Harmonization of individual case safety reports transmission requirements among PAHO reference authorities: a review of their current regulation.

To perform optimal monitoring of the safety profile in the postmarketing phase, Marketing Authorization Holders and National Regulatory Authorities (NRAs) must evaluate the adverse drug reactions (ADRs) that occurred and characterize their nature, frequency, and severity. Management is possible through Individual Case Safety Reports (ICSRs), which are the reports of organized and processed data. Globally, the International Council for Harmonisation (ICH) E2B guideline suggests harmonized activities for the ICSR electronic content and transmission. In America, the Pan American Health Organization (PAHO) is the agency responsible to implement cooperation among its members, which are recognized as National Regulatory Authorities of Reference (NRARs) such as Argentina, Brazil, Canada, Chile, Colombia, Cuba, Mexico, and the United States. PAHO published the 'Good Pharmacovigilance Practices for the Americas' suggesting improvement and harmonization in the region. After reviewing the regulatory framework, it is assumed that all NRARs have a regulated ICSR transmission system (i.e. a systematic vigilance system for collecting, analyzing, and disseminating information from ADRs). However, significant differences exist, such as the requirement for social media vigilance, expedited and non-expedited ICSRs, coding, severity, and transmission. The volume of ICSRs has significantly increased, due to using electronic standards managed by the NRAs, which facilitates early identification of new ADRs, allowing the implementation of novel minimization activities, contributing to the continuous assessment of the benefit-risk balance of medicines. Nevertheless, there is still area for improvement, especially in Latin America.

Transmission of spontaneous adverse drug reactions by industry in countries designated as a reference by the Pan American Health Organization (PAHO): comparison on regulatory requirements This review aims to describe regulatory criteria and compare harmonization across regions that marketing authorization holders must fulfill when transmitting spontaneous adverse drug reactions to the authorities for postmarketing surveillance. It centers on the regulatory requirements of authorities designated as a reference by the PAHO. Consequently, it is important to review the regulatory framework, to evaluate the requirements for transmission and have the context of the current harmonization among these agencies in America. This review contains the minimum criteria for transmission and harmonized guidelines according to the International Council for Harmonisation (ICH) and PAHO. However, identifying the differences is only the first step, future research in harmonization must continue to advance the understanding and establish guidelines that allow a better evaluation of the safety profile of medical products.

Ocular Cyclopentolate: A Mini Review Concerning Its Benefits and Risks.

Cycloplegic and mydriatic agents are essential in ophthalmological clinical practice since they provide the means for diagnosing and treating certain eye conditions. In addition, cyclopentolate has proven to possess certain benefits compared to other available cycloplegics and mydriatics. Still, the incidence of some adverse drug reactions related to this drug, especially in susceptible patients, has created interest in reviewing the literature about the benefits and risks of using cyclopentolate. A literature search was conducted in Medline/PubMed and Google Scholar, focusing on identifying cyclopentolate's benefits and risks; the most important benefit was its usefulness for evaluating refractive errors, especially for hyperopic children, pseudomyopia, anterior uveitis, treatment of childhood myopia, idiopathic vision loss, and during examinations before refractive surgery, with particular advantages compared to other cycloplegics. While the risks were divided into local adverse drug reactions such as burning sensation, photophobia, hyperemia, punctate keratitis, synechiae, and blurred vision, which are relatively frequent but mild and temporary; and systemic adverse drug reactions such as language problems, visual or tactile hallucinations and ataxia, but unlike ocular, systemic adverse drug reactions are rare and occur mainly in patients with risk factors. In addition, six cases of abuse were found. The treatment with cyclopentolate is effective and safe in most cases; nevertheless, special care must be taken due to the potential severe ADRs that may occur, especially in susceptible patients like children, geriatrics, patients with neurological disorders or Down's syndrome, patients with a low blood level of pseudocholinesterase, users of substances with CNS effects, and patients with a history of drug addiction. The recommendations are avoiding the use of 2% cyclopentolate and instead employing solutions with lower concentrations, preferably with another mydriatic such as phenylephrine. Likewise, the occlusion of the nasolacrimal duct after instillation limits the drug's absorption, reducing the risk of systemic adverse events.

Underreporting and Triggering Factors for Reporting ADRs of Two Ophthalmic Drugs: A Comparison between Spontaneous Reports and Active Pharmacovigilance Databases.

(1) Aims of the study: calculating the underreporting ratio for two different medications, a fixed combination of 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide (antiglaucoma) and a fixed combination of sodium hyaluronate 0.1% + chondroitin sulfate 0.18% (artificial tears) for characterizing the features influencing the reporting of adverse drug reactions (ADRs) in spontaneous reporting. (2) Methods: The underreporting ratio was calculated by comparing the adverse drug reactions reported in the spontaneous reporting database for every 10,000 defined daily doses marketed and the adverse drug reactions from an active surveillance study for every 10,000 defined daily doses used for different drugs (antiglaucoma and artificial tears). The factors related to the report in spontaneous reporting through statistical tests were also determined. (3) Results: The underreporting ratio of spontaneous reporting was 0.006029% for antiglaucoma and 0.003552% for artificial tears. Additionally, statistically significant differences were found for severity, unexpected adverse drug reactions, and incidence of adverse drug reactions in females when compared with spontaneous reporting and active surveillance. (4) Conclusions: The underreporting ratio of ADRs related to ophthalmic medications indicates worry since the cornerstone of pharmacovigilance focuses on spontaneous reporting. Additionally, since underreporting seems to b selective, the role of certain aspects, such as gender, seriousness, severity, and unexpected ADRs, must be considered in future research.

Real-Life Active Surveillance of a Naphazoline/ Hypromellose Fixed Combination's Safety Profile in Peruvian Population.

OBJECTIVE: Identifying the adverse reactions and the possible risks associated with the use of naphazoline 0.1% + hypromellose 0.5% (NAPH), thereby evaluating its tolerability and safety profile. METHODS: A total of 236 Peruvian patients were included in an active pharmacovigilance study drug event monitoring consisting in 2 phone calls conducted in order to register adverse drug reactions (ADRs), the product's tolerability and to assess the risk concerning specific clinical and demographic characteristics using a binary logistic regression model. RESULTS: A total of 54 ADRs (one per patient) were reported after the use of NAPH; classified (according to the Medical Dictionary for Regulatory Activities) into two groups of System Organ Class (SOC): eye disorders and nervous system disorders; and four groups of preferred term (PT): eye irritation, vision blurred, eye pruritus and headache. All ADRs were expected, mild and not serious. No risk factors related to the clinical and demographic characteristics of the patients were identified. CONCLUSION: The low incidence of ADRs, their short recovery time, and their categorization as "mild" and "not serious" demonstrates the high tolerability in the studied population; therefore, according to the study, the safety profile for NAPH seems to be adequate, with a suitable tolerability.

Ophthalmic Solution Safety Profile: Active Surveillance of a Sodium Hyaluronate/Chondroitin Sulfate Combination in Peruvian Population.

BACKGROUND: Sodium hyaluronate/chondroitin sulfate fixed combination plays an essential role in the treatment of keratoconjunctivitis sicca, a multifactorial disease accompanied by ocular symptoms like alteration of the tear film. Despite low or no absorption of such drugs, these can cause secondary effects. An essential tool in the study of medication behavior is active pharmacovigilance. Unlike spontaneous reporting pharmacovigilance, this tool allows an appraisal of adverse drug reactions (ADRs)' real incidence, a higher capacity to identify safety signals, the relationship with concomitant drugs and pathologies prevalent in the study population. This study aimed to evaluate the safety profile and identify and/or assess adverse reactions in an uncontrolled population. METHODS: Active pharmacovigilance by Drug Event Monitoring was performed. A total of 3 follow-up calls were made for 30 days for the identification of the ADRs, tolerability (ADR severity, seriousness, long term sequelae, and duration) and the possible risks (safety signals, medical interactions) of sodium hyaluronate and chondroitin sulfate (HUM). RESULTS: Thirty-five ADRs were identified in the 212 patients included in the study (0.17 ADR/patient). The 35 ADRs were classified into 3 System Organ Class (SOC) groups: general disorders and administration site conditions (74.2%), eye disorders (22.9%), and nervous system disorders (2.9%); and 4 Preferred Term (PT) groups: burning sensation (74.2%), followed by blurred vision (20%), ocular pain (2.9%) and headache (2.9%). All the ADRs were categorized as mild and not serious. No statistically significant differences were found in concomitantly medications, posology and age groups. CONCLUSION: Good tolerability to the solution was identified, with a low incidence of ADRs. Just the same, all the associated ADRs were consistent with the information found in HUM's physicochemical profile and the physiopathology of DED. No unknown risks were identified, reinforcing HUM's safety profile.

Active Pharmacovigilance in Peruvian Population: Surveillance of a Timolol/Brimonidine/Dorzolamide Ophthalmic Fixed Combination.

PURPOSE: In this study active pharmacovigilance was used in an uncontrolled population to enrich the safety profile and canvass the Adverse Drug Reactions (ADRs) associated with the use of a fixed combination of 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide (TBD). METHODS: Active pharmacovigilance consisting of 3 follow-up calls within 60 days was used to monitor the product's safety and identify new risks by searching for unexpected ADRs and increased incidence, tolerability, drug interactions and special population-related ADRs. RESULTS: Ninety-four ADRs were reported by a total of 246 patients (0.38 ADRs/patient); all of them were classified as "mild". We found an increased risk of ADRs with a Relative Risk (RR) for simultaneous use of TBD + ophthalmic ciprofloxacin and TBD + oral atorvastatin; 2.0309 (95% CI, 1.2467-3.3083) and 1.8864 (95% CI, 1.0543-3.3754), respectively. Two unexpected ADRs were discovered, both of which presented belonged to the System Organ Class (SOC) of "infections and infestations" and the preferred term (PT) of "nasopharyngitis.". CONCLUSION: Three safety signals were identified, two of them corresponded to an increase in the incidence of ADRs and the last one is associated with 2 unexpected ADR. Nevertheless, we found a good tolerability profile for TBD in the study population.

A Drug Safety Surveillance Study of a Ciprofloxacin/Dexamethasone Ophthalmic Fixed Combination in Peruvian Population.

(1) Background: drugs provide a significant benefit for patients who require medical treatment; however, their use implies an intrinsic potential danger, with the possibility of causing unwanted effects. These effects are known as adverse drug reactions (ADRs). Post-marketing drug safety surveillance detects unknown risks that have not been identified in clinical trials, and it is necessary to monitor marketed medications under real-life practice. Due to the scarce information about fixed combination of ciprofloxacin 0.3%/dexamethasone 0.1% (SDO), we performed a drug safety surveillance study. (2) Methods: A prospective non-controlled drug safety surveillance study was conducted in Peruvian population. A total of 236 patients prescribed SDO were included derived from 12 sites. Patients' standardized information was collected through two phone calls, including demographics, medical history, prescribing patterns of SDO, concomitant medication, and ADRs in detail. The ADRs were classified by causality and severity, followed by outcome measures to identify new risk. (3) Results: 236 patients prescribed with SDO participated in the study and 220 were included. A total of 82 ADRs/220 patients were reported after the use of SDO, presenting a ratio 0.37 ADR/patient. The most frequent ADR with SDO administration was eye irritation (30%). All ADRs were classified as non-serious, and 97.5% (n = 80) were classified as mild while 2.5% as moderate (n = 2). No cases under the severe category were identified. (4) Conclusion: No new risks were found in the population where this study was conducted.

Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury.

Adenoviral vector AdhMMP8 (human Metalloproteinase-8 cDNA) administration has been proven beneficial in various experimental models of liver injury improving liver function and decreasing fibrosis. In this study, we evaluated the potential therapeutic AdhMMP8 effect in a chronic kidney damage experimental model. Chronic injury was induced by orogastric adenine administration (100mg/kg/day) to Wistar rats for 4 weeks. AdhMMP8 (3x1011vp/kg) was administrated in renal vein during an induced-ligation-ischemic period to facilitate kidney transduction causing no-additional kidney injury as determined by histology and serum creatinine. Animals were sacrificed at 7- and 14-days post-Ad injection. Fibrosis, histopathological features, serum creatinine (sCr), BUN, and renal mRNA expression of αSMA, Col-1α, TGF-ß1, CTGF, BMP7, IL-1, TNFα, VEGF and PAX2 were analyzed. Interestingly, AdhMMP8 administration resulted in cognate human MMP8 protein detection in both kidneys, whereas hMMP8 mRNA was detected only in the left kidney. AdhMMP8 significantly reduced kidney tubule-interstitial fibrosis and glomerulosclerosis. Also, tubular atrophy and interstitial inflammation were clearly decreased rendering improved histopathology, and down regulation of profibrogenic genes expression. Functionally, sCr and BUN were positively modified. The results showed that AdhMMP8 decreased renal fibrosis, suggesting that MMP8 could be a possible therapeutic candidate for kidney fibrosis treatment.

Protective Effects of Moringa oleifera on HBV Genotypes C and H Transiently Transfected Huh7 Cells.

Chronic hepatitis B infection treatment implicates a long-lasting treatment. M. oleifera extracts contain compounds with antiviral, antioxidant, and antifibrotic properties. In this study, the effect of M. oleifera was evaluated in Huh7 cells expressing either HBV genotypes C or H for the antiviral, antifibrotic, anti-inflammatory, and antioxidative responses. Huh7 cells were treated with an aqueous extract of M. oleifera (leaves) at doses of 0, 30, 45, or 60 µg/mL. The replicative virus and TGF-ß1, CTGF, CAT, IFN-ß1, and pgRNA expressions were measured by real time. HBsAg and IL-6 titers were determined by ELISA. CTGF, TGF-ß1, IFN-ß1, and pgRNA expressions decreased with M. oleifera treatment irrespective of the HBV genotype. HBsAg secretion in the supernatant of transfected Huh7 cells with both HBV genotypes was decreased regardless of the dose of M. oleifera. Similar effect was observed in proinflammatory cytokine IL-6, which had a tendency to decrease at 24 hours of treatment. Transfection with both HBV genotypes strongly decreased CAT expression, which is retrieved with M. oleifera treatment. M. oleifera treatment reduced fibrosis markers, IL-6, and HBsAg secretion in HBV genotypes C and H. However, at the level of replication, only HBV-DNA genotype C was slightly reduced with this treatment.