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Neuroinflammation in Alzheimer's disease (AD) revamped the role of a preventive therapeutic action of non steroidal anti-inflammatory drugs; flurbiprofen could delay AD onset, provided its access to brain is enhanced and systemic exposure limited. Nasal administration could enable direct drug access to central nervous system (CNS) via nose-to-brain transport. Here, we investigated the insufflation, deposition, dissolution, transmucosal permeation, and in vivo transport to rat brain of flurbiprofen from nasal powders combined in an active device. Flurbiprofen sodium spray-dried microparticles as such, or soft pellets obtained by agglomeration of drug microparticles with excipients, were intranasally administered to rats by the pre-metered insufflator device. Blood and brain were collected to measure flurbiprofen levels. Excipient presence in soft pellets lowered the metered drug dose to insufflate. Nevertheless, efficiency of powder delivery by the device, measured as emitted fraction, was superior with soft pellets than microparticles, due to their coarse size. Both nasal powders resulted into rapid flurbiprofen absorption. Absolute bioavailability was 33% and 58% for microparticles and pellets, respectively. Compared to intravenous flurbiprofen, the microparticles were more efficient than soft pellets at enhancing direct drug transport to CNS. Direct Transport Percentage index evidenced that more than 60% of the intranasal dose reached the brain via direct nose-to-brain transport for both powders. Moreover, remarkable drug concentrations were measured in the olfactory bulb after microparticle delivery. Bulb connection with the entorhinal cortex, from where AD initiates, makes flurbiprofen sodium administration as nasal powder worth of further investigation in an animal model of neuroinflammation. © 2021 Elsevier B.V.

Neuroinflammation occurs in the early stages of Alzheimer's disease (AD). Thus, anti-inflammatory drugs in this asymptomatic initial phase could slow down AD progression, provided they enter the brain. Direct nose-to-brain drug transport occurs along olfactory or trigeminal nerves, bypassing the blood-brain barrier. Nasal administration may enable the drug to access the brain. Here, flurbiprofen powders for nose-to-brain drug transport in early AD-related neuroinflammation were studied. Their target product profile contemplates drug powder deposition in the nasal cavity, prompt dissolution in the mucosal fluid and attainment of saturation concentration to maximise diffusion in the tissue. Aiming to increase drug disposition into brain, poorly soluble flurbiprofen requires the construction of nasal powder microparticles actively deposited in nose for prompt drug release. Two groups of powders were formulated, composed of flurbiprofen acid or flurbiprofen sodium salt. Two spray dryer apparatuses, differing for spray and drying mechanisms, and particle collection, were applied to impact on the characteristics of the microparticulate powders. Flurbiprofen sodium nasal powders disclosed prompt dissolution and fast ex vivo transport across rabbit nasal mucosa, superior to the acid form, in particular when the powder was prepared using the Nano B-90 spray dryer at the lowest drying air temperature. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Background & Aims: The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. Methods: From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. Results: Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon α. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7–15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. Conclusions: Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

BACKGROUND & AIMS: The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS: From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS: Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS: Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

BACKGROUND AND AIMS: Aging implies a physiological decline in skeletal muscle mass and strength, pain perception, transmission and processing, causing pain thresholds to increase (presbyalgesia). This study compares the pressure pain thresholds (PPTs) of 18 head and neck muscles in groups of young and elderly subjects. METHODS: A cross-sectional study was conducted on 40 subjects, selected from a group of 97, referred for dental consultation. The inclusion criterion was subjects' age (from 20 to 30, and over 65 years). Exclusion criteria were all conditions which may alter PPTs. In two groups, A (young subjects; 10 men, 10 women) and B (elderly subjects; 11 men, 9 women) PPTs were evaluated by one calibrated examiner with a Fischer algometer. Data are described with mean values ± standard error and the 95% confidence interval. The Mann-Whitney test was used to compare PPT values between the two groups (α=0.05). RESULTS: There was a significant difference between the PPTs of group A and B, which were higher in the elderly group in all muscles except five. CONCLUSIONS: These preliminary data demonstrate that PPTs increase with aging in the muscles examined. Other confirmatory studies with a larger sample size are necessary.

Objective The aim of this longitudinal prospective study is to evaluate the efficacy of reversible therapies in pediatric patients with temporomandibular disorders (TMD). Methods 37 TMD patients and 37 healthy controls (12 children and 25 adolescents in both groups) were recruited and the first group received reversible therapy. Diagnosis were made using MRDC/TMD for children and RDC/TMD for adolescents. Results have been evaluated with a 12 years follow up. Results Comparisons between case and control groups during the study were made using Fisher exact test and chi-square test on the basis of the cells counts; α-level was set at 0.05. A significant decrease in the number of patients with maximum unassisted opening ≤ 35 mm was observed (from 11 to 0; χ2=12.92, p=0.003). Similarly, a significant decrease in the number of patients with controlateral excursion ≤ 7 mm was observed (from 9 to 1; χ2=7.40, p=0.007). Concerning passive stretch opening increase < 2 mm, a significant gain was observed (from 8 to 37 patients; χ2=13.22, p=0.0003); a significant decrease in opening click was observed (from 23 to 5 patients, p=0.01); also for clicking during lateral excursion or protrusion a significant decrease was observed (from 10 to 1 patients, p=0.01). Bruxists decrease in both groups, but no significant difference was observed between patients and controls. Conclusions The data confirm the long term effectiveness of reversible therapy in the treatment of TMD in pediatric patients. The patients vs control group did not differ significantly in signs and symptoms of TMD after treatment.

BACKGROUND AND AIMS: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. METHODS: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. RESULTS: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p

Introduction: Little is known on the clinical relevance of HCV genotypes in children with chronic hepatitis C, therefore we investigated epidemiological and clinical features in a large series of Italian children with different genotypes. Methods: The retrospective study was conducted as part of the Italian Observatory for pediatric HCV infection of the SIGEP hepatologic group and included 373 consecutive HCV RNA+, otherwise healthy children recruited in the outpatient clinic in 15 centers, since 1990. Genotypes were investigated by a commercial serologic assay (InnoLipa, Innogenetics). Results: The table synthesizes the features associated with the principal genotypes (10 cases had mixed or rare types). Genotypes 3 and 4 were largely associated with maternal transmission and thus infection with these types was usually recognized earlier in life. Ninety-six children were treated with IFN (sustained response = no viremia 6 months after stopping IFN). A statistically significant (p

Hepatitis C virus infection in infancy largely depends on vertical transmission. The transfer of hepatitis C virus from mother to child is almost invariably restricted to children whose mother is viremic, and the rate of transmission seems to be influenced by maternal virus load, although, in the single patient, the levels of viremia cannot be used as predictors of pediatric infection. In fact, the flow-chart for screening children at risk for vertically transmitted hepatitis C virus infection takes into account maternal viremia. In children born to anti-hepatitis C virus antibody positive, hepatitis C virus-RNA negative mothers, alanine aminotransferase and anti-hepatitis C virus should be investigated at 18-24 months of life. If alanine aminotransferase values are normal and anti-hepatitis C virus is undetectable, follow-up should be interrupted. In children born to hepatitis C virus-RNA positive mothers, alanine aminotransferase and hepatitis C virus RNA should be investigated at 3 months of age: (1) hepatitis C virus-RNA positive children should be considered infected if viremia is confirmed by a second assay performed within the 12th month; (2) hepatitis C virus-RNA negative children with abnormal alanine aminotransferase should be tested again for viremia at 6-12 months, and for anti-hepatitis C virus at 18 months; (3) hepatitis C virus-RNA negative children with normal alanine aminotransferase should be tested for anti-hepatitis C virus and alanine aminotransferase at 18-24 months, and should be considered non-infected if alanine aminotransferase is normal and anti-hepatitis C virus undetectable; (4) anti-hepatitis C virus seropositivity beyond the 18th month in a never-viremic child with normal alanine aminotransferase is likely consistent with past hepatitis C virus infection.

Background: A retrospective-prospective survey of Italian children with hepatitis C virus (HCV) infection was planned in 1998 to explore the epidemiologic features of infection during the past decade. Methods: Anti-HCV-positive patients (or HCV RNA-positive infants) aged I month to 16 years, consecutively observed in 20 pediatric Institutions, were considered. An anonymous epidemiologic questionnaire based on clinical records was used. Results: From 1990 through March 1999, 606 patients were observed (296 boys, average age 5.8 years). Maternal infection (46% of cases) and blood transfusions (34%) were the most frequent risk factors. Of 279 infected mothers, 61% did not recall a putative source of infection (by history, many could possibly have had exposure through routes such as therapeutic injections with nondisposable material), whereas 94 (34%) admitted drug abuse, including 49 (17%) coinfected with human immunodeficiency virus (HIV). Only 157 (26%) children were born after 1991: 90% of their mothers were infected (11% were HIV coinfected vs. 25% mothers of older children, P < 0.01). Conclusions: Maternal infection is a prominent source of pediatric HCV infection in Italy. The fact that most mothers had a history of covert exposure to HCV, probably through percutaneous routes that are no longer operating, and that the number of those with HIV coinfection has decreased suggests that the frequency of pediatric infection could decrease in the future.

Aims: To carry out a randomized clinical trial to compare the effect of palmitoylethanolamide (PEA) versus ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), for pain relief in temporomandibular joint (TMJ) osteoarthritis or arthralgia. PEA acts as an endogenous agent with an autacoid local inflammation antagonism and modulates mast cell behavior controlling both acute and chronic inflammation. Methods: A triple-blind randomized clinical trial was conducted on 24 patients (16 women and 8 men) aged 24 to 54 years and suffering from TMJ osteoarthritis or arthralgia. The patients were enrolled from a group of 120 consecutive patients referred to the University of Bologna's Department of Orthodontics. Patients were randomly divided into two groups: group A (12 subjects) received PEA 300 mg in the morning and 600 mg in the evening for 7 days and then 300 mg twice a day for 7 more days. Group B (12 subjects) received ibuprofen 600 mg three times a day for 2 weeks. Every patient recorded the intensity of spontaneous pain on a visual analog scale twice a day. Maximum mouth opening was recorded by a blind operator during the first visit and again after the 14th day of drug treatment. A t test was used for data comparisons. Results: Pain decrease after 2 weeks of treatment was significantly higher in group A than in group B (P = .0001); maximum mouth opening improved more in group A than in group B (P = .022). Conclusion: These data suggest that PEA is effective in treating TMJ inflammatory pain.