Although pharmacologic manipulation of intrinsically photosensitive retinal ganglion cells and the neural pathways that mediate photophobia may be possible in the future, current therapies are directed at the underlying cause of the photophobia and optical modulation of these cells and pathways. N Engl J Med. 2003;290:1134. Initially, research has been oriented towards drug repurposing, which is time-saving compared with new drug discovery [3]. Epub 2023 Apr 20. Usually, photophobia affects both eyes equally. Sensitivity analysis using leave-one-out method revealed the overall effect was substantially altered when the study by Shakhsi Niaee et al. Ivermectin, a US Food and Drug Administration-approved anti-parasitic agent, was found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro. They will also ask whether you experience other symptoms along with your photophobia. Funding source of the studies and its association with the reported results raises concerns regarding the validity of results of the studies since conflicts of interest may affect the outcome of the trials. In terms of publication bias existence, a trim and fill analysis were used to evaluate the number of missing studies and the effect of imported studies on effect size. Zein A, Sulistiyana CS, Raffaelo WM, Pranata R. Ivermectin and mortality in patients with COVID-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials. The authors declare that they have no Competing interests. doi: 10.3329/jbcps.v38i0.47512. This assurance could be achieved by journals and editors emphasizing the importance of this issue and demanding authors to provide sufficient information about their funding. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Schiano di Cola F, Ceccardi G, Bolchini M, Caratozzolo S, Liberini P, Padovani A, Rao R. Front Neurol. Seven participants belonged to arm B and three to arm C, and in two of the latter the third time point was 72 h after the fifth dose. Ivermectin is available in the following brand-name forms: Sklice. It is one of the symptoms that may occur in quite a few conditions . BMC Med Res Methodol. Some of the conditions that trigger photophobia are related to the eye itself and some affect the way the body detects pain. Co-morbidities were reported by one-third of participants. Padhy BM, Mohanty RR, Das S, Meher BR. Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) Infection, Updated March 7, 2020. This site needs JavaScript to work properly. 2022;56:3825. 2008;336:9246. Serious adverse events (SAEs) or serious adverse drug reactions (SADRs) had to be immediately (not later than 24 h) reported to the sponsor as well as to the Study Safety Desk. Following these publications, several low-quality studies were conducted to evaluate the effect of ivermectin on COVID-19 patients [14, 15]. Careers. For these reasons and for feasibility considerations, it was planned to collect blood samples in a subset of participants at three timepoints: just before and 4 h and 48 h after the fifth dose. (Fig. Articles eligible for inclusion were: 1) confirmed COVID-19 patients, 2) randomized clinical trials comparing ivermectin to standard of care (SOC) or placebo, 3) evaluated relevant outcomes in this topic. In addition, number of studies had the standard of care or other co-interventions plus ivermectin as intervention and different type of comparators as control. J Antimicrob Chemother. You should seek medical attention if you are having photophobia for the first time because you may need treatment. Popp M, Stegemann M, Metzendorf MI, Gould S, Kranke P, Meybohm P, et al. Customized designed notch filters and applied effects on glare and contrast sensitivity in patients with dry eye syndrome. Shakhsi Niaee M, Namdar P, Allami A, Zolghadr L, Javadi A, Karampour A, Varnaseri M, Bijani B, Cheraghi F, Naderi Y, et al. J Pharm Pharm Sci. official website and that any information you provide is encrypted Their findings are in line with our study, which demonstrates that studies with a high risk of bias or probable medical fraud were necessary to find a substantial positive effect of ivermectin on survival [56]. Received 2021 Nov 9; Accepted 2021 Dec 22. The https:// ensures that you are connecting to the the contents by NLM or the National Institutes of Health. Tension headaches, dental problems, meningitis, or optic nerve disease (such as optic neuritis due to multiple sclerosis) can all irritate your eyes, triggering photophobia. Accidental poisoning has also been reported in dogs ingesting feces from horses that were recently dewormed. Recent evidence indicates that the intrinsically photosensitive retinal ganglion cells play a key role in the pathophysiology of photophobia. 2023 May 10;15(5):1138. doi: 10.3390/v15051138. Google Scholar, WHO COVID-19 Dashboard [https://covid19.who.int/]. The https:// ensures that you are connecting to the 2021;27:1568. What constitutes success in the roll-out of COVID-19 vaccines? Fig S1: Quality assessment based on ROB2 checklist. TCR was described in symptomatic participants (80 participants). government site. PubMed Discuss the pros and cons of prescription pain medication with your healthcare provider. Cookies policy. Study flow chart. Prescribing patterns of low vision devices in patients with cone-related dystrophies. Chopra SS. 2018;27:1785805. 2021 Oct;69(4):103309. doi: 10.1016/j.retram.2021.103309. (1) Limitations of Use: Moxidectin Tablets do not kill. TCR was calculated as the time from randomisation to clinical resolution or death. There were no significant differences between funded (log OR 0.44, 95%CI 0. Chaudhry MW, Zubair SM, Zubairi ABS, Irfan M. Role of ivermectin in patients hospitalized with COVID-19: a systematic review of literature. https://doi.org/10.1186/s12985-022-01829-8, DOI: https://doi.org/10.1186/s12985-022-01829-8. 2021;596:1734. aDepartment of Infectious Tropical Diseases and Microbiology, IRCCS Sacro CuoreDon Calabria Hospital, Negrar di Valpolicella, Verona, Italy, bDipartimento ad attivit integrata medico-generale, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy, cDepartment of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario NegriIRCCS, Milan, Italy, dDepartment of Oncology, Istituto di Ricerche Farmacologiche Mario NegriIRCCS, Milan, Italy, eDepartment of Neuroscience, Istituto di Ricerche Farmacologiche Mario NegriIRCCS, Milan, Italy, fDipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Universit degli Studi di Milano, Milan, Italy, gDepartment of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario NegriIRCCS, Milan, Italy, hInfectious Disease Unit, IRCCS Azienda OspedalieroUniversitaria di Bologna, Bologna, Italy, iClinical Analysis Laboratory and Transfusional Medicine, IRCCS Sacro CuoreDon Calabria Hospital, Negrar di Valpolicella, Verona, Italy, jHospital Pharmacy, IRCCS Sacro CuoreDon Calabria hospital, Negrar di Valpolicella, Verona, Italy, kDepartment of Diagnostics and Public Health, University of Verona, Verona, Italy. Vallejos J, Zoni R, Bangher M, Villamandos S, Bobadilla A, Plano F, Campias C, Chaparro Campias E, Medina MF, Achinelli F, et al. Ivermectin for preventing and treating COVID-19. These blackflies breed along fast-flowing rivers and streams, close to remote villages located near fertile land where people rely on agriculture. "The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Our subgroup analysis based on study quality revealed that ivermectin had no significant effect in disease progression in trials with low ROB (log OR -0.16, 95%CI -0.42 to 0.10; I2=0.00%, Tau=0) and high ROB (log OR -0.26, 95%CI -0.99 to 0.47; I2=47.22%, Tau=0.26) (Fig. Dodd LE, Follmann D, Wang J, Koenig F, Korn LL, Schoergenhofer C, et al. Due to lack of data of one of the studies, we attempted to contact the corresponding, but received no response [32]. Roman et al. 2012;443:8516. Effect of Early Treatment with Ivermectin among Patients with Covid-19 In December 2019, a cluster of cases of pneumonia with unknown etiology was reported in Wuhan, China [1]. It is true that symptomatic subjects at greater risk of illness progression might be more motivated to continue a treatment in the presence of minor side effects. Attempts were made to implement appropriate treatment strategies against the disease. Provided by the Springer Nature SharedIt content-sharing initiative. CAS Mahmud R, Rahman MM, Alam I, Ahmed KGU, Kabir A, Sayeed S, Rassel MA, Monayem FB, Islam MS, Islam MM, et al. Ivermectin and cost: Generic, brand names, and more - Medical News Today Figure2 shows the overall risk of bias of included studies. The study biostatistician prepared the sequence of treatments, generated using SAS 9.4 software according to a randomised permuted blocks procedure. Self-administration of veterinary formulations of ivermectin has been widely reported since the initial (and weak) evidence about its possible efficacy against COVID-19. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. for all randomised participants and in Supplementary Table S2 for participants included in the evaluable analysis set. There are some concerns regarding the accuracy of the results of previous studies that should be addressed. Photophobia (Light Sensitivity): Causes, Treatments & Prevention 2023 May 22;10:1139046. doi: 10.3389/fmed.2023.1139046. Temple C, Hoang R, Hendrickson RG. Bangladesh; COVID-19; Doxycycline; Ivermectin; SARS-CoV-2. 2020. The latter study showed a reduction in viral load in treated subjects versus controls in a subgroup of participants in whom the plasma concentration of the drug, measured 4 h after dosing, exceeded 160 ng/mL. It analysed 14 randomised trials with ivermectin for COVID-19 published until 26 May 2021 including a total of 1678 participants, finding no evidence favouring ivermectin for clinical outcomes or for viral clearance. Finally, a total of 19 and 17 studies (involving 4328 participants) were included in the systematic review and meta-analysis, respectively. Several clinical trials were conducted to determine the efficacy of candidate drugs, however further investigations on other promising drugs are still required [5]. In particular, chloroquine/hydroxychloroquine and ivermectin were of interest for use in low- and middle-income countries as these drugs are widely available (for treatment of parasitic infections) and inexpensive [3]. The dosages used in our study were selected according to the PK considerations reported in the study protocol and in the Introduction: the C 2021;13:989. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Schraer R. Ivermectin: How false science created a Covid 'miracle' drug. Federal government websites often end in .gov or .mil. 1986;1:1558. Secondary outcomes were: (i) trend over time in quantitative viral load at Days 7, 14 and 30; (ii) time to clinical resolution (TCR) (if symptomatic); (iii) proportion of participants with virological clearance at Days 14 and 30; (iv) hospitalisation rate; and (v) COVID-19 severity score at Days 14 and 30. Babalola OE, Bode CO, Ajayi AA, Alakaloko FM, Akase IE, Otrofanowei E, Salu OB, Adeyemo WL, Ademuyiwa AO, Omilabu S. Ivermectin shows clinical benefits in mild to moderate COVID19: a randomised controlled double-blind, dose-response study in Lagos. max) are observed at approximately 4 h after dosing, with an elimination half-life of 1835 h [11,12]. We also identified that some registered RCTs finished without reporting results and so there may be publication bias. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Seven participants received only 1 day of treatment, three participants received 2 days and 3 days, respectively, and one participant received 4 days (Supplementary Table S6). Precision therapeutic targets for COVID-19. Izcovich A, Peiris S, Ragusa M, Tortosa F, Rada G, Aldighieri S, Reveiz L. Bias as a source of inconsistency in ivermectin trials for COVID-19: A systematic review. Toxic effects from ivermectin use associated with prevention and treatment of COVID-19. log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P=0.099 and 0.122 for C vs. A and B vs. A, respectively). Details of the main physical findings, baseline laboratory examinations and concomitant treatments are summarised in Supplementary Tables S3S5. The median age was 47.0 years [interquartile range (IQR) 31.058.0]. Qjm. the time corresponding to the published C 2021;7:10914. In cases of eye trauma, it may affect one eye rather than both. PMC Chaccour C, Ruiz-Castillo P, Richardson MA, Moncunill G, Casellas A, Carmona-Torre F, Girldez M, Mota JS, Yuste JR, Azanza JR, Fernndez M, Reina G, Dobao C, Brew J, Sadaba B, Hammann F, Rabinovich R. Trials. While in trials with high ROB, there was a considerable reduction in mortality rate in the ivermectin group (log OR 1.06, 95%CI 1.65 to 0.47; I2=0.00% Tau=0.00) (Fig. A Mortality, B Progression to severe disease, C Negative RT-PCR, Funnel plot of primary outcomes for evaluation of publication bias. High dose ivermectin for the early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof of concept clinical trial. J Pharm Pharm Sci. Viruses 2021. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. Keywords: Meta-analyses do not establish improved mortality with ivermectin use in COVID-19. MEDLINE (Pubmed), Scopus, Web of Science, Cochrane library, Google scholar and Clinicaltrials.gov were searched for RCTs assessing the efficacy of Ivermectin up to 20 February 2022. On the contrary, the four participants whose disease worsened enough to cause hospitalisation were all in the treatment arms, and three of these were in the higher-dose arm. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, Phru CS, Rahman M, Zaman K, Somani J, et al. The drug was not detectable in the plasma of five participants of arm A (placebo). Pre-print databases were not included due to concerns around non-peer-reviewed studies regarding ivermectin [14, 15]. Dr. Moawad regularly writes and edits health and career content for medical books and publications. Cochrane Database Syst Rev. Ivermectin is used to treat river blindness (onchocerciasis), intestinal infection from threadworms (strongyloidiasis), and other kinds of worm infections. The reduction (expressed in log10) was 2.9 for the higher dose (arm C), 2.5 for the lower dose (arm B) and 2.0 for placebo, but the differences were not statistically significant. The pooled results showed that ivermectin does not have an effect on decreasing the time to negative RT-PCR. Article Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. Therefore, if both experimental treatments proceeded to step 2 and were compared with the control group, the total number of participants to be analysed had to be 102. Academic Press; New York, NY: 1988. Through our manual MEDLINE search, we identified several systematic reviews and meta-analyses based on the results of these fraught studies, reporting an independently significant effect of this drug in their analyses which results in confusion in both clinicians and patients [16,17,18, 61,62,63,64]. The pooled results showed that ivermectin may have a possible effect on lowering the mortality rate. A randomized, double-blind, placebo-controlled trial was conducted to determine the rapidity of viral clearance and safety of ivermectin among adult SARS-CoV-2 patients. FOIA Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. Unable to load your collection due to an error, Unable to load your delegates due to an error. All publications were retrieved up to 20 February 2022. Our study was designed to impartially address this issue to provide a clear perspective on the subject of ivermectin for clinicians and researchers. Our subgroup analysis based on study quality revealed that ivermectin had no significant effect in negative RT-PCR rate in trials with low ROB (log OR -0.14, 95%CI -0.43 to 0.15; I2=0.00%, Tau=0). Stata version 17 statistical software (Stata Corp, College Station, TX, USA) was used for quantitative synthesis. Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise The daily doses were self-administered on an empty stomach with water. A 5-day course of ivermectin was found to be safe and effective in treating adult patients with mild COVID-19. MeSH A systematic review and meta-analysis of studies was performed based on the PRISMA 2020 statement criteria. Major strengths of this study were the double-blind design, the inclusion of a placebo arm and the lack of any other major deviations from the study protocol. A total of 5 RCTs, including 908 COVID-19 patients, reported duration of hospitalization in their studies. CAS The most important concerns are several retractions of clinical trials [21], the availability of inaccurate or outdated meta-analyses [14, 22, 23], and three RCTs recently published in 2022 [19, 20, 24] which their final results were not included in previous meta-analyses. 2021;88:105906. To address the conflicts and clear up the gray area; we precisely assessed the risk of bias of studies using the Cochrane risk-of-bias tool for randomized trials. See this image and copyright information in PMC. We have provided our detailed explanation for each study in the supplementary data (Additional file 1: Fig. Actually, photophobia isn't a condition, but a symptom of other conditions. However, most of them include studies by Elgazzar et al. Larger trials will be needed to confirm these preliminary findings. Therapeutic potential of ivermectin as add on treatment in COVID 19: a systematic review and meta-analysis: ivermectin in COVID-19: a meta-analysis. 2023 Jun 17. doi: 10.1007/s10792-023-02735-w. Online ahead of print. Virology Journal Diabetes Metab Syndr. Shahbaznejad L, Davoudi A, Eslami G, Markowitz JS, Navaeifar MR, Hosseinzadeh F, Movahedi FS, Rezai MS. All participants provided written informed consent. 2021;11:2359. photophobia, and decreased . Ravikirti, Roy R, Pattadar C, Raj R, Agarwal N, Biswas B, Manjhi PK, Rai DK, Shyama, Kumar A, Sarfaraz A. The proportion of participants in each group experiencing AEs was compared by 2 test (or Fisher's exact test when appropriate). BMJ Evid Based Med. Migraine causes severe headaches that can be triggered by a number of factors, including hormonal changes, foods, stress, and environmental changes . Deng et al. Information regarding arm of randomisation, number of subjects screened and enrolled, and detailed reasons for missing inclusion are presented. Stat Methods Med Res. Temple C, Hoang R, Hendrickson RG. Ivermectin Is Toxic To Dogs | Pet Poison Helpline When eye problems are at the root of photophobia, the sensation may be accompanied by severe pain, redness of the eye, and vision changes. Many meta-analyses were conducted based on results obtained from retracted RCTs or those with high ROB without addressing their impact sufficiently. However, they stated that the quality of evidence was very low due to the risk of bias. This can be associated with everything from brow aches to symptoms of nausea and tiredness. Hill A, Garratt A, Levi J, Falconer J, Ellis L, McCann K, et al. Metabolism and tissue residues; pp. Clinical symptoms of fever, cough, and sore throat were comparable among the three groups. A five-day course of ivermectin for the treatment of COVID-19 may There are some studies suggesting significant association between the source of funding and outcome of the studies [65, 66]. This is particularly noticeable in the context of an outbreak such as COVID-19, where there is a pressing need for demonstrating whether novel therapy options are clinically beneficial, and a plethora of low-quality and dubious research are widely available due to the pressing demand. Photophobia - Wikipedia investigated the efficacy and safety of high-dose ivermectin in the early treatment of COVID-19 patients [20]. The pooled SMD was 0.17 (95% CI 0.450.12) with low heterogeneity (I^2=0%, Tau=0.00). Toxicol Rep. 2021;8:50510. 2023 Jan 18;13:1088036. doi: 10.3389/fneur.2022.1088036. Evaluation of ivermectin as a potential treatment for mild to moderate covid-19: a double-blind randomized placebo controlled trial in eastern India. The protocol of our study is registered at Alborz University of Medical Sciences with the number IR.ABZUMS.REC.1400.321. In the concept of COVID-19, useful lessons were learned from ivermectin for researching future potential therapeutic targets during a pandemic, which are critical for both researchers and clinicians. 3E) [19, 34, 36, 45, 47]. Publication bias, subgroup, sensitivity, and meta-regression analyses were only done on primary outcomes as a small number of studies have been included in the secondary outcomes. Can Hot Weather Give You a Heat Headache? . The first thing your healthcare provider will ask you is whether your symptoms occur all the time or at certain times. This may affect the accuracy of findings of studies as a proper comparison may not be possible under these circumstances. You may need to have your pupils dilated with medicated eye drops to make this part of your examination more sensitive. Nature. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. 5A). However, they reported a non-significant difference between ivermectin and placebo in their primary outcome, which was viral reduction. Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis. At Day 30 all participants had a severity score of 1. Jans DA, Wagstaff KM. However, other considerations make a new trial on high-dose ivermectin problematic. Your healthcare provider will also examine the retina, nerves, and blood vessels behind your eyes using ophthalmoscopy, a painless and non-invasive method of examining your eyes. The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis. 2018 Nov;26:55-57. doi:10.1016/j.msard.2018.09.005, Diel RJ, Kroeger ZA, Levitt RC, Sarantopoulos C, Sered H, Martinez-Barrizonte J, Galor A. Botulinum Toxin A for the Treatment of Photophobia and Dry Eye. Mahalingam M, Gopalakrishnan S, Parasuraman D, Jayaraj PJ, Raman R. Indian J Ophthalmol. Lawrence JM, Meyerowitz-Katz G, Heathers JAJ, Brown NJL, Sheldrick KA. The aim of this study was to assess the efficacy and safety of high doses of ivermectin (namely doses of 600 g/kg and 1200 g/kg for 5 consecutive days) for the treatment of SARS-CoV-2 infection. Book In such controversial state with possible conflicts of interest, it is crucial to carefully consider the funding source of the studies so as to reduce the probability of the study results to be affected by such confounding factors. In cases of eye trauma, it may affect one eye rather than both. The mean of the differences in viral load decline from baseline to Day 7 between each experimental group and the control group was described by standard summary measures for continuous data and was compared by Student's T-test and Wilcoxon test (according to ShapiroWilk test for normality). This leads to the spread of misinformation and the formation of low-quality evidence. Photophobia is a heightened sensitivity to light, which can manifest in eye pain or an aversion response to a brightly lit area. 2021;73:14739. They found that ivermectin did not reduce primary or secondary outcomes in patients with mostly mild disease and claimed that ivermectin is not a viable option for treating COVID-19 and should be used only in the context of clinical trials. Forest plots showing the results of meta-analyses for secondary outcomes. This level of bias raises concerns regarding the accuracy of the results and quality of the studies and should be noted to prevent wrong conclusions. Recurrent surges in the mortality rates and economic consequences of the COVID-19 pandemic led to a distressing situation for societies. Campbell W.C., editor. Measurement of plasma concentrations of ivermectin was included as an ancillary study to inform on the maximal drug levels and drug accumulation following repeated doses, on the interindividual variability and, possibly, on the association between blood drug concentration and clinical endpoints.
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