Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

COVID-19 salivary Raman fingerprint: innovative approach for the detection of current and past SARS-CoV-2 infections.

The pandemic of COVID-19 is continuously spreading, becoming a worldwide emergency. Early and fast identification of subjects with a current or past infection must be achieved to slow down the epidemiological widening. Here we report a Raman-based approach for the analysis of saliva, able to significantly discriminate the signal of patients with a current infection by COVID-19 from healthy subjects and/or subjects with a past infection. Our results demonstrated the differences in saliva biochemical composition of the three experimental groups, with modifications grouped in specific attributable spectral regions. The Raman-based classification model was able to discriminate the signal collected from COVID-19 patients with accuracy, precision, sensitivity and specificity of more than 95%. In order to translate this discrimination from the signal-level to the patient-level, we developed a Deep Learning model obtaining accuracy in the range 89-92%. These findings have implications for the creation of a potential Raman-based diagnostic tool, using saliva as minimal invasive and highly informative biofluid, demonstrating the efficacy of the classification model.

Human salivary Raman fingerprint as biomarker for the diagnosis of Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease leading to progressive and irreversible muscle atrophy. The diagnosis of ALS is time-consuming and complex, with the clinical and neurophysiological evaluation accompanied by monitoring of progression and a long procedure for the discrimination of similar neurodegenerative diseases. The delayed diagnosis strongly slows the potential development of adequate therapies and the time frame for a prompt intervention. The discovery of new biomarkers could improve the disease diagnosis, as well as the therapeutic and rehabilitative effectiveness and monitoring of the pathological progression. In this work saliva collected from 19 patients with ALS, 10 affected by Parkinson's disease, 10 affected by Alzheimer's disease and 10 healthy subjects, was analysed using Raman spectroscopy, optimizing the parameters for detailed and reproducible spectra. The statistical multivariate analysis of the data revealed a significant difference between the groups, allowing the discrimination of the disease onset. Correlation of Raman data revealed a direct relationship with paraclinical scores, identifying multifactorial biochemical modifications related to the pathology. The proposed approach showed a promising accuracy in ALS onset discrimination, using a fast and sensitive procedure that can make more efficient the diagnostic procedure and the monitoring of therapeutic and rehabilitative processes in ALS.

Lamotrigine induced Brugada-pattern in a patient with genetic epilepsy associated with a novel variant in SCN9A.

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.

Does timing of initiation influence acceptance and adherence to NIV in patients with ALS?

BACKGROUND: The role of nocturnal non invasive ventilation (NIV) to prolong tracheostomy-free survival, is still controversial in amyotrophic lateral sclerosis (ALS) patients and the best timing to initiate NIV is unclear. OBJECTIVE: As NIV acceptance and adherence can be influenced by many factors, we aimed to compare immediate acceptance and short-term NIV adherence between NIV initiated very early and NIV initiated later. METHODS: This is a post hoc analysis of our previous cohort retrospective study of 88 ALS patients: 53 under later NIV (late group - LG) (forced vital capacity [FVC]<80% pred. at NIV prescription) and 35 under very early NIV (very early group - VEG) (FVC>80%). We compared hours of NIV use as immediate acceptance of NIV (use ≥4h/night) and dherence at 4 months post-initiation (defined as use ≥4h/night or 120h/month). RESULTS: No differences were found between VEG and LG in use of NIV (>5h/night in both groups), immediate acceptance (85.7% vs. 85.0%, p=0.927) and short-term adherence (81.3% vs. 87.2%, p=0.469); 39.7% of patients increased their NIV use (35% by >60min/night). A decline in adherence was observed in 12.5% of patients irrespective of group affiliation. CONCLUSIONS: In ALS patients, initiation of very early NIV does not reduce its immediate acceptance or the short-term adherence. However, at least 1 in 10 patients may be at risk of reducing their adherence irrespective of early or late NIV prescription. As still under debate and not conclusive, further literature on early NIV benefit is welcomed.

Impact of an early respiratory care programme with non-invasive ventilation adaptation in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Forced vital capacity (FVC) <80% is one of the key indications for starting non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). It was hypothesized that a very early start of NIV could lengthen the free interval before death compared to later-start NIV; as a secondary outcome, the survival rate of patients on NIV without tracheotomy was also evaluated. METHODS: This retrospective study was conducted on 194 ALS patients, divided into a later group (LG) with FVC <80% at NIV prescription (n = 129) and a very early group (VEG) with FVC ≥80% at NIV prescription (n = 65). Clinical and respiratory functional data and time free to death between groups over a 3-year follow-up were compared. RESULT: At 36 months from diagnosis, mortality was 35% for the VEG versus 52.7% for the LG (P = 0.022). Kaplan-Meier survival curves adjusted for tracheotomy showed a lower probability of death (P = 0.001) for the VEG as a whole (P = 0.001) and for the non-bulbar (NB) subgroup (P = 0.007). Very early NIV was protective of survival for all patients [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.28-0.74; P = 0.001] and for the NB subgroup (HR 0.43; 95% CI 0.23-0.79; P = 0.007), whilst a tracheotomy was protective for all patients (HR 0.27; 95% CI 0.15-0.50; P = 0.000) and both NB (HR 0.26; 95% CI 0.12-0.56; P = 0.001) and bulbar subgroups (HR 0.29; 95% CI 0.11-0.77; P = 0.013). Survival in VEG patients on NIV without tracheotomy was three times that for the LG (43.1% vs. 14.7%). CONCLUSION: Very early NIV prescription prolongs the free time from diagnosis to death in NB ALS patients whilst tracheotomy reduces the mortality risk in all patients.

Meditation training for people with amyotrophic lateral sclerosis: a randomized clinical trial.

BACKGROUND AND PURPOSE: Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population. METHODS: A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model. RESULTS: A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (ß = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment. CONCLUSIONS: An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS.

Spontaneous Breathing Pattern as Respiratory Functional Outcome in Children with Spinal Muscular Atrophy (SMA).

INTRODUCTION: SMA is characterised by progressive motor and respiratory muscle weakness. We aimed to verify if in SMA children 1)each form is characterized by specific ventilatory and thoraco-abdominal pattern(VTAp) during quiet breathing(QB); 2)VTAp is affected by salbutamol therapy, currently suggested as standard treatment, or by the natural history(NH) of SMA; 3)the severity of global motor impairment linearly correlates with VTAp. MATERIALS AND METHODS: VTAp was analysed on 32 SMA type I (SMA1,the most severe form), 51 type II (SMA2,the moderate), 8 type III (SMA3,the mildest) and 20 healthy (HC) using opto-electronic plethysmography. Spirometry, cough and motor function were measured in a subgroup of patients. RESULTS: In SMA1, a normal ventilation is obtained in supine position by rapid and shallow breathing with paradoxical ribcage motion. In SMA2, ventilation is within a normal range in seated position due to an increased respiratory rate(p<0.05) with reduced tidal volume(p<0.05) secondary to a poor contribution of pulmonary ribcage(%ΔVRC,P, p<0.001). Salbutamol therapy had no effect on VTAp during QB(p>0.05) while tachypnea occurred in type I NH. A linear correlation(p<0.001) was found between motor function scales and VTAp. CONCLUSION: A negative or reduced %ΔVRC,P, indicative of ribcage muscle weakness, is a distinctive feature of SMA1 and SMA2 since infancy. Its quantitative assessment represents a non-invasive, non-volitional index that can be obtained in all children, even uncollaborative, and provides useful information on the action of ribcage muscles that are known to be affected by the disease.Low values of motor function scales indicate impairment of motor but also of respiratory function.

Effectiveness and safety of mouthpiece ventilation and nocturnal non-invasive ventilation in patients with kyphoscoliosis: Short and long-term outcomes after an episode of acute respiratory failure.

BACKGROUND: Kyphoscoliosis is a skeletal condition involving the hyperflexion of the thoracic spine. It is characterized by reduced chest wall compliance and impaired respiratory mechanisms leading to progressive hypo-ventilation. We evaluated the effectiveness and the safety of non-invasive ventilation (NIV) in patients after an episode of acute respiratory failure (ARF). METHODS: Eighteen patients with severe kyphoscoliosis who had been hospitalized for an episode of ARF were followed for 4 years. NIV was applied via mouthpiece (MPV) during the daytime and via mask during the night. The primary outcomes were changes in physiological and functional parameters as well as quality of life. Secondary outcomes were considered re-hospitalization and mortality rate after discharge. A set of control subjects was used for comparison. RESULTS: All patients showed a significant improvement in several clinical, physiological, functional and quality of life parameters. Four of them (22.2%) died during the four year follow-up period. In the uni-variate analysis patients who died had higher cardiac co-morbidity, lower MIP and SNIP, higher paCO2, and oxygen desaturation index at initial admission. CONCLUSIONS: Diurnal MPV associated with nocturnal NIV had significantly improved lung function, clinical outcomes and quality of life. It should be considered as a safe alternative to traditional administering of NIV.

Non-invasive ventilation in the treatment of sleep-related breathing disorders: A review and update.

Non-invasive mechanical ventilation (NIV) was originally used in patients with acute respiratory compromises or exacerbations of chronic respiratory diseases as an alternative to intubation. Over the last thirty years NIV has been used during the night in patients with stable chronic lung diseases such as obstructive sleep apnea, the overlap syndrome (COPD and obstructive sleep apnea), neuromuscular disorders, obesity-hypoventilation syndrome and in other conditions such as sleep disorders associated with congestive heart failure. In this review we discuss the different types of NIV, the specific conditions in which they can be used as well as the indications, recommendations, and evidence supporting the efficacy of NIV.

Sleep apnoea/hypopnoea syndrome: combination therapy with the Pillar palatal implant technique and continuous positive airway pressure (CPAP). A preliminary report.

A preliminary report. The objective of this study was to evaluate the possibility of reducing CPAP pressure levels and improving patient adherence to CPAP therapy by stiffening the soft palate tissue with a Pillar palatal implant. Many patients have difficulty complying with CPAP therapy if high levels of airway pressure are necessary for their therapy to be successful. Twenty-one patients (16 males and 5 females) with moderate to severe OSAHS treated with CPAP therapy underwent Pillar palatal treatment in an office-based procedure. The mean age was 49.6 +/- 11.2 years, mean baseline body mass index (BMI) was 31.4 +/- 3.2 Kg/m2. At 3 months follow-up a significant reduction of CPAP pressure levels was found. Mean CPAP pressure levels before and after Pillar application were 11.2 +/- 1.69 cm H2O vs. 9.3 +/- 2.5 cm H2O respectively (p < 0.001). The Pillar system is intended for use in stiffening the soft palate tissue, so this minimally invasive procedure, which was introduced to clinical practice as a treatment for the palatal component of OSAHS, could make it possible to reduce CPAP pressures and improve patient adherence to CPAP therapy. The preliminary results of this combined therapeutic approach indicate the safety and efficacy of the treatment of OSAHS. Further studies are needed to evaluate the long-term results.

[Towards a multi-step informed consent: considerations and proposals for a good practice]. / Verso un consenso informato a più fasi: considerazioni e proposte per una buona prassi.

Any therapeutic intervention needs consent from the patient, after have received information from the physician. This is often seen as a bureaucratic accomplishment but it could enhance therapeutic alliance. We propose to divide consent from information, offering a place in which doubts and emotions can be explored, with the assistance of a psychological interview. We believe that this new approach can enhance physician-patient relationship, with an improvement in patient satisfaction and a decrease of claims and complaints.

Encefalitis: ¿cuáles y cómo tratar? / Encephalitis: which are and how to treat?

La causa más frecuente de encefalitis es la infección viral que invade el SNC por vía sanguínea (p ej.: enterovirus) , nervios periféricos (p ej.: rabia) y menos frecuentemente, vía nervio olfatorio (p ej.: amebas de vida libre). El compromiso focal de las células nerviosas explica las variaciones sintomáticas. En nuestro medio ningún virus predomina ostensiblemente y las características epidemiológicas y clínicas pueden crear confusión inicial. La encefalitis herpética es una emergencia neurológica por la necesidad de un diagnóstico precoz, para instalar el tratamiento específico. El VHS-1 es importante en niños y los adultos; VHS-2 en el neonato. El rendimiento del aislamiento viral en el LCR es bajo, la RPC tiene una sensibilidad aproximada de 91 por ciento y alta especificidad permaneciendo positiva hasta cinco a siete días después de iniciada la sintomatología y/o el tratamiento. El EEG es sensible pero poco especifico. La RM es el examen imagenológico indicado en etapa aguda; la TAC permite controlar la evolución. La biopsia cerebral se reserva para casos con falta de respuesta objetiva al tratamiento. El aciclovir reduce la letalidad y las secuelas de la encefalitis herpética, dosis de 60 mg/kg/d en recién nacidos han elevado su sobrevida. Valaciclovir y famciclovir, con similar actividad antiviral, podrían emplearse para prolongar el efecto antiviral más allá de 21 días. En la encefalitis por enterovirus las manifestaciones cutáneas o la miocarditis pueden orientar el diagnóstico etiológico inicialmente. Se debate la capacidad de Mycoplasma pneumoniae para producir trastornos del SNC, si bien invade el LCR, no se ha logrado definir su rol patógeno. Menos importantes son VHH-6, virus de Epstein-Barr, adenovirus, Bartonella henselae, Cryptococcus neoformans, Leptospira sp. y otros. Es posible que nuevos tratamientos específicos estimulen el desarrollo de tecnologías que nos permitan conocer mejor los reales agentes de encefalitis aguda en nuestro país.

Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure.

OBJECTIVE: To investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with beta myosin heavy chain (beta MHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure. DESIGN: Molecular analysis of beta MHC and mtDNA gene defects in patients with HCM. SETTING: Cardiovascular molecular diagnostic and heart transplantation reference centre in north Italy. PATIENTS: Four patients with HCM who underwent heart transplantation for end stage heart failure, and after pedigree analysis of 60 relatives, eight additional affected patients and 27 unaffected relatives. A total of 111 unrelated healthy adult volunteers served as controls. Disease controls included an additional 27 patients with HCM and 102 with dilated cardiomyopathy. INTERVENTION: Molecular analysis of DNA from myocardial and skeletal muscle tissue and from peripheral blood specimens. MAIN OUTCOME MEASURES: Screening for mutations in beta MHC (exons 3-23) and mtDNA tRNA (n = 22) genes with denaturing gradient gel electrophoresis or single strand conformational polymorphism followed by automated DNA sequencing. RESULTS: One proband (kindred A) (plus seven affected relatives) had arginine 249 glutamine (Arg249Gln) beta MHC and heteroplasmic mtDNA tRNAIle A4300G mutations. Another unrelated patient (kindred B) with sporadic HCM had identical mutations. The remaining two patients (kindred C), a mother and son, had a novel beta MHC mutation (lysine 450 glutamic acid) (Lys450Glu) and a heteroplasmic missense (T9957C, phenylalanine (Phe)-->leucine (Leu)) mtDNA mutation in subunit III of the cytochrome C oxidase gene. The amount of mutant mtDNA was higher in the myocardium than in skeletal muscle or peripheral blood and in affected patients than in asymptomatic relatives. Mutations were absent in the controls. Pathological and biochemical characteristics of patients with mutations Arg249Gln plus A4300G (kindreds A and B) were identical, but different from those of the two patients with Lys450Glu plus T9957C(Phe-->Leu) mutations (kindred C). Cytochrome C oxidase activity and histoenzymatic staining were severely decreased in the two patients in kindreds A and B, but were unaffected in the two in kindred C. CONCLUSIONS: beta MHC gene and mtDNA mutations may coexist in patients with HCM and end stage congestive heart failure. Although beta MHC gene mutations seem to be the true determinants of HCM, both mtDNA mutations in these patients have known prerequisites for pathogenicity. Coexistence of other genetic abnormalities in beta MHC linked HCM, such as mtDNA mutations, may contribute to variable phenotypic expression and explain the heterogeneous behaviour of HCM.

Synthesis of alkyl chain-modified ether lipids and evaluation of their in vitro cytotoxicity.

A series of alkyl lysophospholipid (ALP) analogs of ET-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) containing modifications in the long C-1 chain has been synthesized and evaluated in human tumor cell line cytotoxicity assays. The compounds have also been evaluated in platelet activating factor (PAF) receptor agonism and hemolysis tests. Two modifications have been studied, introduction of a carbonyl group at different positions of the C-1 chain and branching of this chain, in some compounds with incorporation of a phenyl group. Several compounds showed a cytotoxic potency comparable to that of the reference compound ET-18-OCH3, associated with reduced proaggregating and hemolytic effects. The two enantiomers of 1-O-(7-oxooctadecyl)-2-O-methyl-rac-glycero-3-phosphocholine (2) showed the same level of cytotoxicity or antiproliferative activity, with the PAF-agonistic effect confined to R-2. The very low stereoselectivity found in the in vitro cytotoxicity confirms earlier results and indicates a lack of stereospecific interactions with a macromolecular target.

The daunorubicin-binding protein of Mr 54,000 is an aldehyde dehydrogenase and is down-regulated in mouse liver tumors and in tumor cell lines.

A rabbit antiserum developed against purified rat liver daunorubicin-binding protein of M(r) 54,000 (DNR-BP54) cross-reacted with a mouse protein of the same molecular weight. This protein was expressed in the liver and several other organs of mice. A series of tumors and cell lines tested for the presence of the protein were negative. By immunocytochemistry, we found that DNR-BP54 was abundantly expressed in the cytoplasm of normal hepatocytes but was expressed at much lower levels in urethane-induced mouse liver tumors. By immunoscreening of a mouse liver cDNA library, we cloned the cDNA coding for DNR-BP54 and we found that this protein is aldehyde dehydrogenase-2 (EC 1.2.1.3). This result was confirmed by the dehydrogenase activity found in pure preparations of DNR-BP54 from normal rat and mouse livers, assayed with acetaldehyde as substrate and NAD as cofactor. The enzyme activity was inhibited by daunorubicin. The inhibition was found to be competitive with respect to NAD.

Effect of protein kinase C inhibitors on invasiveness of human melanoma clones expressing different levels of protein kinase C isoenzymes.

The involvement of protein kinase C (PKC) in the mechanism of chemotaxis and invasiveness of human melanoma has been studied in 6 clones of 665/2 cell line characterized by a different integrin profile, differentiation grade and in vitro invasive ability. The levels of total protein kinase C activity revealed a direct correlation with the chemotactic and invasive ability of these clones. Protein kinase C inhibitors, sphingosine and staurosporine, reduced chemotaxis and invasiveness of the highly invasive clone 2/60, while 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) was ineffective. Immunofluorescence analysis revealed high levels of protein kinase C alpha in clone 2/60, while the less invasive clone 2/21 expressed low levels of protein kinase C alpha and beta, but surprisingly appreciable levels of protein kinase C gamma. Downregulation with phorbol 12-myristate 13-acetate (TPA) did not affect invasiveness of clone 2/60 unless the compound was present during the assay. H7 strongly increased invasiveness of clone 2/21 and was able to reverse the inhibitory effect of TPA on clone 2/60. Preliminary experiments showed higher levels of diacylglycerol in clones with lower protein kinase C, suggesting a constitutive downregulation of the enzyme in low invasive clones. Our results support a role for protein kinase C in the invasion process, but point out the complexity of the mechanism which might involve the proteolytic fragment of the enzyme, protein kinase M.

Dilated cardiomyopathy requiring cardiac transplantation as initial manifestation of Xp21 Becker type muscular dystrophy.

A neurologically asymptomatic 32-yr-old man recently transplanted for end-stage dilated cardiomyopathy presented with progressively increasing serum creatine kinase level (hyperCKemia) while receiving cyclosporin and simvastatine treatment. Revised family history led to suspicion of X-linked inherited myopathy, then confirmed by muscle biopsy findings showing myopathic dystrophic changes, a patchy distribution of immunoreactivity on the sarcolemma of several muscle fibres with anti-dystrophin antibodies and a double dystrophin band of normal and lower molecular weight on immunoblot analysis. A molecular genetic study demonstrated a deletion spanning over exons 45-47 at Xp21 locus. Routine neurological evaluation and currently available laboratory investigation may lead to early diagnosis of otherwise unrecognized Xp21 BMD among patients presenting with dilated cardiomyopathy alone, thus avoiding subsequent diagnostic difficulties.

Levodropropizine (LD) activity in allergic asthmatic patients, challenged with ultrasonically nebulized distilled water, metacholine and allergen-induced bronchospasm.

The antitussive compound Levodropropizine (LD) is active in animal bronchoconstriction induced by histamine and capsaicin and in man protects from bronchoconstriction induced by capsaicin. The primary objective of this study was to evaluate the mechanism of action of LD given at 60 mg t.i.d. as oral drops, for 8 days by means of specific bronchial challenges (allergens) and of aspecific challenges acting via different receptors and fibers (i.e. metacholine via cholinergic receptors and ultrasonically nebulized distilled water (UNDW) via histamine and neuropeptide release). The study design is randomized, double-blind, cross-over versus placebo in 30 allergic asthmatic patients. Baseline bronchial tone and bronchoconstrictor response to metacholine (MCh) were not modified by active treatment nor by placebo. On the contrary, in airway responsiveness to UNDW, the active treatment showed an antagonist effect against induced bronchoconstriction of 59% [activity ratio (AR) as antilog = 0.41; 95% confidence interval 0.35-0.54; p < or = 0.05] in comparison to no effect for placebo. Similarly, in airway responsiveness to specific allergen, active treatment antagonized the bronchoconstrictor effect of grass pollen by 83% and of various allergens (dermatophagoides and grass pollen) by 72%, i.e. AR of 0.17 (95% confidence interval 0.045-0.65; p < 0.01) and of 0.28 (95% confidence interval 0.07-1.04; p < 0.05), respectively. No antagonist effect was evident with placebo at all times. Besides inhibiting cough, LD is also partially effective in inhibiting bronchial hyperreactive response against specific allergen and UNDW bronchoconstriction. Hence, LD might act by partly inhibiting histamine and neuropeptide release.