Subspecialisation in cardiology care and outcome: should clinical services be redesigned, again?

BACKGROUND: Inpatient management of cardiac patients by cardiologists results in reduced mortality and hospitalisation. With increasing subspecialisation of the field because of growing management complexity and use of technological innovations, the impact of sub-specialisation on patient outcomes is unclear. AIM: To investigate whether management by subspecialty cardiologists impacts the outcomes of patients with subspecialty-specific diseases. METHODS: All patients admitted to a tertiary centre over nine years with a diagnosis of heart failure, acute coronary syndrome (ACS) or primary arrhythmia were reviewed. The outcomes of these patients managed by cardiologists subspecialised in their admission diagnosis (heart failure specialists, interventionalists and electrophysiologists) were compared with those treated by general cardiologists. RESULTS: Heart failure was diagnosed in 1704 patients, ACS in 7763 and arrhythmia in 4398. There was no difference in length of stay (LOS) (P = 0.26), mortality (P = 0.57) or cardiovascular readmissions (P = 0.50) in heart failure patients treated by general cardiologists compared with subspecialists. In ACS patients, subspecialty management was associated with reduced LOS, cardiovascular readmissions and mortality (all P < 0.05). This reduction in mortality was seen mainly in lower risk patients (P < 0.05). There was a reduction in LOS and cardiovascular readmissions in arrhythmia patients receiving subspecialty management (both P < 0.05) but no difference in mortality (P = 0.14). ACS patients managed by interventionalists were more likely to undergo coronary intervention (P < 0.05). Electrophysiologists more frequently referred patients for catheter ablation and pacemaker implantation than general cardiologists (P < 0.05). CONCLUSIONS: The benefits of subspecialty care seem attributable to the appropriate selection of patients who would benefit from technological innovations in care. These results suggest that the development of healthcare systems which align cardiovascular disease with the subspecialist may be more effective.

Effect of farming system and cheesemaking technology on the physicochemical characteristics, fatty acid profile, and sensory properties of Caciocavallo Palermitano cheese.

Caciocavallo Palermitano is a typical stretched-curd cheese that has been produced over the centuries in Sicily according to traditional cheesemaking technology and using raw milk from autochthonous cow breeds reared at pasture. The objective of this experiment was to evaluate the effects of the farming system and processing technology on the characteristics of Caciocavallo Palermitano cheese, with particular regard to the fatty acid profile. The farming system was either extensive, using autochthonous cows fed a pasture-based diet, or intensive, with specialized dairy cow breeds fed mainly hay and concentrate. The cheese-processing technology was either artisanal, using traditional wooden tools and endemic lactic bacteria, or advanced, using modern steel equipment and selected lactic bacteria. Twelve Caciocavallo Palermitano cheeses, 3 from each of the 4 experimental theses (2 farming systems × 2 cheesemaking technologies), were obtained and aged for 1, 30, 60, and 120 d. Milk of origin and cheeses were analyzed for the main chemical and rheological parameters. Fatty acids were methylated in lyophilized cheese and analyzed by gas chromatography. Sensory analysis was carried out by trained panelists. The PROC GLM of SAS 9.1.2 (SAS Institute Inc., Cary, NY) was used for the statistical analysis. The physical, chemical, and sensory characteristics of Caciocavallo Palermitano cheese were influenced more by the farming system than by the cheesemaking technology. Compared with cheese produced through intensive farming, cheese from extensive farming was richer in polyunsaturated, n-3, and odd- and branched-chain fatty acids, as well as in conjugated linoleic acid (cis-9,trans-11 C18:2), with accompanying improved human health benefits. The cheesemaking technology produced variation in the evolution of proteolysis during aging, due presumably to the different active microflora, which influenced the sensory profile of the resulting cheese. Indeed, cheese produced by artisanal manufacturing was described as less "bitter" and more "piquant" than cheese produced through the advanced process.

Outcome trial data on sodium glucose cotransporter-2 inhibitors: Putting clinical benefits and risks in perspective.

BACKGROUND: Sodium glucose cotransporter-2 (SGLT2) inhibitors have significant heart failure and renoprotective benefits with a wide spectrum of unfamiliar and potentially serious adverse effects. Limited understanding of the risk-benefit profile of SGLT2 inhibitor treatment may result in under utilisation by prescribers and patients. METHODS: Data from recent seminal randomized, placebo-controlled, outcome trials for multiple SGLT2 inhibitors were incorporated. Trial populations were sub-classified into high cardiovascular risk T2DM, HFrEF, and CKD. Efficacy outcomes of heart failure hospitalisation (HFH), cardiovascular (CV) mortality, total mortality, and prevention of renal deterioration were examined. Safety outcomes included were major hypoglycaemia, diabetic ketoacidosis (DKA), urinary tract infections (UTI), mycotic genital infections (MGI), hypotension, amputations and fractures. Absolute risk reduction/increase were used to calculate number needed to treat/harm. RESULTS: Trial data comprised 71,545 patients, of which 53,144 were high risk T2DM, 9696 HFrEF and 8705 CKD. For HFrEF, NNT for HFH was 18, CV mortality 93, total mortality 76, prevention of renal deterioration 143 and prevention of DKA 6224. NNH for UTI was 557, MGI 356, hypotension 120, hypoglycaemia 574, amputations 707 and fractures 858. For CKD, NNT for HFH was 116, CV mortality 245, total mortality 138, and prevention of renal deterioration was 63. NNH for DKA was 1458, UTI 309, MGI 291, hypotension 165, hypoglycaemia 374, amputations 4450 and fractures 696. In the T2DM cohort, NNT for HFH was 139, CV mortality 851, total mortality 601 and prevention of renal deterioration 558. NNH DKA was 1525, UTI 239, MGI 69, hypotension 325, hypoglycaemia 472, amputations 1578 and fractures 9569. CONCLUSIONS AND RELEVANCE: The cardiovascular and renal protective benefits of SGLT2 inhibitors far outweigh the risks. This paper puts into perspective the benefits and risks of treatment with SGLT2 inhibitors for clinicians and patients.

Acute effects of 5-methyltetrahydrofolate on endothelial function and asymmetric dimethylarginine in patients with chronic heart failure.

BACKGROUND AND AIMS: Folic acid enhances endothelial function in vascular disease states but its effects in chronic heart failure (CHF) are largely unknown. We studied the acute effects of i.v. methyltetrahydrofolate (5MTHF), the active metabolite of folic acid, on endothelial function and asymmetric dimethylarginine (ADMA) in CHF patients. METHODS AND RESULTS: Twenty two CHF patients and 22 controls received one of the following three-step infusions (1h per each step) in a randomized, parallel group, placebo-control study: (1) active treatment (saline, 5MTHF, and 5MTHF+the endothelial nitric oxide inhibitor N(G)-monomethyl l-arginine, LNMMA); or (2) placebo (salinex3). Endothelium-dependent vasodilatation was assessed by pulse-wave analysis (salbutamol-mediated changes in augmentation index, AIx). 5MTHF did not exert any significant effects on endothelium-dependent vasodilatation both in controls [DeltaAIx post-salbutamol baseline -7.6% (-24.8/-4.1) vs. 5MTHF -5.5% (-16.7/-3.6), medians and interquartile range, and CHF patients [-1.8% (-17.3/+1.3) vs. -2.4% (-3.8/-1.2)]. However, a significant reduction in ADMA concentrations was observed in both groups [controls baseline 0.68micromol/L (0.64/0.77) vs. 5MTHF 0.65 (0.57/0.74); CHF baseline 0.76 (0.63/0.82) vs. 5MTHF 0.69 (0.66/0.71), P=0.05 for both vs. baseline and placebo. These effects persisted during co-infusion with LNMMA. CONCLUSION: 5MTHF did not affect endothelial function but significantly reduced serum ADMA concentrations both in CHF patients and controls. This suggests a direct effect of 5MTHF on ADMA metabolism.

Lower gray matter volumes of frontal lobes and insula in adolescents with anorexia nervosa restricting type: Findings from a Brain Morphometry Study.

BACKGROUND: Brain atrophy in anorexia nervosa (AN) is one of the most marked structural brain changes observed in mental disorders. In this study, we propose a whole brain analysis approach to characterize global and regional cerebral volumes in adolescents with restricting-type anorexia nervosa (AN-r). METHODS: A total of 48 adolescent females (age range 13-18 years) were enrolled in the study (24 right-handed AN-r in the early stages of the illness and treated in the same clinical setting and 24 age-matched healthy controls [HC]). High-resolution T1-weighted magnetic resonance images were acquired. Cerebral volumes, including the total amounts of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were obtained with the Statistical Parametric Mapping software (SPM8); specific cortical regional volumes were computed by applying an atlas-based cortical parcellation to the SPM8 GM segments. Analysis of variance (ANOVA) was performed to identify any significant between-group differences in global and regional brain volumes. RESULTS: The analyses revealed reduced total GM volumes (p = 0.02) and increased CSF (p = 0.05) in AN-r, compared with HC. No significant between-group difference was found in WM volumes. At the regional level, significantly lower GM volumes in both frontal lobes (p = 0.006) and in the left insula (p = 0.016) were detected. No significant relationships were found between cerebral volumes and duration of illness, psychiatric comorbidities, psychopharmacological treatment, prepubertal phase, or presence of amenorrhea. CONCLUSIONS: The topographic distribution of GM reduction in a homogenous group of AN-r involves regions responsible for the emotional and cognitive deficits associated with the illness. These findings are discussed in relation to the roles of the insular cortex and the frontal lobes.

Assisted reproduction and Coronavirus in Italy.

OBJECTIVE: A novel type of Coronavirus was identified in China in December 2019. The first cases of a form of pneumonia of unknown etiology were detected at the beginning of that month in Wuhan. The virus is believed to have emerged at the Wuhan Huanan Seafood Market, where transmission of a zoonotic pathogen to humans occurred. PATIENTS AND METHODS: Some studies conducted in China during the epidemic report small numbers of pregnant women infected with SARS-CoV-2 and some pregnancy complications in patients with COVID-19. However, they fail to document the transplacental passage of the virus from mother to fetus. RESULTS: Following the COVID-19 outbreak, guidelines for couples who are undergoing treatments of assisted reproduction have been issued by the International Federation for Fertility Societies (IFFS), the American Society for Reproductive Medicine (ASRM), the European Society of Human Reproduction and Embryology (ESHRE) and the Latin American Network of Assisted Reproduction (REDLARA). They recommend couples to discuss assisted reproduction with their doctors while those at risk or with SARS-CoV-2 should consider freezing oocytes or embryos and retransferring them later. CONCLUSIONS: Other than the US, Italy is the country with the highest number of cases (197675 positives, 26644 deaths) (updated on April 26). The Italian National Transplant Centre and the Higher Institute of Health advised on March 17 to complete the cycles already started and not to start new cycles. Phase 2 will begin on 4 May with an increase in freedom of action and fertilization treatments will start again. The Society that brings together embryologists (SIERR) has issued the guidelines to be followed when this happens.

Return to Work and Quality of Life: A Psychosocial Survey After Kidney Transplant.

BACKGROUND: The main goals of kidney transplantation are to recreate a condition of psychophysical well-being and to improve the quality of life of the patient, including going back to work after transplant. Returning to work after a kidney transplant is an important health care indicator. The aim of the study was to assess the psychophysical well-being and work condition in kidney transplant recipients and to identify possible predictors of return to work. PATIENTS AND METHODS: A total of 81 patients (mean age, 46.3; SD, 11.47) were selected among patients undergoing 1 or more kidney transplants during follow-up 12 months after transplant. Pre- and post-transplant employment were evaluated using a sociodemographic schedule. Short Form Health Survey 36 was used for the quality of life study. RESULTS: Only 38.3% of patients were back to work 12 months after transplant compared with 67.90% of pretransplant patients (P = .004). The unemployment rate increased from 32.1% to 61.7% (P = .005) after kidney transplant. The reasons for not returning to work included the type of work (eg, factory) and the disability pension. The sociodemographic characteristics of the study population was significantly correlated with the dimensions of the Short Form Health Survey 36. CONCLUSIONS: Kidney transplant recipients should be encouraged to go back to work until it is a risk to physical health. In this regard, there is a need for multidisciplinary collaboration with the psychologist and the psychiatrist on the team, which provides psychological support and cures any psychological fragility in the post-transplant condition.

Psychological and Emotional Aspects in Living Donor Kidney Transplantation.

BACKGROUND: The decision to resort to living donor transplantation determines a particular condition characterized by a strong mental and emotional anguish, both for the patients and their families. The purpose of the study was to correlate the relational dynamics between donor-recipient, donor/recipient couple with the health team, and the family support perceived by the couple with the quality of life 6 months before transplant and 12 months after transplant and compare the data between the 2 time points after participating in the psychotherapy program of counseling about behavioral change. PATIENTS AND METHODS: Twenty-seven donor and recipient pairs consented to participate. The quality of life was studied through the Complete Form Health Survey (SF-36). All subjects completed a questionnaire that investigated the 3 types of fundamental relationships (donor-recipient, donor/recipient with the health team, and family support perceived by the couple). All participants were involved in an 18-month psychotherapy program in the pre- and post-transplant phase. RESULTS: The quality of the donor-recipient relationship significantly positively influences the subjective perception of psychophysical well-being before and after transplant. Post-transplant family support is crucial in ensuring a good perception of psychological and emotional health in donors and recipients. The relationship with the health team is important in ensuring a good perception of psychophysical health only in recipients after transplant. CONCLUSIONS: This study suggests that patients should be assisted by a multidisciplinary health care team and receive continuous support from relatives during the post-transplant adaptation process. This facilitates the donor and recipient postoperative quality of life.

Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells.

Retinaldehyde dehydrogenases belong to a superfamily of enzymes that regulate cell differentiation and are responsible for detoxification of anticancer drugs. Chemical tools and methods are of great utility to visualize and quantify aldehyde dehydrogenase (ALDH) activity in health and disease. Here, we present the discovery of a first-in-class chemical probe based on retinal, the endogenous substrate of retinal ALDHs. We unveil the utility of this probe in quantitating ALDH isozyme activity in a panel of cancer cells via both fluorescence and chemical proteomic approaches. We demonstrate that our probe is superior to the widely used ALDEFLUOR assay to explain the ability of breast cancer (stem) cells to produce all-trans retinoic acid. Furthermore, our probe revealed the cellular selectivity profile of an advanced ALDH1A1 inhibitor, thereby prompting us to investigate the nature of its cytotoxicity. Our results showcase the application of substrate-based probes in interrogating pathologically relevant enzyme activities. They also highlight the general power of chemical proteomics in driving the discovery of new biological insights and its utility to guide drug discovery efforts.

Isolation of Gram-positive n-alkane degraders from a hydrocarbon-contaminated Mediterranean shoreline.

AIMS: To investigate the petroleum hydrocarbon (HC)-degrading potential of indigenous micro-organisms in a sandy Mediterranean coast, accidentally contaminated with petroleum-derived HCs. METHODS AND RESULTS: Using culturable methods, a population of Gram-positive n-alkane degraders was detected in the contaminated soil. Five isolates, identified as one Nocardia, two Rhodococcus and two Gordonia strains, were able to degrade medium- and long-chain n-alkanes up to C(36) as assessed by growth assays and gas chromatography-mass spectrometry analysis. Diverging alkane hydroxylase-encoding genes (alkB) were detected by PCR, using degenerated primers, in all the strains; multiple sequences were obtained from the Nocardia strain, while only one alkB gene was detected in the Rhodococcus and Gordonia strains. The majority of the alkB sequences were related to Rhodococcus alkB2, but none was identical to it. CONCLUSIONS: Actinomycetes might have a key role in bioremediation of n-alkane-contaminated sites under dry, resource-limited conditions, such as those found in the Mediterranean shorelines. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge, this is the first study on the bioremediation potential in Mediterranean contaminated beaches.

Medicinal plants in the Mediterranean area: synthesis of the results of the project Rubia.

AIM OF STUDY: Within the scope of the European project RUBIA (ICA3-2002-10023), research has been performed on the traditional use and handling of plant species in several Mediterranean countries, Albania, Algeria, Cyprus, Egypt, Italy, Morocco, and Spain. This paper synthesises the chief results related to the medicinal utilization of those plants. MATERIAL AND METHODS: The information has been gathered by means of semi-structured interviews (1256) and techniques of participant observation with 803 informants. In each of the participating countries the study areas were selected by means of uniform criteria defined at the beginning of the study. RESULTS AND CONCLUSIONS: A total of 985 species have been catalogued, of which 406 have medicinal use. This work constitutes the first comparative study performed with ethnobotanical data gathered by a coordinated methodology in the Mediterranean area. An exhaustive list is provided for the species catalogued, indicating the regions where each plant was mentioned. ETHNOPHARMACOLOGICAL RELEVANCE: This information underlines the ethnobotanical richness of the region and the need to broaden this study to other areas of the Mediterranean. Furthermore, this constitutes a base for future phytochemical and pharmacological studies which could lead to new therapeutic products.

Alexithymia in Kidney Transplantation Patients.

Alexithymia is a marked difficulty in recognizing, exploring, and expressing inner feelings. Studies have proven the presence of a significant proportion of patients with alexithymia in samples from the transplantation population. This study aims to analyze the presence of alexithymia in a sample of 32 kidney transplantation patients from a deceased donor and to compare this construct with the presence of psychological symptoms and the physical and mental state of health perceived by the patients. Alexithymia assessment was analyzed using the Toronto Alexithymia Scale. The psychological symptoms were studied through the Symptom Checklist-90-R. The quality of life was studied through The Complete Form Health Survey. The study showed a high percentage of the presence of alexithymia in the examined transplant recipients. The construct is more present where the perception of their quality of life is low and where there is a greater presence of psychosomatic symptoms.

Effects of ewes grazing sulla or ryegrass pasture for different daily durations on forage intake, milk production and fatty acid composition of cheese.

Sulla (Sulla coronarium L.) forage is valued for its positive impact on ruminant production, in part due to its moderate content of condensed tannin (CT). The duration of daily grazing is a factor affecting the feed intake and milk production of ewes. In this study, the effects of grazing sulla pasture compared with annual ryegrass, and the extension of grazing from 8 to 22 h/day, were evaluated with regard to ewe forage intake and milk production, as well as the physicochemical properties and fatty acid (FA) composition of cheese. During 42 days in the spring, 28 ewes of the Comisana breed were divided into four groups (S8, S22, R8 and R22) that grazed sulla (S) or ryegrass (R) for 8 (0800 to 1600 h) or 22 h/day, and received no feeding supplement. In six cheese-making sessions, cheeses were manufactured from the 48 h bulk milk of each group. Compared with ewes grazing ryegrass, those grazing sulla had higher dry matter (DM) intake, intake rate and milk yield, and produced milk that was lower in fat and higher in casein. Ewes grazing for 22 h spent more time eating, which reduced the intake rate, increased DM and nutrient intake and milk yield, and reduced milk fat. Due to the ability of CT to inhibit the complete ruminal biohydrogenation of polyunsaturated fatty acids (PUFA), the FA composition of sulla cheese was more beneficial for consumer health compared with ryegrass cheese, having lower levels of saturated fatty acids and higher levels of PUFA and n-3 FA. The FA profile of S8 cheese was better than that of S22 cheese, as it was higher in branched-chain FA, monounsaturated FA, PUFA, rumenic acid (c9,t11-C18:2), and had a greater health-promoting index. The effect of short grazing time on sulla was attributed to major inhibition of PUFA biohydrogenating ruminal bacteria, presumably stimulated by the higher accumulation of sulla CT in the rumen, which is related to a higher intake rate over a shorter eating time. Thus, grazing sulla improved the performance of ewes, thereby increasing, especially with short grazing time, the nutritional properties of cheese fat.

Patterns of Personality in Living Kidney Donors.

BACKGROUND: The decision to undergo living donor transplantation determines a particular condition characterized by strong mental and emotional anguish, both for the patient and his family. Many recent studies showed the concern of living donors who, rather than being driven by altruistic reasons, meet the decision to donate with ambivalence, liabilities, and/or in response to family pressures. The aim of this study was to analyze the more frequently encountered personality variables in a sample of potential kidney living donors, together with any psychological variables that can express possible risks of an impulsive decision and/or poorly processed from a cognitive and emotional point of view. METHODS: We examined 32 potential kidney donors. The personality study was performed using The Millon Clinical Multiaxial Inventory-III. The psychic symptoms were studied through the Symptom Checklist-90-R. The quality of life was studied through the Complete Form Health Survey (SF-36). RESULTS: The study showed that the ability to express free and therefore invalid consent, in the role of donor, is an expression of specific personality patterns, cognitive, emotional aspects and interpersonal experiences. CONCLUSIONS: The psychological-psychiatric evaluation of potential donors is fundamental to certify the state of mental health and psychological well-being, an indispensable prerequisite for the donation.

Hypotension is associated with diuretic resistance in severe chronic heart failure, independent of renal function.

BACKGROUND: Diuretic resistance and systemic hypotension are common in chronic heart failure (CHF), however, the two have not been associated. AIMS: Since blood pressure (BP) might be an important determinant of sodium excretion, we searched for an association between BP and diuretic dosage in severe CHF. METHODS: Our heart failure database was retrospectively reviewed for patients with severe left ventricular systolic dysfunction. The 54-patient cohort was divided on the basis of frusemide dosage (high-dose > or = 250 mg daily, n=26). RESULTS: Patients taking high-dose frusemide had higher serum creatinine, and lower systolic and diastolic BP. On logistic regression analysis, increased serum creatinine and reduced diastolic BP were independent predictors of the use of high-dose frusemide. Grouping these variables into tertiles, the odds ratio for the use of high-dose frusemide was 4.0 as diastolic BP decreased (p<0.01), and 6.8 as serum creatinine increased (p<0.001). CONCLUSIONS: We have found an association between hypotension and the use of high-dose frusemide in severe CHF, which is independent of renal function, and which may be an important physiologic mechanism of diuretic resistance in severe CHF.

A Study on Emotional-Affective Aspects and the Perception of General Health in Kidney Transplant Subjects.

BACKGROUND: Transplantation has profound psychological implications. Psychodiagnostic assessments with structured instruments (scales, questionnaires) may be insufficient for bringing out the deeper aspects of the personality. PATIENTS AND METHODS: Thirty kidney transplant recipients underwent the Thematic Apperception Test to detect significant variables hypothetically related to characteristics of the study sample and the SF-36 to assess quality of life. RESULTS: The variable of Thematic Apperception Test (TAT) "communication difficulties" was significantly correlated with the dimensions of the SF-36 "emotional role functioning," "social activities," and "mental health." The dimension of SF-36 "general health" did not interfere with the variable of TAT "constricted effect." CONCLUSIONS: This study is considered to be particularly useful in detecting the emergence of "removed difficulties" that transplanted subjects are not inclined to recognize. The analysis of these aspects is necessary to plan individualized psychotherapy pathways.

Interference of cetirizine with the late eosinophil accumulation induced by either PAF or compound 48/80.

1. The effect of topical or systemic treatment with the histamine H1-receptor antagonist, cetirizine, on the rat pleural eosinophil accumulation induced by PAF or compound 48/80 was investigated. The number of pleural resident eosinophils increased 6 h after the intrathoracic (i.t.) injection of PAF (1 microgram/cavity), peaked within 24 h and persisted significantly augmented for at least 96 h. Compound 48/80 (25 micrograms/cavity) also produced a long lasting pleural eosinophilia but this was first noted only 24 h after stimulation. 2. Intraperitoneal pretreatment with cetirizine inhibited eosinophilia induced by either PAF (ED50 = 19 mg kg-1) or compound 48/80 (ED50 = 14 mg kg-1) whereas meclizine, another histamine H1-receptor antagonist, was inactive. 3. Administered locally, cetirizine (5 and 15 micrograms/cavity) also dose-dependently inhibited both PAF- and compound 48/80-induced eosinophilia, providing evidence that its inhibitory effect is not due to any action upon circulating eosinophils. Consistent with this result, incubation of isolated peritoneal eosinophils with cetirizine failed to modify in vitro eosinophil migration caused by PAF. 4. Since the late eosinophilia induced by PAF may depend on the synthesis of a transferable protein mediator, cetirizine was administered to donor or recipient rats in order to determine whether it interferes with the generation or with the expression of this protein. We showed that only the treatment of recipient rats abolished the transfer of the eosinophilotactic activity, indicating that cetirizine does not modify the generation but inhibits the expression of this activity. 5. Our findings indicate that cetirizine is able to inhibit eosinophil accumulation by acting locally. The mechanism is neither related to its recognized ability to antagonize histamine H,-receptors nor to a direct action upon circulating eosinophils.

Long-lasting inhibitory activity of the hetrazepinic BN 50730 on exudation and cellular alterations evoked by PAF and LPS.

1. Inhibitory effects of the hetrazepinic derivative BN 50730 on the rat pleural inflammatory response, triggered by PAF or lipopolysaccharides (LPS), were examined. The type of pharmacological blockade exerted by this antagonist in in vitro assays of eosinophil chemotaxis and platelet aggregation were also investigated. 2. Intrathoracic injection of PAF (1 microgram per cavity) caused a 4 fold increase in the extravasated protein within 15 min and led to a marked eosinophil accumulation 24 h post-challenge. BN 50730 (0.5-10 micrograms per cavity) inhibited exudation by PAF dose-dependently without modifying the response induced by histamine, bradykinin or 5-hydroxytryptamine (5-HT). 3. The kinetics of the inhibitory effect on exudation revealed that the actions of WEB 2086 and BN 52021 (10 micrograms per cavity) were over within 2 and 4 h respectively, whereas BN 50730 (10 micrograms per cavity) retained 80% of its inhibitory activity for 4 days. 4. Oral treatment with BN 50730 (10-20 mg kg-1, 1 h beforehand) suppressed the leucocyte accumulation and late eosinophilia observed 6 and 24 h after PAF respectively, but did not modify the eosinophilia induced by leukotriene B4 (LTB4) or bradykinin. BN 50730 also failed to reduce the eosinophil accumulation induced by LPS but drastically inhibited the neutrophil influx. 5. The pre-incubation of rat peritoneal eosinophils for 10 min with BN 50730 (30 nM-1 microM) dose-dependently inhibited the chemotaxis induced by PAF (0.1 microM) in vitro. The IC50 values for BN 52021, WEB 2086 and BN 50730 in this system were 5, 5 and 0.05 microM respectively. 6. In separate assays, rat peritoneal eosinophils and rabbit washed platelets were preincubated with BN 50730 or WEB 2086 (1 pM) then subjected to a series of at least two consecutive washings in order to remove the antagonist from the receptor environment. Under such conditions, only the cells pretreated with WEB 2086 recovered the sensitivity to the lipid.7. We conclude that BN 50730 is a potent, specific and long-acting PAF antagonist and its effect seems to result from a high affinity and non-competitive interaction of the drug with the PAF receptor.

Homologous tachyphylaxis to bradykinin and its interference with allergic pleurisy in actively sensitized rats.

After recovery from a first intraplantar or intrathoracic stimulation with bradykinin, repeated daily provocation with this peptide resulted in a progressive loss of its ability to cause paw or pleural oedema, reaching 0-20% of the control within seven and four consecutive provocations, respectively. The phenomenon was shown to be time reversible, since the unresponsiveness ceased when stimulations were discontinued, and localized, since paw oedema evoked by the peptide was not modified after desensitization of either the contralateral paw or the pleural cavity. Furthermore desensitization to bradykinin did not influence the pleurisy elicited by either histamine (200 micrograms/cavity), 5-hydroxytryptamine (5-HT) (100 microgram/cavity) or platelet-activating factor (PAF) (1 microgram/cavity), suggesting that the desensitization was selective. In contrast, when actively sensitized animals were submitted to bradykinin-induced tachyphylaxis, pleural exudation and leukocyte influx induced by antigen were drastically reduced, strongly implying bradykinin in this process. We demonstrated that repeated daily stimulation with bradykinin cause selective, local and reversible auto-refractoriness, which may be useful as a tool in attempting to evaluate the role of this peptide in inflammation.

Suppression by cetirizine of pleurisy triggered by antigen in actively sensitized rats.

The efficacy of cetirizine in comparison with meclizine, another piperazine H1 receptor antagonist, in rat pleurisy caused by allergen or autacoid was investigated. Sensitization was achieved by subcutaneous injection of a mixture of ovalbumin and aluminium hydroxide. Fourteen days later, the animals were challenged with an intrathoracic injection of ovalbumin (12 micrograms/cavity), which caused drastic mast cell degranulation, followed by pleural oedema and leucocyte influx. Cetirizine and meclizine (2.5-30 mg/kg i.p.), 1 h before challenge, inhibited the exudatory response evoked by antigen, under conditions where neutrophil and eosinophil accumulation was affected only by the former. When administered intrathoracically 22 h after allergen, i.e. using a curative approach, cetirizine (15 micrograms/cavity) drastically reduced the pleural eosinophilia noted 24 h post-challenge, indicating that this drug can reverse an already established eosinophilia. Cetirizine (15 mg/kg i.p.) also restored, to about 39% (P < 0.001), the number of uninjured mast cells recovered from the pleural cavity following allergen stimulation. In normal rats, cetirizine (5-15 micrograms/cavity) completely inhibited the pleural exudation elicited by histamine and only partially the exudation caused by 5-hydroxytryptamine or bradykinin, but was quite inactive against platelet-activating factor. We conclude that the pleural exudation triggered by allergen, vasoactive amines or bradykinin is clearly sensitive to cetirizine. In addition, the ability of the drug to interfere with pleural neutrophil or eosinophil mobilization and mast cell degranulation seems not to be associated with its ability to block the histamine H1 receptor.