Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study.

BACKGROUND: In both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0-∞, AUC0-t, and Cmax. METHODS: In this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child-Pugh A) and eight with moderate liver impairment (Child-Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography-mass spectrometry method was used to determine PFD plasma concentrations. RESULTS: The exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child-Pugh A and Child-Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child-Pugh B and Child-Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. CONCLUSION: The pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.

Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C.

BACKGROUND & AIMS: Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program. METHODS: Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 µg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. RESULTS: There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations. CONCLUSIONS: Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

[Epidemiology, physiopathology and diagnosis of pulmonary hypertension in hepatic (PH) cirrhosis]. / Epidemiología, fisiopatología y diagnóstico de la hipertensión arterial pulmonar (HAP) en el cirrótico.

Liver cirrhosis is a complex and progressive disease associated with high mortality. In developing countries, alcoholic liver disease is the most common form of liver cirrhosis, followed by chronic viral disease, especially hepatitis C virus infection. Cirrhosis is associated with systemic and splanchnic hemodynamic abnormalities, including increased vascular volume, decreased systemic vascular resistance, and increased cardiac output. At the splanchnic vascular bed, increases in portal flow and intrahepatic resistance have been described, inducing portal hypertension. Pulmonary arterial hypertension is a progressive disease of pulmonary circulation, without left ventricle and valvular heart disease; it is closely related with structural changes in pulmonary arteries. Idiopathic pulmonary arterial hypertension is related to abnormalities in cellular signals, inducing arterial hypertrophy and increased vascular tone. Porto-pulmonary hypertension includes simultaneous portal and pulmonary arterial hypertension. To confirm disease, it is important to exclude concomitant heart disease. Porto-pulmonary hypertension requires important components: portal hypertension, shear vascular stress, and cellular activation with pulmonary arterial hypertrophy. In this short manuscript, the epidemiology, patho-physiology, and diagnostic criteria of the disease are reviewed to optimize early diagnosis and treatment.

Effect of Prolonged-Release Pirfenidone on Renal Function in Septic Acute Kidney Injury Patients: A Double-Blind Placebo-Controlled Clinical Trial.

BACKGROUND: There is no treatment for septic acute kidney injury (sAKI). The anti-inflammatory activity of prolonged-release pirfenidone (PR-PFD) could be beneficial in this clinical setting. METHODS: This study was a double-blind randomized clinical trial in sAKI patients with nephrology consultation at the Civil Hospital of Guadalajara, in addition to the usual treatment of AKI associated with sepsis; patients were randomized to receive either PR-PFD at 1,200 mg/day (group A) or 600 mg/day (group B) or a matched placebo for 7 consecutive days. The primary objective was the decrease in serum creatinine (sCr) and increase in urinary volume (UV); the secondary objectives were changes in serum electrolytes, acid-base status, and mortality. RESULTS: Between August 2016 and August 2017, 88 patients were randomized. The mean age was 54 (17 ± SD) years, and 47% were male. The main site of infection was the lung (39.8%), septic shock was present in 39.1% of the cases, and the mean SOFA score was 8.8 points. 28 patients received PFD 1,200 mg, 30 patients received PFD 600 mg, and 30 patients received placebo. During the study, sCr did not differ among the groups. The reversion rate of sCr, UV, and mortality was not different among the groups (p=0.70, p=0.47, and p=0.38, respectively). Mild adverse events were not different among the groups. CONCLUSION: PR-PFD did not improve the clinical course of sAKI and seemed to be safe in terms of adverse events. This trial is registered with NCT02530359.

Benefits of prolonged-release pirfenidone plus standard of care treatment in patients with advanced liver fibrosis: PROMETEO study.

BACKGROUND AND AIMS: Pirfenidone (PFD), an oral antifibrotic drug, has been authorized by the EMA and FDA for treatment of idiopathic pulmonary fibrosis. Few studies have addressed its use in advanced liver fibrosis (ALF). We evaluated a prolonged-release formulation (PR-PFD) plus standard of care on disease progression in ALF. METHODS: 281 ALF patients from 12 centers receiving PR-PFD (600 mg bid) were screened; 122 completed 1 year of treatment. Additionally, 74 patients received only standard of care regimen. Average age was 64 ± 12 years, 58% female. 43.5% had fatty liver disease (NAFLD), 22.5% viral hepatitis C (VHC), 17% autoimmune hepatitis (AIH), and 17% alcoholic liver disease (ALD). Baseline fibrosis was F4 in 74% and F3 in 26%. Antifibrotic effects were assessed by transient elastography (Fibroscan®) and Fibro Test® (FT); Cytokines and PFD plasma levels were tracked and quality of life evaluated. RESULTS: We found a significant reduction in fibrosis in 35% of PR-PFD patients and only in 4.1% in non PR-PFD patients. Child-Pugh score improved in 29.7%. Biochemical values remained stable; 40.6% and 43.3% decreased ALT or AST, respectively. TGFß1 (pg/mL) levels were lower in PFD-treated patients. PFD serum concentration (µg/mL) was higher (8.2 ± 1.7) in fibrosis regression profile (FRP) patients compared to fibrosis progression profile (FPP) patients (4.7 ± 0.3 µg/mL, p < 0.01). 12% reported transient burning or nausea and 7% photosensitivity. Quality of life (Euro-Qol scale) improved from 62 ± 5 to 84 ± 3 (p < 0.001) and from 32 ± 3 to 42 ± 2 (p < 0.008) (FACIT scale). CONCLUSIONS: PR-PFD is efficacious and safe in ALF and associated with promising antifibrotic effects. TRIAL REGISTRATION: Clinical trial number: NCT04099407.

Bioavailability of two single-dose oral formulations of omeprazole 20 mg: an open-label, randomized sequence, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Omeprazole is a proton-pump inhibitor that acts to reduce acid secretion in the stomach and is used for treating various acid-related gastrointestinal disorders. There are several generic formulations of omeprazole available in Mexico; however, a literature search failed to identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of this study was to compare the bioavailability of 2 oral formulations of omeprazole 20-mg capsules, marketed for use in Mexico, in healthy volunteers: Inhibitron (test formulation) and LosecA 20 mg (reference formulation). METHODS: This study used a single-dose, open-label, randomized sequence, 2 x 2 crossover (2 administration periods x 2 treatments) design to compare the 2 formulations. Eligible subjects were healthy adult Mexican volunteers of both sexes. Subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test formulation followed by the reference formulation, or vice versa, with a 7-day washout period between administration periods. After a 12-hour (overnight) fast, subjects received a single, 20-mg dose of the corresponding formulation. Plasma samples were obtained over a 12-hour period after administration. Plasma omeprazole concentrations were analyzed by a nonstereospecific high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to time t (AUC(0-t)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and 0.17, 0.33, 0.50, 0.75, 1, 1.25, 1.50, 1.75, 2, 2.50, 3, 4, 6, 8, and 12 hours after administration. The formulations were considered bioequivalent if the natural log (ln)-transformed ratios of C(max) and AUC were within the predetermined equivalence range of 80% to 125%, and if P

Bioavailability of two sublingual formulations of ketorolac tromethamine 30 mg: a randomized, open-label, single-dose, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Ketorolac tromethamine (ie, ketorolac) is an NSAID that appears to have several mechanisms of action, including inhibition of prostaglandin synthesis, modulatory effect on opioid receptors, and nitric oxide synthesis. Ketorolac is used in the treatment of pain. There are various generic formulations of sublingual ketorolac available in Mexico. However, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of this study was to compare the bioavailability of 2 sublingual formulations of ketorolac 30-mg tablets in healthy Mexican adult volunteers. METHODS: This was a randomized-sequence, open-label, single-dose, 2-period crossover (2 dosing periods x 2 treatments) study comparing the bioavailability of two 30-mg sublingual tablet formulations of ketorolac. Healthy Mexican adult (aged, 18-55 years) men and women were eligible for inclusion. Subjects were randomly assigned in a 1:1 ratio to receive a single dose of the test formulation or the reference formulation. After a 12-hour overnight fast, subjects received a single dose of the corresponding formulation. There was a 7-day washout period between administration periods. Plasma samples were obtained over a 24-hour period after administration. Plasma ketorolac concentrations were analyzed by high-performance liquid chromatography for analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity. Blood samples were drawn immediately after sublingual placement of the drug and at 10, 20, 30, 40, 50, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of Cmax and AUC were within the predetermined range of 80% to 125% and if P for the 90% CIs was <0.05. Tolerability was assessed by vital sign monitoring, laboratory analysis results, and subject interviews. RESULTS: A total of 27 subjects (18 women, 9 men; mean [SD] age, 27 [9] years [range, 18-47 years]; weight, 61 [8] kg [48-79 kg]; height, 163 [8] cm [150-180 cm]) were enrolled and completed the study. Fourteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding differences in natural log Cmax, AUC0-24, and AUC0-infinity were 95.94% to 114.66%, 98.34% to 105.90%, and 99.25% to 108.36%, respectively (all, (P) < 0.05), meeting the predetermined criteria for bioequivalence. Sixteen subjects experienced a total of 20 adverse events (AEs) during the study. None of the AEs were considered serious. One AE (nausea) appeared to be related to use of the reference formulation. CONCLUSIONS: In this small study in 27 healthy Mexican adult volunteers, the test formulation of a single, 30-mg sublingual tablet of ketorolac appeared to be bioequivalent to the reference formulation based on the rate and extent of absorption. Both formulations were well tolerated.

Efficacy of triple therapy with thymalfasin, peginterferon alpha-2a, and ribavirin for the treatment of hispanic chronic HCV nonresponders.

BACKGROUND/AIMS: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon alpha-2a (PEG-IFN alpha-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-alpha)/ribavirin. METHODS: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN alpha-2a (180 microg once a week), and ribavirin (800-1,000 mg/day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. RESULTS: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN alpha-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. CONCLUSION: Triple therapy with thymalfasin, PEG IFN alpha-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.

Hepatic hematoma and hepatic rupture in pregnancy.

Hepatic perforation is an unusual complication of woman pregnancy associated with a poor outcome. A comprehensive review of epidemiology, clinical spectrum, diagnostic methods and therapeutic options is presented in this short paper.

Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study.

Despite steady progress in therapeutics of liver disease, portal systemic encephalopathy remains to be a great challenge for clinicians because of the heterogeneity of neuropsychiatric symptoms, multiple risk factors and complexity on achieving a sustained response. We aimed to evaluate the efficacy of L-Ornithin, L-Aspartate versus lactulose in Mexican patients with hyperammonemic hepatic encephalopathy. A total of 20 patients were randomly allocated to receive either lactulose(n = 10) or L-ornithine - L-aspartate (n = 10) for 2 weeks. At baseline, patients of both groups were comparable in age (64 +/- 7 versus 60 +/- 6) and degree of hepatic failure according to the Child-Pugh scale (9.2 +/- 1.3 versus 9.2 +/- 1.1). A significant decrease in ammonia levels was observed both in the lactulose group (120.4 +/- 8.1 versus 91.4 +/- 10, p < 0.05) and in the LOLA group (141.6 +/- 9.1 versus 96.9 +/- 9.3, p < 0.05). Moreover, in patients who received LOLA a significant improvement was observed in mental status (1.0 +/- 0.14 versus 0.4 +/- 0.16, p < 0.05), Number Connection Test (184 +/- 43 versus 88 +/- 7, p < 0.05), asterixis (14.6 +/- 2.8 versus 6.7 +/- 1.5, p < 0.05), as well as EEG findings (6.8 +/- 0.6 versus 8.1 +/- 0.2 cycles per second, p < 0.05). Compliance with study medications was similar between the lactulose group (94%) and the LOLA group (100%). No serious adverse events were reported in the two groups; however, in the lactulose group an increase in the number of weekly defecations was reported, as well as a higher incidence of abdominal pain or flatulence. Finally, both patient groups reported an improvement in the Visual Analogue Scale for EuroQol index (51.1 +/- 24.1 versus 61.5 +/- 15.8, p < 0.05, in the lactulose group; 56.5 +/- 24.5 versus 70 +/- 19.4, p < 0.05, in the LOLA group). In conclusion, oral administration of lactulose or L-ornithine - L-aspartate to Mexican patients with cirrhosis and hyperammonemic encephalopathy significantly reduced serum ammonia levels in study groups and additionally improved mental status parameters, number connection test, asterixis scores, and EEG activity in the group receiving L-ornithine-L-aspartate.

Hepatitis C virus infection and non-Hodgkin's lymphoma: a review and case report of nine patient.

The role of hepatitis C virus (HCV) is well established in the development of chronic hepatitis, cirrhosis and hepatic carcinoma, as well as in mixed type II cryoglobulinemia, membranoproliferative glomerulonephritis(MPGN) and porphyria cutanea tarda (PCT). Increasing evidence has been reported of a close association of HCV infection with autoimmune and hematological processes, mainly cytopenias and lymphoproliferative disorders such as B cell non-Hodgkin's lymphoma. We describe the demographic, clinical and histopathological findings of nine patients from the Mexican population with non-Hodgkin's lymphoma and HCV infection.

Hepatobiliary diseases in patients with human immunodeficiency virus (HIV) treated with non highly active anti-retroviral therapy: frequency and clinical manifestations.

OBJECTIVE: To evaluate the frequency of hepatobiliary diseases and the clinical manifestations in patients with HIV treated with non highly active anti-retroviral therapy. METHODS: Seven hundred clinical records of patients with HIV infection who entered the Instituto Nacional de Ciencias Médicas y de la Nutrición Salvador Zubirán from January 1987 to December 1996 were reviewed. All patients with alterations associated to hepatobiliary disease and/or liver function tests derangement throughout the clinical development of their disease were included. Demographic variables, date of diagnosis and clinical stage of the disease, as well as the presentation forms, diagnostic approach and image studies were analyzed. RESULTS: One hundred and sixty-one patients (22.8%) with hepatobiliary manifestations were found. The average time between the HIV diagnosis and the presentation of hepatic manifestations was 2-12 years. The majority of patients 124/161 (77%) did not show clinical signs of liver damage. The diagnostic suspicion was established by the presence of alkaline phosphatase above normal in 29% and alkaline phosphatase plus aminotransferases above normal in 45%. Hepatomegaly and jaundice were present in 18% and 4% of the patients, respectively. The most frequent ultrasonographic diagnosis were hepatomegaly (40%) and steatosis (30%). Liver biopsies were performed in 85 (51%) of the patients. The main histologic diagnoses were granulomatous hepatitis (29%), steatosis plus granulomatous hepatitis (19.5%), and steatosis alone (14.6%). Microorganisms were isolated in 27.9% being the most frequent Mycobacterium tuberculosis (26.6%), Histoplasma capsulatum (20%), Cytomegalovirus (13.3%), and Mycobacterium avium intracellulare (11%). The HBsAg was positive in 21 of the 69 patients (30.4%). CONCLUSIONS: The clinical presentation was asymptomatic in most of cases and the main etiology could be explained by the presence of associated infections, granulomatoses and liver steatosis.

Diagnostic value of the copper/zinc ratio in hepatocellular carcinoma: a case control study.

BACKGROUND: The aim of this study was to assess the accuracy of the copper/zinc ratio in the evaluation of a group of patients with hepatocellular carcinoma (HCC). METHODS: A total of 105 patients were studied and separated into three groups: group I ( n = 40), patients with HCC, group II ( n = 25), patients with liver cirrhosis, and group III ( n = 40), patients with benign digestive disease. Serum levels of copper and zinc were measured by atomic absorption spectrophotometry. RESULTS: The serum levels of copper microg/dl) in patients with HCC (97.4 +/- 27.2; P < 0.05) were significantly higher than those in patients with liver cirrhosis (73.7 +/- 17.5) or benign digestive disease (77.1 +/- 20.8), and the serum levels of zinc microg/dl) were significantly lower (71.6 +/- 30.5; P < 0.05) than those in patients with benign digestive disease (81.7 +/- 17.7 microg/dl) and were similar to those in cirrhotic patients (68.5 +/- 17.1). The Cu/Zn ratio was also significantly higher in patients with HCC (1.52 +/- 0.64; P < 0.05) than in patients with liver cirrhosis (1.06 +/- 0.2) or patients with benign digestive disease (0.95 +/- 0.39). Considering a cutoff value of 1.15, the sensitivity of the Cu/Zn ratio was 87.5%, with a specificity of 86.1%, a positive predictive value of 79.5%, and a negative predictive value of 91.8%. CONCLUSIONS: The Cu/Zn ratio was found to be significantly higher in patients with HCC compared with that in age and sex-matched controls, with a sensitivity of 87.5%; this ratio might be useful in the evaluation of suspected hepatocellular malignancy.

Triple combination of thymalfasin, peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior interferon and ribavirin treatment: 24-week interim results of a pilot study.

Despite steady progress in antiviral treatment for patients with chronic hepatitis C virus (HCV), many patients still have detectable serum HCV RNA levels by the end of interferon-based treatment and are known as virological non-responders. Re-treatment of these patients not responding to previous therapy remains challenging. Studies of the dynamics of the HCV population show a marked decline in new cases since 1996; however, the relative proportion of non-responders is expected to increase over time and, similarly, the number of patients eligible for first-line treatment is expected to decrease. The current standard of care for treatment involves the use of pegylated interferons in combination with ribavirin. However, many difficult-to-treat groups still have low response rates. Newer combinations are being investigated to optimize chances of attaining a sustained response in these groups: one such triple therapy regimen is peginterferon alfa-2a, ribavirin and thymalfasin, which was given to 23 previously non-responder patients. Viral response was 60.8% at week 12 and 47.8% at week 24. These preliminary results encourage further evaluation of this promising combination.

Etiology of liver cirrhosis in Mexico.

BACKGROUND: In the last decades it has been suggested that the main cause of liver cirrhosis in Mexico is alcohol. Currently in Western countries hepatitis C virus stage liver disease and liver transplantation. In Mexico, we have no data relative to the etiology of liver cirrhosis. The aim of this study was to investigate the main causes of liver cirrhosis in Mexico. METHODS: Eight hospitals located in different areas of the country were invited to participate in this study. Those hospitals provide health care to different social classes of the country. The inclusion criteria were the presence of either an histological or a clinical and biochemical diagnosis of liver cirrhosis. RESULTS: A total 1,486 cases were included in this study. The etiology of liver cirrhosis was alcohol in 587 (39.5%), HCV 544 (36.6%), cryptogenic 154 (10.4%), PBC 84 (5.7%), HBV 75 (5.0%) and other 42 (2.8%). There was no statistical difference between alcohol and HCV. CONCLUSIONS: We conclude that the main causes of liver cirrhosis in Mexico are alcohol and HCV.

[Treatment of patients with recurrence or who do not respond to the first treatment against hepatitis C]. / Tratamiento de los pacientes con recaída o que no responden al primer tratamiento contra el virus de la hepatitis C.

The current criteria to confirm the absence of therapeutic response to HCV is based on the viral findings. Lack of response is defined as the failure to achieve a negative serological response to the virus in peripheral blood (serum or plasma) after 12 weeks of treatment with interferon alpha (2a or 2b), or 24 weeks of treatment with IFN and ribavirin. Up to 60% of patients treated with standard IFN alpha and ribavirin are considered non-responders. According to viral genotype, figures are still worse in the group with genotype 1. Recently, the use of pegylated interferon allowed the reduction of the number of non-responding patients. The investigators propose different approaches in the search for better therapeutic strategies. The most effective of them all are the addition of ribavirin to the therapeutic scheme and the use of pegylated interferon which greatly increased the number of responders. Nevertheless, there are still many patients who are resistant to therapy. These are the proposed therapeutic alternatives for non-respondent patients: 1. Another tretment cycle with standard IFN and ribavirin (low probability) 2. Another treatment cycle with pegylated IFN and ribavirin. 3. Another treatment cycle with IFN, ribavirin and amantadine. 4. Another treatment cycle with IFN, ribavirin and timosine. 5. Other antiviral agents. It's important to clarify that "real non-responders" are those patients who remain positive in the viral load tests after 12-24 months of treatment. On the other hand, patients who "escape from treatment" or those with "recurrence" are not real non-responders, compared to those who are negative after 12-24 weeks of treatment.

Live-attenuated Tetravalent Dengue Vaccine in Dengue-naïve Children, Adolescents, and Adults in Mexico City: Randomized Controlled Phase 1 Trial of Safety and Immunogenicity.

BACKGROUND: Preliminary results in healthy, young US adults showed that a tetravalent, live-attenuated dengue vaccine (TDV) was safe and immunogenic, but no data are available in children. METHODS: In a multicenter, randomized, controlled, observer-blinded study in the city of Mexico, children aged 2 to 5, 6 to 11, and 12 to 17 years (36 children per age group), and adults (n = 18) aged <45 years received the following: 3 injections of TDV at months 0, 3.5, and 12 (TDV-TDV-TDV), or 1 injection of yellow fever vaccine (YF) at month 0, and 2 injections of TDV at months 3.5 and 12 (YF-TDV-TDV). Adverse events and biologic safety (biochemistry and hematology) were documented. Plaque reduction neutralization test (PRNT50) antibody titers against the TDV parental viruses were measured 28 days after vaccination. Seropositivity was defined as antibody titers ≥10 1/dil. RESULTS: No vaccine-related serious adverse events, other significant clinical adverse events, or clinically significant trends in biologic safety were observed. Reactogenicity did not increase with successive TDV injections, and mild-to-moderate injection site pain, headache, myalgia, and malaise were most commonly reported (14%-40% after each vaccination). After 3 TDV vaccinations, the seropositivity rate against each dengue serotype was in the range 77% to 92%, compared with 85% to 94% after completion of the YF-TDV-TDV regimen. Of the 2- to 11-year-old participants, 95% were seropositive against ≥3 serotypes after 3 vaccinations. CONCLUSIONS: A 3-dose TDV regimen had a favorable safety profile in children and adults and elicited neutralizing antibody responses against all 4 serotypes. These findings support the continued development of this vaccine.

Bioavailability of two oral formulations of a single dose of levofloxacin 500 mg: an open-label, randomized, two-period crossover comparison in healthy Mexican volunteers.

BACKGROUND: Levofloxacin is a synthetic fluoroquinolone with a broad spectrum of antibacterial activity. It is indicated for the treatment of respiratory, sinus, skin, and urinary tract infections. Although generic formulations of oral levofloxacin are marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations; these data would be relevant to secure marketing of a test formulation in Mexico. OBJECTIVE: The aim of this study was to compare the bioavailability and determine the bioequivalence of a test formulation (an oral tablet containing levofloxacin 500 mg) with its corresponding listed reference-drug formulation in Mexico (a list issued by Mexican Health Authorities). METHODS: A single-dose, open-label, randomized-sequence, 2-period crossover design was used in this study. Eligible participants were healthy Mexican adults of either sex, randomly assigned to receive the test formulation followed by the corresponding reference formulation, or vice versa, with a 1-week washout period between doses. After a 10-hour overnight fast, the participants received the assigned formulation. Plasma concentrations of levofloxacin were determined using high-performance thin-layer chromatography, and densitometric analysis was performed at 300 nm. For the analysis of pharmacokinetic parameters, including C(max), AUC0(-24), and AUC(0-infinity)), blood samples were drawn at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. The test formulation was considered to meet the criteria for bioequivalence if the geometric mean ratios (test/reference) were with- in the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, vital signs, laboratory analysis, and interviews with participants about adverse events. RESULTS: A total of 26 participants were enrolled, including 14 men and 12 women with a mean (SD) age of 24 (4) years (range, 18-34 years), weight of 62.2 (10.0) kg (range, 45.5-80.0 kg), height of 163 (9) cm (range, 148-176 cm), and body mass index of 23.3 (2.4) kg/m(2) (range, 19.2-27.1 kg/m(2)). The 90% CIs for log-transformed C(max), AUC(0-24), and AUC(0-infinity) were 94.48% to 106.22%, 90.01% to 116.44%, and 85.11% to 114.00%, respectively. Eleven participants reported a total of 20 adverse events during the study. None of the adverse events were considered serious. CONCLUSIONS: In this small study in healthy, fasting Mexican adults, a single 500-mg dose of the test formulation of orally administered levofloxacin met the regulatory requirements to assume bioequivalence based on the rate and extent of absorption. Both formulations were well tolerated.

A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE).

BACKGROUND/AIMS: To compare the pharmacokinetics, pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1. METHODS: Thirty-six patients were randomised to peginterferon alfa-2b (1.5 microg/kg/week) or peginterferon alfa-2a (180 microg/week) for 4 weeks, then in combination with ribavirin (13 mg/kg/day) for a further 4 weeks. The pharmacokinetic profile of both peginterferons, mRNA expression of a selected group of interferon-induced gene transcripts, and serum HCV-RNA levels were assessed. RESULTS: Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a. Correspondingly, patients treated with peginterferon alfa-2b also had a significantly greater log10 maximum and log10 time-weighted average decrease in serum HCV-RNA. A greater proportion of peginterferon alfa-2b patients achieved a > or = 2.0 log10 reduction in serum HCV-RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a patients, P = 0.09). There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a. CONCLUSIONS: These findings suggest that the biological activity, measured by early interferon-induced gene transcripts and early antiviral responsiveness, may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a.