell count in these 21 patients was 137 (92) x 10(6)/land the median viral load was 24,043 cop/ml. At the time of OE diagnosis, these parameters were 218 (114) x 10(6)/l (p = 0.012) and < 500 cop/ml, respectively. OE were distributed as follows: herpes zoster, 9 cases (43%), Pneumocystis carinii pneumonia, 5 cases (24%), Kaposi sarcoma,3 cases (14%) and tuberculosis, cerebral toxoplasmosis, cytomegalovirus retinitis, and non-Hodgkin lymphoma, 1 case each. Overall, 78% of OE occurred within first 4 months after beginning HAART. In addition, an OE was developed by 8% patients treated with NRTI and PI, 2% treated with NRTI and NNRTI, and 10% treated with NRTI,NNRTI and PI (p = 0.44). CONCLUSIONS: HIV-infected subjects with low CD4 counts are prone to develop OE within the first few moths after beginning HAART. An inflammatory response to latent antigens due to the immune recovery might explain this fact.

Overall trends in CD4 counts and plasma viremia in an urban clinic since the introduction of highly active antiretroviral therapies.

OBJECTIVE: To assess whether the benefit of highly active antiretroviral therapies (HAART) is continuing, a longitudinal retrospective study of CD4 counts and viral load (VL) in a large group of human immunodeficiency virus (HIV)-infected subjects was undertaken in Madrid. METHODS: Consecutive plasma VL values and CD4+ T-lymphocyte counts were collected during a 3-month period yearly from 1996 to 2000 in one HIV/acquired immune deficiency syndrome (AIDS) reference institution, where currently around 1500 HIV-infected individuals are on regular follow-up. RESULTS: VL values and CD4+ counts were collected at each time-point from an average of 375 and 391 patients, respectively. The proportion of subjects receiving HAART among those on any kind of antiretroviral treatment increased between 1996 (61%) and 2000 (95.1%) (P < 0.01). The number of subjects with undetectable VL (<500 HIV-RNA copies/mL) increased from 12% in 1996 to 64% in 2000 (P < 0.01). Accordingly, the proportion of individuals with CD4+ counts >500 cells/microL increased from 16% in 1997 to 54% in 2000 (P < 0.01). Notably, the number of subjects with VL values >10 000 copies/mL has declined over time, and currently represents only 17% of the population. Despite this favorable trend, the proportion of subjects with low CD4+ counts (<200 cells/microL) seems to have reached a plateau, in the range of 10%. CONCLUSIONS: A dramatic virological and immunological benefit has followed the introduction of HAART in HIV-infected patients since 1996. This favorable trend seems to be maintained over time, despite the negative impact of drug-related toxicity and/or adherence issues. However, a subgroup of subjects seems to persist with low CD4 counts despite having good virological control. They should be managed with alternative treatment strategies, including immune stimulatory agents.

Prevention of nevirapine-associated exanthema using slow dose escalation and/or corticosteroids.

OBJECTIVE: The appearance of rash is one of the most frequent and limiting side-effects during the first 4 weeks of treatment with nevirapine (NVP). We explored the efficacy and safety of four different strategies for reducing the incidence of this complication. PATIENTS AND METHODS: Four-hundred and sixty-nine patients were assigned randomly to accomplish the induction phase of NVP following either the standard recommendation of 200 mg daily during the first 2 weeks (n = 166), or any of three new strategies: adding prednisone 50 mg each other day during the first 2 weeks (n = 93); using a slowly escalating dose, beginning with 100 mg daily the first week, and increasing the dose by 100 mg/week up to the full daily dose of 400 mg (n = 107); and combining both the addition of prednisone with the slowly escalating dose (n = 103). A pharmacokinetic substudy was performed in seven patients receiving 100 mg of NVP during the first week. RESULTS: The incidence of rash diminished from 18.7% using the standard recommendation to 9.2% using the alternative approaches (P = 0.003). Rash appeared in 11.2%, 8.6%, and 7.7% of subjects assigned to receive the slowly escalating dose, prednisone, or both, respectively, without significant differences among them. The rate of drug discontinuation was also diminished by one-half using the new approaches (8.5% versus 4.3%; P = 0.06). NVP plasma concentrations within the first week of treatment using 100 mg daily were above the 90% inhibitory concentration for wild-type HIV-1 in all instances. CONCLUSION: The incidence of rash complicating the first few weeks of treatment with NVP can be diminished by adding corticosteroids for 2 weeks to the standard recommendation, or by using a slowly escalating dose. This second approach is proven to be pharmacokinetically safe.

Effect of thyroid hormones on urea biosynthesis and related processes in rat liver.

The results of the few studies on the effect of the thyroid status on nitrogen metabolism have been inconclusive and/or contradictory. In an attempt to elucidate this important relationship, we have studied the effect of experimental hypo- and hyperthyroidism on urea biosynthesis and related processes. We have found that the capacity of the liver to synthesize urea was increased in hypothyroid rats, as were the activities of the urea cycle enzymes; there were also changes in the activities of some related enzymes and in the levels of intermediates and amino acids. Isolated hepatocytes from these rats showed an increased capacity for urea synthesis. In hyperthyroid rats the picture was more complicated, since there was no change in the urea-synthesizing capacity of the liver, although there were changes in some enzymes and metabolites. Our results suggest that there may be more endogenous proteolysis in hypothyroidism which would increase ammonia production, the ammonia being used primarily for urea biosynthesis and, to a lesser extent, for glutamate and aspartate synthesis. These overall effects might be the result of an increase in glucagon and/or cAMP, which, as is well known, increase the urea-synthesizing capacity of liver. In hyperthyroidism, on the other hand, the changes in nitrogen metabolism could be the result of an increase in protein synthesis, a decrease in catabolic activity, or both.

In vitro effect of caffeine on some aspects of nitrogen metabolism in isolated rat hepatocytes.

Long-term exposure to high doses of caffeine affects several aspects of nitrogen metabolism, such as purine, pyrimidine and urea synthesis. However, little is known about the mechanisms of these changes and if they occur at shorter term. We have studied in isolated hepatocytes: 1) the in vitro effect of high doses of caffeine on amino acid levels, 2) the main destination of ammonia and carbon chains from amino acid catabolism, and 3) the cytosolic and mitochondrial redox states. We have found that, whereas it has a small effect on urea synthesis and on the levels of the cofactors and intermediates, it decreases the levels of several amino acids, the gluconeogenesis and the redox state. Our results suggest that a longer exposure to caffeine is necessary to affect the normal functions of some metabolic pathways.