Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for at-Home Treatment of Feline Infectious Peritonitis

Sarah Jones 1, Wendy Novicoff 2, Julie Nadeau 3 and Samantha Evans 1,*

1 Department of Veterinary Life Sciences, College of Veterinary Medicine, Ohio State University, Columbus, OH 43210, USA
2 Department of Orthopedic Surgery and Public Health, Faculty of Medicine, University of Virginia, Charlottesville, VA 22903, USA
3 Hamilton Region Veterinary Emergency Clinic, Hamilton, ON L8P 4W3, Canada
* The author to whom the correspondence should be addressed.

Academic Editor: Clive JC Phillips
Animals 2021, 11 (8), 2257; https://doi.org/10.3390/ani11082257
Delivered: April 22, 2021 / Revised: May 29, 2021 / Accepted: July 27, 2021 / Published: July 30, 2021

Original article: Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for at-Home Treatment of Feline Infectious Peritonitis

Brief summary

Feline infectious peritonitis (FIP) is a fatal feline disease caused by feline coronavirus. The aim of this study was to formally evaluate the administration of unlicensed antiviral therapy GS-441524 from group sources for cats with suspected infectious peritonitis in cats (FIP). Members of social networking support groups and GS-441524-based drug distribution groups were interviewed via the Internet. Of the 393 surveys that met the inclusion criteria, 73.7% owners were receiving this therapy from the United States. Only 8.7% owners reported that they received significant help from their veterinarian in treating their cat. The average cost of treatment was $ 4,920. The majority of owners (88.2%) reported a marked improvement in clinical symptoms within one week of starting therapy. At the time of the survey, 96.7%s (380 cats) lived, of which 54.0%s were considered cured and another 43.3%s were monitored over a 12-week observation period. A total of 12.7% cats had a relapse of clinical signs of FIP and 3.3% cats died despite GS-441524 therapy. The reported complications were mostly related to the administration of subcutaneous injections of GS-441524 acidic solution to the owner, such as vocalization, pain, wrestling and wounds at the injection site. Limitations of this study include retrospective design, bias in case selection, reliance on owner-reported data, and inability to validate unlicensed drugs; however, important lessons can be learned from the experience of these owners. Although unconventional and certainly not without health and legal risks, unlicensed, home therapy similar to GS-441524, according to information from the owners, can obviously bring benefits in the treatment of cats with a suspected diagnosis of FIP.

Abstract

The aim of this study was to formally evaluate the administration of unlicensed antiviral therapy similar to GS-441524 from group sources for cats with suspected infectious peritonitis in cats (FIP), a recently fatal disease. Members of FIP support groups on social networks and drug distributor groups with GS-441524 were interviewed via the Internet. The survey focused on owners who treated their cats for at least 12 weeks with unlicensed drugs with GS-441524. Of the 393 polls analyzed that met the inclusion criteria, 73.7% owners were receiving this therapy from the United States. Only 8.7% owners stated that a veterinarian helped them provide treatment to their cat. The average cost of treatment was $ 4,920. The majority of owners (88.2%) reported a marked improvement in clinical symptoms within one week of starting therapy. At the time of the survey, 96.7%s (380 cats) lived, of which 54.0%s were considered cured and another 43.3%s were monitored over a 12-week observation period. A total of 12.7% cats had a relapse of clinical signs of FIP and 3.3% cats died despite GS-441524 therapy. The reported complications were mostly related to the administration of subcutaneous injections of GS-441525 acidic solution to the owner, such as vocalization, pain, discomfort and wounds at the injection site. Limitations of this study include retrospective design, bias in case selection, reliance on owner-reported data, and inability to validate unlicensed drugs; however, important lessons can be learned from the experience of these owners. Although unconventional and certainly not without health and legal risks, unlicensed, home therapy with GS-441524, according to owners, can obviously bring benefits in the treatment of cats with suspected FIP.

Keywords: FIP; GS-441524; COVID-19; black market; coronavirus; cat; remdesivir

Introduction

Since March 2020, the spread of the coronavirus known as SARS-CoV2 has evolved into the global COVID-19 pandemic. A similar but cat-specific virus known as feline coronavirus (FCoV) is the cause of a fatal feline disease known as feline infectious peritonitis (FIP). Antiviral drugs that inhibit viral RNA replication offer potential therapeutic and preventive benefits to COVID-19, including the adenosine nucleoside monophosphate prodrug GS-5734, more commonly known as remdesivir (marketed by Gilead Sciences, Inc. (Foster City, CA, USA)). [1]. A 2018 study published by Murphy et al. GS-441524, a less chemically complex parent nucleoside (also patented by Gilead), was highly effective against experimentally induced FIP at a dose of 4.0 mg / kg subcutaneously every 24 hours for 12 weeks (84 days) in 10 laboratory cats [ 2]. Later in 2019, the same group conducted a clinical study using GS-441524 to treat 31 cats owned by FIP clients, and the results indicated that this once fatal disease is clinically reversible using this nucleoside analog [3]. The name of GS-441524 is (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5 - (hydroxymethyl) tetrahydrofuran-2-carbonitrile, which is known by many other synonyms [4]. For the sake of brevity, we list several unlicensed drug formulations that claim to contain this compound as "similar to GS-441524", although not manufactured by Gilead Sciences.

FCoV (feline coronavirus) is an extremely common virus that is considered ubiquitous worldwide [5], with a seroprevalence between 26 and 87% (depending on the study and region of the world) in cats from a high-concentration environment (kennels or breeders). and animal shelters) [6]. Active FCoV infections cause mild to subclinical transient GI infections in most patients [7,8]. While 70% of these cats is transiently infected with FCoV, 13% remains permanently infected and chronically excretes the virus in its feces [9]. FIP arises from a mutated form of FCoV in approximately 5% cats [8] and is estimated to kill 0.3 to 1.4% cats worldwide each year [3]. The two main clinical forms of FIP include the effusive ("wet") form, in which the patient develops effusions in the body cavities, and the non-fusive ("dry") form. Until recently, the development of FIP in cats was uniformly fatal and it was often difficult to make an accurate diagnosis of anemorrhea (before death) [10].

Probably due to the ambition to continue research into human RNA viruses that could be inhibited by GS-441524, Gilead stopped further development of GS-441524 therapy in cats. This has sparked demand for GS-441524 in cat owners diagnosed with FIP cats and facing the same death. As a result, several unlicensed drug manufacturers (sometimes referred to as the "black market") have begun selling the compound to cat owners over the Internet, which is not currently authorized by the U.S. patent by Gilead Sciences [4]. The evolution continued into an extensive online network for the treatment and support of FIP, based on crowd-sourcing, in veterinary medicine to an unprecedented extent. There are currently several large groups on social networks that help cat owners obtain medication with GS-441524, plan a protocol, and treat their cats with suspected FIP. Because GS-441524 remains an unlicensed therapy in the United States and elsewhere in the world, most of this drug is manufactured, purchased, administered, and monitored without much, if any, veterinary supervision.

The aim of this study was to formally evaluate the administration of this unlicensed therapy for FIP from various sources and to determine which factors may lead to the success of the treatment. To this end, we conducted a survey of members of the largest of the above groups on social networks and drug distribution groups with GS-441524. What we discovered was truly amazing; Not only do laymen routinely attempt this therapy on their cats, but according to the owners, it is effective and leads to a cure. This report analyzes additional patient characteristics, treatments, and outcomes.

Materials and methods

The questionnaire was created using Google Forms (docs.google.com/forms). The questionnaire was distributed on the group's prominent social networking site ("FIP Warriors") dedicated to the treatment and distribution of GS-441524. It has been advertised and targeted at owners of cats suspected of having FIP (based on the variable criteria used by their individual veterinarians) and have undergone at least some GS-441524 treatment. Some of these patients underwent a full 84 days of treatment, while others started the treatment protocol and subsequently died of the disease or were euthanized due to complications. Inclusion criteria were responses for any cat who underwent treatment of GS-441524 suspected of having FIP and who had completed at least 84 days of treatment (regardless of outcome) or who started treatment and subsequently died. The exclusion criteria were responses for patients who completed <84 days of therapy (due to the existence of a half-duration treatment protocol) or who did not answer most of the survey questions.

It took the cat owners about thirty minutes to complete the questionnaire, and the questions consisted of a multiple-choice format and a short-answer format. Some questions arose from previous answers in a hierarchical arrangement. Permission to share and distribute the survey was obtained from social group administrators, and was often shared and published on all related sites. Survey data were collected from July 31, 2020 to October 25, 2020. The study was approved by the Ohio State University Institutional Review Board (Protocol No. 2021E0162).

All data were analyzed in Minitab version 19 (State College, PA, USA). Descriptives and frequencies were calculated for all categorical variables. Basic descriptive statistics were calculated for all continuous variables. Two-sample t-tests or one-way ANOVA with alpha set at 0.05 and 80% power were used to compare differences between groups.

The results

Owner / patient characteristics

During the study period, 411 surveys were collected, of which 393 cases met the inclusion criteria and were known (alive vs. dead). The remaining 18 surveys were incomplete to obtain sufficient information. Of these 393 cases, 64.9% males (52.3% castrated males and 12.6% intact males) and 35.1% females (25.9% sterilized females and 9.2% intact females).

Most owners were from the US (73.7%), the next highest number came from Canada (6.6%) (table 1). The mean age at diagnosis was 1.65 years (approximately 1 year and 8 months) with a standard deviation of 2.28 years and a range of 2 months to 18 years. More than two thirds of cats (67,2%) were crossed breeds, long-haired domestic or short-haired domestic. The remaining 32,8% consisted of a wide range of purebred breeds, with the most common breed being reported as Siamese (5,6% of all cats) (table 2). This supports a 16-year retrospective study conducted in 2006 by Pesteanu-Somogyi et al., Which found that purebred cats were significantly more likely to be diagnosed with FIP [11]. Nearly a quarter of owners reported that a veterinarian told them directly (14.5%) or indirectly (12.0%) about the unlicensed GS-441524, while 30,36% owners said they found the information in their own online survey, and 23,21% reported that they learned about GS-441524 therapy on social networking group websites for owners of cats with FIP (table 3).

Table 1: Country of origin of survey respondents.

CountryNumber of answers%
USA28973.72
Canada266.63
Great Britain153.83
Italy133.32
Bulgaria82.04
Croatia41.02
Netherlands41.02
Romania41.02
Australia30.77
Ireland30.77
China20.51
Germany20.51
Hong Kong20.51
Mexico20.51
New Zealand20.51
Poland20.51
Portugal20.51
Czech Republic10.26
Hungary10.26
Malaysia10.26
Peru10.26
Serbia10.26
Singapore10.26
Sweden10.26
Switzerland10.26
Turkey10.26
In sum392100%
Not specified 1

Table 2. Breeds of cats treated with GS-441524.

TribeNumber of answers%
Mixed26467.18
Siamese cat225.6
Maine Coons123.05
Bengal cat112.8
British Shorthair102.54
Siberian cat92.29
Ragdoll82.04
Devon Rex71.78
Persian71.78
Russian blue71.78
Scottish Fold51.27
Sphynx51.27
Burma41.02
Exotic shorthair30.76
Himalayan cat20.51
Norwegian Forest Cat20.51
Snowshoe20.51
Abesín cat10.25
Balinese cat10.25
Bombay cat10.25
Burmese cat10.25
Lykoi10.25
Mandalay (Bombay)10.25
Munchkin10.25
Ocicat10.25
Oriental shorthair10.25
Ragamuffin10.25
Selkirk Rex10.25
Singapore10.25
School10.25
In sum393100.0

Table3. How cat owners first learned of the existence of GS-441524 therapy for FIP. Owners could cite more than one source, so the total number of responses is higher than the total number of respondents.

The wayNumber of answers%
Internet, not Facebook11930.36
Facebook9123.21
Veterinarian (directly)5714.54
A friend5614.29
Veterinarian (indirectly)4711.99
Rescue station123.06
Breeder82.04
Conference20.51

While most owners (291 responses, 74.3%) reported that they had at least some help from a veterinarian (usually diagnostic monitoring), only 34 (8.7%) reported that they received significant treatment assistance from their veterinarians such as assistance. with drug injections or oral administration of the compound. It should be noted that 101 (25.7%) owners stated that they did not receive any veterinary assistance other than the initial diagnosis. These owners have treated the cat all by themselves, which raises animal welfare concerns if the owners are untrained or inexperienced in the field of injection or post-injection wound management. The average cost reported for the various GS-441524 treatment brands was $ 4,920, with a standard deviation of $ 3,115 and a median of $ 4,000. These costs ranged from the lowest $ 500 to the highest $ 21,000.

Disease characteristics

Most owners (224 responses, 57.0%) reported that their cat had signs of effusive ("wet") FIP, often with apparently visible effusions observed by the owners. A large contingent (169 responses, 43.2%) of the owners reported symptoms of neurological and / or ocular disease. The most common clinical signs were lethargy / apathy (347 responses, 88.3%), decreased appetite (308 responses, 78.4%) and fever (258 responses, 65.7%) (table 4).

Table 4. Clinical signs reported in cats treated with GS-441524. Owners could provide more than one answer, so the total number of responses is higher than the total number of respondents.

Clinical signsNumber of answers%
Lethargy34788.3%
Anorexia30878.4%
Weight loss28271.8%
Fever25865.7%
Refusal to eat (anorexia)18847.8%
Enlarged abdomen16742.5%
Concealment / Avoidance14737.4%
Outflow11629.5%
Difficult walking10326.3%
Neurological symptoms10326.3%
Breathing difficulties / cough9524.2%
Jaundice5313.5%

The most common signs of response to therapy were increased appetite (287 responses, 73.8%), improved movement / walking / jumping (205 responses, 52.7%), improved energy (153 responses, 39.3%), and fever resolution (104 responses). 26.7%).
Among the 50 cats that relapsed (12.7%), more than half (69.0%) developed worsening symptoms related to appetite, lethargy, weakness, and fever. Another 14,3% owners observed neurological or ocular symptoms.

Treatment characteristics

Many different unlicensed brands of GS-441524 drugs have been reported. The country of origin of these compounds is not easily traceable. Mutian (19,4%) was most commonly reported, followed by owners who used several different brands (18,1%) during treatment, mainly because the original brand was no longer available when they needed to re-order (table 5). Perhaps due to confusion among survey respondents regarding the difference in "dose" (mg / kg) versus "dose" (mg total), only 203 owners specified the initial and final dosing for their cats. The mean initial dose was 6.7 mg / kg (range 2 mg / kg to 16 mg / kg) with a standard deviation of 2.24 and a median of 5 mg / kg, and the mean final dose was 8.5 mg / kg ( range 3 mg / kg to 25 mg / kg) with a standard deviation of 3.34 and a median of 8 mg / kg. Initial dosing was loosely based on a previous study by UC Davis [3], and owners sought help from group social group webmasters for individual changes based on patient response and recent laboratory findings. It should be noted that no dosage was allegedly reduced during the treatment period. Using a paired t-test, the difference between initial and final dosing was very significant (p <0.001). This dose differs from the 2018 study, which found that the optimal dose was 4.0 mg / kg subcutaneously every 24 hours for at least 12 weeks [3]. The initial and final doses were significantly different for cats with neurological or ocular symptoms reported by owners compared to cats that did not have neurological or ocular impairment (mean dose 8.01 mg / kg vs. 5.44 mg / kg at baseline; mean dose 10 , 47 mg / kg versus 6.62 mg / kg at the end of treatment).

Table 5. Reported brand GS-441524. Many respondents used more than one brand during treatment.

GS Brand (Concentration)Number of answers%
Mutian (various dosages and formulations)7619.13
More brands *7118.11
Shire (15 mg / mL)6215.82
Capella (15 mg / mL)389.69
Hero-White (17 mg / mL)389.69
Other *369.18
Oscar (15 mg / mL)328.16
Hero-Blue (15 mg / mL)205.1
Pine (15 mg / mL)194.85
In sum392100.00
Not specified1-

Of the 393 patients, 348 (88.5%) were treated for 12 weeks (84 days), with 45 patients (11.4%) receiving extended treatment (an average of 4 additional weeks). Prolongation of treatment was based on whether symptoms completely resolved at the end of standard 12 weeks of therapy and did not include cats that relapsed during or after the observation phase. Most patients (71.7%) were treated with GS-441524 injection, 8.2% received oral formulations, and 20.1% received a combination of oral and injectable formulations. Treatment with other drugs and supportive therapies were also included in the survey (table 6). The most common adjunctive therapies included vitamin B1 or B12 (41.8%) and steroid use (37.9%). Only 8.2% owners reported using gabapentin.

Table 6. Supportive therapies reported for cats treated with GS-441524. Owners could provide more than one answer, so the total number of responses is higher than the total number of respondents.

Supportive therapyNumber of answers%
Vitamin B1 or B1213841.8%
Steroids12537.9%
Other vitamins and supplements10331.3%
Fluids (SQ or IV, unspecified)9027.4%
Antibiotics7422.4%
Light therapy3911.9%
Vomiting agents3611.1%
Appetite stimulators3410.3%
Gabapentin278.2%

The owners of most patients who received injections reported vocalization at the time of injection (309 responses, 82.0%) and / or pain at the injection site (287 responses, 76.1%). More than half (203 responses, 51.7%) reported scarring and scabs at the injection site (s) (table 7).

Table 7. Complications and adverse events reported in cats treated with GS-441524. Owners could provide more than one answer, so the total number of responses is higher than the total number of respondents.

ComplicationsNumber of answers%
Vocalization during injection30982.0%
Injection site pain28776.1%
The cat fought during the application23662.6%
Rattles / scars20351.7%
Lesions / wounds at the application site15742.2%
Bleeding at the application site14739.4%
Increased activity13335.5%
Swelling at the application site9625.7%
Increased appetite5414.3%

The results

In the case of cats that met the inclusion criteria at the time of the survey, 380 (96.7%) lived and 13 (3.3%) died. Regarding the current treatment phase, 54.0% were reported as "cured", 43.3% was at the observation period (surviving at least 12 weeks of treatment) and 2.7% was again treated for relapse of FIP symptoms. Among the 224 cats with signs of effusive ("wet") FIP, eight cats (3.6% cats in this group) died by the time the owner completed the questionnaire. Of the 169 cats with non-fusion (dry) FIP, five (2,96%) died by the time the questionnaire was completed. Of the 169 cats in which neurological or ocular symptoms were reported, eight died (4.7% cats in this group). Four of these cats that died had neurological / ocular as well as symptoms of effusive (wet) FIP, and four cats that died had neurological / ocular as well as symptoms of non-fusive (dry) FIP. The difference in mortality between these groups was not statistically significant.

The majority of owners (88.2%) reported a marked improvement within one week of starting treatment with GS-441524, and the mean time to "return to normal behavior" was 3.85 weeks (range 1 to 16 weeks). Owners of cats with neurological or ocular symptoms reported that 66% responded to treatment within one week and 16.3% of these cats showed significant improvement within one day. Recurrence of suspected FIP (defined as recurrence of symptoms after the 12-week treatment period) was reported in 50/393 cases (12.7%), with 48 of these 50 cat owners (96%) reporting only one relapse. Five cats (10%) with reported relapse died or were euthanized, all after one relapse. Of the 45 cats (90%) with FIP relapse that were alive at the time of the survey, 9 were currently treated, 17 were in the 12-week observation period, and 19 were considered cured. Four (8%) out of fifty cats with reported relapse showed neurological or ocular symptoms at the time of diagnosis; this was not a statistically significant difference from the number of cats without neurological or ocular signs at the time of diagnosis.

Discussion

We present the first scientific report on unlicensed antiviral therapy used for the successful home treatment of feline infectious peritonitis (FIP) by cat owners. To the best of the author's knowledge, this is the first widespread use of an unlicensed group drug for the treatment of a veterinary disease. We do not advocate unauthorized use of this drug; Our aim was to present this information in order to better inform cat owners and veterinarians who are facing decisions on the treatment of suspected FIP cases.

Males were above average (64.9%) in our study, similar to the previous findings of Riemer et al. which showed that male sex correlated significantly with FIP [12]. Nearly three-quarters (72.7%) of surveyed owners were based in the United States. This may be due in part to the fact that the survey is written in English, and although the social network targeted here is an international platform, members appear to be based mostly in the United States. The average age of the cats in our study was one year and eight months, which corresponds to Riemer et al. (2016) who found that FIP is significantly more common in cats less than two years old [12]. More than two-thirds (67.2%) of the reported cats were mixed breeds or domestic cats, which is slightly less than reported by Riemer et al. in cats with FIP in 2016 (78.8%) [12]. The survey found that 32.8% cats treated with GS-441524 were purebreds, with Siamese (5,6%), Maine Coon (3,05%), Bengal (2,8%) and British Shorthair (2,54%) being the most frequently reported breeds. The over-representation of purebred cats reported in our study may be due to the increased prevalence of FIP, as previously reported by Pesteanu-Somogyi et al. (2006) [11]; due to its location in an environment with a higher number of cats; or perhaps because purebred cat owners are more affluent on average and invest more money in their cats.

Interestingly, about a quarter (26%) of owners reported that after being diagnosed with FIP, they treated their cats all by themselves, without the help or knowledge of their veterinarians. It is important to note that although most respondents to our survey did not receive treatment assistance from their veterinarians, we suspect that the vast majority received a presumed FIP diagnosis through a veterinarian in the form of clinical and laboratory data (eg complete blood count, biochemistry, analysis). fluids, etc.), as they are required by social group administrators before starting therapy. These owners were able to find the support needed to administer GS-441524 therapy at home through the online help of groups on social networks, especially from group administrators. Only 8.7% reported that their veterinarian significantly helped them in treating their cat GS-441524 by helping to administer the compound instead of offering only routine examinations and re-diagnostic tests. Most owners (65.6%) nevertheless continued their veterinarian's care, which usually consisted of repeat blood tests and further diagnosis. It is not clear from our results what proportion of those who visited their veterinarians informed the veterinary team about home treatment GS-441524. It is known that group administrators monitor the progress of individual cats through a treatment protocol in a table. They monitor various parameters such as weight, hematocrit, white blood cell count, lymphocyte count, neutrophil count, monocyte count, albumin, globulin, serum A: G ratio (albumin / globulin ratio), total bilirubin, BUN (blood urea nitrogen), creatinine and ALT (alanine transaminase). Based on progress in monthly blood count values, owners may consult their assigned administrator whenever the attending veterinarian is unable to assist, either due to limited knowledge of treatment or reluctance to assist for fear of losing a medical license. This finding raises important questions as to whether administrators could be accused of performing unlicensed veterinary medicine in an effort to assist patients with FIP and could unknowingly cause harm, or what role veterinarians could and should play in this effort.

Initial unofficial reports from owners obtaining the drug from unlicensed sources in desperation to help their sick cats came with rumors of $ 10,000 - $ 20,000, and some of our survey respondents said they had paid those prices. Although it is certainly still an expensive treatment, the owners in our survey reported an average cost of just under $ 5,000 ($ 4,920). This difference may be partly due to the increase in companies producing this unlicensed drug, which reduces costs through competition. We suspect that the cost of treatment has decreased over time, but we cannot definitively determine this because our survey did not ask about the calendar date of therapy.

Mutian, an international brand and probably the best-known formulation of GS-441524, does not list GS-441524 on its label and is instead listed as a "dietary supplement" for the treatment of FIP [13]. However, this was the GS-441524 brand most often mentioned by the owners, suggesting that both the owners and the webmasters believe that the brand contains GS-441524. The owners of the survey reported higher starting doses than in the original study (4.0 mg / kg) [3], and even higher final doses, probably based on their cat's response to treatment. The mean starting dose was 6.7 mg / kg and the mean final dose was 8.5 mg / kg; this difference was statistically significant (p <0.001). Owners of cats that showed neurological or ocular symptoms of FIP were instructed by group administrators to start with higher doses (8 mg / kg). It is unclear whether this practice is justified, given the lack of published evidence of the use of GS-441524 therapy in neurological or ocular FIP, except for a single case of ocular disease treated with 8 mg / kg Mutian and feline interferon omega [14]. Cats initially diagnosed with non-neurological / neocular FIP and who later developed neurological or ocular symptoms were also advised to increase the dose. Many owners also increased the dose if their cat did not show a significant improvement at the 4 or 8 week time point, i.e., had an A: G of 0.5 or less. According to our findings, some owners decided to start at the lower end of the dosing range first to see if this would be enough to treat the clinical symptoms of their cats, especially due to cost concerns. Original studies at GS-441524 for FIP reported less success in treating FIP in cats starting at 2.0 mg / kg and determined an optimal dose of 4.0 mg / kg given subcutaneously every 24 hours [3]. The difference in effective dosing between a controlled study by UC Davis [3] and those reported by owners in our study who received unlicensed therapy similar to GS-441524 may be due to insufficient quality control from various black manufacturers. It is possible that unlicensed formulations contain a less pure compound or are otherwise less effective than a pharmaceutical grade compound. Therefore, it is difficult to compare these dosages directly.

Based on the original treatment protocol used in the UC Davis study, the recommended duration of treatment is 84 days (12 weeks) [3]. From our group site observations, the decision to discontinue treatment and begin an 84-day (12-week) observation period is based not only on complete remission of clinical symptoms reported by the owner (except for minor residual ocular or neurological symptoms), but also at week 12 of blood tests to normalize serum protein levels. A volunteer veterinarian on the social networking site will often review these owners' blood tests and approve the termination of GS-441524 therapy. Although some cats appear to achieve clinical remission much earlier than 12 weeks, website owners and administrators are reluctant to discontinue treatment in less than 12 weeks for fear that the cat will relapse. Treatments shorter than 12 weeks have not yet been formally evaluated. No survey respondents in our study reported premature (<12 weeks) termination of therapy, except when the cat died or was euthanized.

The protocol created by the social group administrators recommends all owners to start treatment with the injectable drug containing GS-441524. This is considered better due to concerns about enteral absorption of drugs in cats with gastrointestinal symptoms (vomiting, diarrhea) or anorexia. After two to four weeks of injection treatment, the cats are re-evaluated on a case-by-case basis to see if they can switch to the oral formulation. There are patient compatibility issues with both forms of the drug. The concentration of the compound in the oral preparation is low, which requires the administration of several capsules at once, which can be difficult for the owners. Although it is easier to ensure that the patient receives the full dose in the injectable form, the pH 1.5 required to keep the drug in a stable state [3] is very acidic, which is likely to lead to pain and vocalization after the injection. Most owners in our survey (71.7%) stated that they used only the GS-441524 injection form, while only 8.2% stated that they used only the oral formulation. Probably due to the acidic nature of the injection form, most patients (89% of those who received the injections) vocalized after the injection, and for most (83% of those who received the injections) the application was painful at the injection site (s). Injection site pain and morbidity accounted for the majority of reported adverse drug reactions. Many cats (46% from those who received injections) developed ulcers or wounds at previous injection sites, and 43% cats (those who received injections) reported bleeding at the injection site.

Injectable and oral forms of vitamin B1 or vitamin B12 were the most commonly reported supportive therapy used by owners. This was probably to help cats that were anemic, had gastrointestinal symptoms and / or had anorexia [15]. In addition to its haematological effects, vitamin B12 affects other body systems, such as neurological and cardiovascular systems, and may help prevent human disease [16], which could be used therapeutically or prophylactically in cats with suspected FIP. Not surprisingly, the second most common adjunctive therapy was the administration of steroids (probably glucocorticoid; not reported), which are traditionally part of standard FIP care [17]. Various nutraceuticals have been reported and either subcutaneous or intravenous fluid therapy has been commonly used as supportive care (27,4%, our research does not distinguish). Frequent use of antibiotics (presumed due to injection site wounds / abscesses, prophylactic use due to neutropenia or other empirical uses) raises serious concerns about how these drugs were obtained and whether adequate antimicrobial handling was followed. Interestingly, "light therapy" (also known as photobiomodulation) was used by 11.9% owners. This therapy is occasionally used in veterinary medicine as an alternative method to treat inflammatory conditions, provide analgesia and to accelerate wound healing [18,19]. It is suspected that light therapy was mostly used to treat wounds that developed as a result of the injectable treatment. Pain control was not reported as often as expected. NSAIDs (non-steroidal anti-inflammatory drugs) have been mentioned rarely, probably due to concomitant use of steroids. Gabapentin was reported by only 8.2% owners and this drug could be used either for sedation / chemical restraint of the patient or for analgesia.

From the data presented, we considered the most remarkable number of cats, which allegedly responded well to treatment, and at the time of the survey their owners stated that they were in complete clinical remission (without the clinical symptoms previously associated with the diagnosis of FIP). Only a small percentage continued treatment due to relapse (2.7%), which is defined as recurrences of clinical symptoms leading to a diagnosis of FIP or the onset of new clinical symptoms of FIP. This has been the case for various clinical manifestations of FIP, including effusive, non-fusive, ocular and neurological FIP. Almost all (96.7%) cats were alive at the time their owners submitted the questionnaire. It has previously been believed that while GS-441524 has been shown to be an effective treatment for effusive and non-fusive forms of FIP, ocular and neurological forms are much more difficult to treat due to GS441524's inability to cross the blood-blood or blood-brain barrier [2]. In addition, previous measurements of GS-441524 in ventricular and cerebrospinal fluid (CSF) samples showed significantly lower concentrations than serum samples after subcutaneous injections of GS-441524 [2]. In our study, 42,3% owners reported that their cat had neurological or ocular symptoms and only 4.7% allegedly did not survive. Although further research is needed in this area, our study provides evidence that GS-441524 therapy is an option for these patients as well. This may be because the initial and final dosages of cats in this group treated at home by their owners were significantly higher than the originally published dosages [3].

Due to the number of different unlicensed brands of GS-441524 antiviral drugs and the number of owners who used multiple brands during treatment, our study was unable to determine whether one brand is more effective than the other. This was exacerbated by the fact that most of the cats in the study were alive at the time of writing, suggesting the very high effectiveness of most, if not all, of the unlicensed GS-441524 brands. While acknowledging the inherent bias in this study, despite the lack of oversight in the manufacture of drugs with GS-441524, it appears to be very successful in treating FIP according to the data provided by the owners. Nevertheless, it is reasonable to assume that these different formulations may differ in concentration, purity, pH, efficacy, absorption pattern, side effects, and other characteristics, making them a valuable basis for further study. Please note that we cannot directly confirm that any of the marks listed here contain any compound similar to GS-441524; this is an important area of active investigation of our group and others. It is still possible that some of these labels contain other antiviral drugs based on nucleoside analogues, the protease inhibitor GC376 [20] or something else entirely.

One obvious limitation of our study is that there is no definitive anti-mortem diagnostic test for feline infectious peritonitis (other than invasive surgery and biopsy, which is performed very rarely), and respondents to our survey chose to join FIP social groups and respond. for our research. Therefore, although 380 of the 393 cats whose owners participated in the survey were alive, there is no way to confirm the diagnosis of FIP in these cats or in 13 dead cats because no autopsies were reported. Undoubtedly, some of these patients may have been misdiagnosed and their owners were misdirected to GS-441524. Thus, a positive response to therapy in some patients could only be a coincidence. Similarly, cases that were reported not responding well to GS-441524-like therapy (ie, 13 cats that died in this study) may have been because the patient was indeed suffering from another disease. However, given the cost and difficulty of obtaining this treatment, it is reasonable to assume that for many patients, most other diagnoses and therapies have already been performed and exhausted, and that FIP was indeed the most likely differential diagnosis. It should be noted that while there is currently no single, minimally invasive, definitive diagnostic test for FIP, the response to GS-441524 treatment could be considered a supportive or even diagnostic method for FIP. The majority of owners (88.2%) reported a dramatic improvement in clinical symptoms within one week of starting treatment with a mean "return to normal" time of 3.85 weeks. Therefore, in the future, cats with suspected FIP could begin treatment with GS-441524, and a rapid response to drugs could be useful both diagnostically and therapeutically. However, it is important to ensure continuous assessment of renal and hepatic function, as nucleoside analogues can be nephrotoxic and hepatotoxic [21].

In connection with the above limitation, the selection deviation probably played a large role in the apparent success of the therapy in our study. The survey was distributed on the main page of the FIP support group, as well as on pages for cats that were considered either "cured", with relapse and prolonged treatment, suffering from neurological and ocular FIP, or suffering from effusive (wet) FIP. Responses to the survey were requested from owners whose cats had completed at least 12 weeks of treatment. Although this met our goal of obtaining information from Internet users about unlicensed GS-441524, the results undoubtedly show some bias against owners whose cats started treatment with GS-441524 but subsequently died of FIP because they may have left the groups or decided not to fill out. research due to negative emotional states, including lack of enthusiasm for failed treatment. It is reasonable to assume that these owners are more likely to leave the group after losing their cat due to illness, or that the group's website algorithm may not show them these posts as often. This effect is exacerbated by the fact that the FIP Group's original website was removed by the social network operator in August 2020. The remaining members of the group are likely to be affected by "enthusiasm", with only the most enthusiastic and positive members of the group remaining. These factors most likely increased the success reported here; However, a recent study in China found similar, very high survival in cats treated with GS-441524 and GC376 (29/30 clinically cured cats) [22]. These data on the results reported by the owners should therefore be considered preliminary and further research on the true efficacy of GS-441524 therapy in the field is urgently needed.

Other limitations of the study include that it took about 30 minutes to complete the survey, at which point owners may be tired of answering questions. Bias could also play an important role in questions that provided long lists of possible answers [23]. In addition, relying on owners (with unknown medical education) to remember the events of a stressful period when caring for a sick cat can lead to inaccuracies in remembrance. Partly due to these issues, our group is continuing an ongoing prospective analysis of unlicensed therapy similar to GS-441524 for FIP. Nevertheless, the data provided here point to an unprecedented event in veterinary medicine and lessons can be learned from the experience of these owners.

Importantly, although GS-441524 is structurally very similar to remdesivirus and there is good reason to believe that it may be effective against other coronaviruses, no survey respondents reported the use of unlicensed GS-441524 for cats in the treatment of people with SARS-CoV-2. . This was slightly surprising given that the same despair of FIP treatment in cats, which led to the development of the black therapeutic market with GS-441524, can be found in millions of families around the world with a loved one suffering from COVID-19 during the survey period. . However, we have no information on such use, either from our survey data or from unofficial monitoring of these FIP groups. From a regulatory point of view, the unauthorized use of GS-441524 drugs in humans is likely to imply a higher level of legal interest.

Conclusions

Although unconventional and certainly not without health and legal risks, unlicensed, home therapy with GS-441524, according to the owners, effectively addresses clinical signs in cats suspected of having FIP. According to the owners, this unlicensed treatment is clearly effective in various clinical manifestations of the disease (effusive, non-fusive, neurological and ocular FIP). The future of this particular drug for the treatment of FIP is unclear, as the state of manufacture, distribution and patent rights of GS-441524 is constantly evolving. However, this treatment is a test case for social media and crowd-rearing entities to fill the void left by the corporate rejection of the "miracle cure" for the previously 100% deadly disease. This is the first such large-scale case in veterinary medicine, but in today's highly interconnected internet it will almost certainly not be the last.

References

  1. Frediansyah, A .; Nainu, F .; Dhama, K .; Mudatsir, M .; Harapan, H. Remdesivir and its antiviral activity against COVID-19: A systematic review. Clin. Epidemiol. Glob. Health 20219, 123–127. [Google Scholar] [CrossRef] [PubMed]
  2. Murphy, BG; Perron, M .; Murakami, E .; Bauer, K .; Park, Y .; Eckstrand, C .; Liepnieks, M .; Pedersen, NC The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet. Microbiol. 2018219, 226–233. [Google Scholar] [CrossRef] [PubMed]
  3. Pedersen, NC; Perron, M .; Bannasch, M .; Montgomery, E .; Murakami, E .; Liepnieks, M .; Liu, H. Efficacy and safety of the nucleoside analog GS-441524 for the treatment of cats with naturally occurring feline infectious peritonitis. J. Feline Med. Surg. 201921, 271–281. [Google Scholar] [CrossRef] [PubMed]
  4. Pubchem. PubChem Compound Summary for CID 44468216 [Internet]. National Center for Biotechnology Information. 2021. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/gs-441524 (accessed on 28 May 2021).
  5. Pedersen, NC An update on feline infectious peritonitis: Virology and immunopathogenesis. Vet. J. 2014201, 123–132. [Google Scholar] [CrossRef] [PubMed]
  6. Drechsler, Y .; Alcaraz, A .; Bossong, FJ; Collisson, EW; Diniz, PPV Feline coronavirus in multicat environments. Vet. Clin. U.S. Small Anim. Pract. 201141, 1133–1169. [Google Scholar] [CrossRef] [PubMed]
  7. Ettinger, SJ; Feldman, EC; Cote, E. Textbook of Veterinary Internal Medicine — eBook; Elsevier Health Sciences: Amsterdam, The Netherlands, 2017. [Google Scholar]
  8. Lewis, CS; Porter, E .; Matthews, D .; Kipar, A .; Tasker, S .; Helps, CR; Siddell, SG Genotyping coronaviruses associated with feline infectious peritonitis. J. Gen. Virol. 201596, 1358–1368. [Google Scholar] [CrossRef] [PubMed]
  9. Addie, DD; Jarrett, O. Use of a reverse-transcriptase polymerase chain reaction for monitoring the shedding of feline coronavirus by healthy cats. Vet. Rec. 2001148, 649–653. [Google Scholar] [CrossRef] [PubMed]
  10. Pedersen, NC An update on feline infectious peritonitis: Diagnostics and therapeutics. Vet. J. 2014201, 133–141. [Google Scholar] [CrossRef] [PubMed]
  11. Pesteanu-Somogyi, LD; Radzai, C .; Pressler, BM Prevalence of feline infectious peritonitis in specific cat breeds. J. Feline Med. Surg. 20068, 1–5. [Google Scholar] [CrossRef] [PubMed]
  12. Riemer, F .; Kuehner, KA; Ritz, S .; Sauter-Louis, C .; Hartmann, K. Clinical and laboratory features of cats with feline infectious peritonitis — A retrospective study of 231 confirmed cases (2000–2010). J. Feline Med. Surg. 201618, 348–356. [Google Scholar] [CrossRef] [PubMed]
  13. MUTIAN. Cat FIP Symptoms & Treatment: Free Online Support. Available online: https: /www.mutian.us/ (accessed on 1 March 2021).
  14. Addie, DD; Covell-Ritchie, J .; Jarrett, O .; Fosbery, M. Rapid Resolution of Non-Effusive Feline Infectious Peritonitis Uveitis with an Oral Adenosine Nucleoside Analogue and Feline Interferon Omega. Viruses 202012, 1216. [Google Scholar] [CrossRef] [PubMed]
  15. Maunder, CL; Day, MJ; Hibbert, A .; Steiner, JM; Suchodolski, JS; Hall, EJ Serum cobalamin concentrations in cats with gastrointestinal signs: Correlation with histopathological findings and duration of clinical signs. J. Feline Med. Surg. 201214, 686–693. [Google Scholar] [CrossRef] [PubMed]
  16. O'Leary, F .; Samman, S. Vitamin B12 in health and disease. Nutrients 20102, 299–316. [Google Scholar] [CrossRef] [PubMed]
  17. Hartmann, K .; Ritz, S. Treatment of cats with feline infectious peritonitis. Vet. Immunol. Immunopathol. 2008123, 172–175. [Google Scholar] [CrossRef] [PubMed]
  18. Hamblin, MR; Demidova, TN Mechanisms of low level light therapy. Mechanisms for Low-Light Therapy. Int. Soc. Opt. Photonics 20066140, 614001. [Google Scholar]
  19. Venter, M. Light therapy in veterinary practice. Vet. Nurs. J. 201328, 320–323. [Google Scholar]
  20. Pedersen, NC; Kim, Y .; Liu, H .; Galasiti Kankanamalage, AC; Eckstrand, C .; Groutas, WC; Bannasch, M .; Meadows, JM; Chang, K.-O. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J. Feline Med. Surg. 201820, 378–392. [Google Scholar] [CrossRef] [PubMed]
  21. Fan, Q .; Zhang, B .; Ma, J .; Zhang, S. Safety profile of the antiviral drug remdesivir: An update. Biomed. Pharmacother. 2020130, 110532. [Google Scholar] [CrossRef] [PubMed]
  22. Yin, Y .; Li, T .; Wang, C .; Liu, X .; Ouyang, H .; Ji, W .; Liu, J .; Liao, X .; Li, J .; Hu, C. A retrospective study of clinical and laboratory features and treatment on cats highly suspected of feline infectious peritonitis in Wuhan, China. Sci. Rep. 202111, 5208. [Google Scholar] [CrossRef] [PubMed]
  23. Koppell, JG; Steen, JA The Effects of Ballot Position on Election Outcomes. J. Politics 200466, 267–281. [Google Scholar] [CrossRef]

Leave a Reply

Your email address will not be published.

en_GBEN