Predicting Hydroxychloroquine Clearance in Healthy and Diseased Populations Using a Physiologically Based Pharmacokinetic Approach.

Hydroxychloroquine (HCQ), a congener of chloroquine, is widely used in prophylaxis and the treatment of malaria, and also as a cure for rheumatoid arthritis, systemic lupus erythematosus, and various other diseases. Physiologically based pharmacokinetic modeling (PBPK) has attracted great interest in the past few years in predicting drug pharmacokinetics (PK). This study focuses on predicting the PK of HCQ in the healthy population and extrapolating it to the diseased populations, i.e., liver cirrhosis and chronic kidney disease (CKD), utilizing a systematically built whole-body PBPK model. The time vs. concentration profiles and drug-related parameters were obtained from the literature after a laborious search and in turn were integrated into PK-Sim software for designing healthy intravenous, oral, and diseased models. The model's evaluation was performed using observed-to-predicted ratios (Robs/Rpre) and visual predictive checks within a 2-fold error range. The healthy model was then extrapolated to liver cirrhosis and CKD populations after incorporating various disease-specific pathophysiological changes. Box-whisker plots showed an increase in AUC0-t in liver cirrhosis, whereas a decrease in AUC0-t was seen in the CKD population. These model predictions may assist clinicians in adjusting the administered HCQ doses in patients with different degrees of hepatic and renal impairment.

A pilot study of the moderating effect of gender on the physical activity and fatigue severity among recovered COVID-19 patients.

BACKGROUND: Clinical data point toward gender-based differences in COVID-19 severity. However, there is insufficient research examining whether gender predicts physical activity (PA) and fatigue severity in patients recovering from COVID-19. Therefore, this study aimed to characterize the PA and fatigue severity in a cohort of patients recovering from COVID-19 infection and measure the extent to which gender-based differences moderate the relationship of PA with fatigue. METHOD: A cross-sectional survey was conducted in Riyadh, Saudi Arabia. The sample comprised patients recovering from COVID-19 over at least 3 months. Recovered patients were stratified into two groups based on gender. The survey included items pertaining to sociodemographic, a fatigue severity scale and a self-reported international PA questionnaire. RESULTS: Eighty-seven patients (44 women and 43 men) met the inclusion criteria. Compared with men, women reported sedentary behavior (70%) and high fatigue severity (64%). A significantly higher number of women had a low PA score compared with men (p = .002). The findings indicated that gender significantly moderates the effect of total PA in metabolic equivalents (METs; min/wk) on fatigue severity [F = 4.8, p = .03, ΔR2 = 0.24]. CONCLUSIONS: The current study suggests that women might be at risk of higher fatigue severity, in addition to engaging less in PA. Physical activity may plays a significant role in modulate the fatigue severity. Consequently, interventions aimed at promoting physical activity in women stand high chances of addressing the disparity in the distribution of prevalence of fatigue between men and women.

The relationship between hydroxychloroquine plasma concentration and COVID-19 outcomes in rheumatoid arthritis patients in Saudi Arabia.

Background: The drug hydroxychloroquine (HCQ) is widely used to treat rheumatoid arthritis (RA) and has been repurposed for the treatment of COVID-19. This study aims to determine whether HCQ concentration levels in individuals with RA alter the incidence of COVID-19 or its complications. Methods: We collected plasma samples from 13 individuals with confirmed rheumatoid arthritis (RA) to measure HCQ concentration levels. The study included individuals at least 18 years old who had been taking HCQ for at least six months at daily doses ranging from 200 to 400 mg. Results: The study enrolled a total of 13 RA patients. All patients were chronic HCQ users. Among the 13 patients, 7 patients were receiving HCQ at a dose of 200 mg per day, and 6 patients were receiving HCQ at a dose of 400 mg per day. COVID-19 confirmed cases accounted for approximately 46% of all patients. Half of the infected patients (n = 3) were taking a daily dose of 200 mg daily, while the other half were taking 400 mg daily. COVID-19 symptoms ranged from mild to moderate, and the intensity of the symptoms was not severe enough to necessitate hospitalization. COVID-19 symptoms in RA patients included headache, fever, fatigue, dry cough, and loss of taste or smell. Conclusions: Our findings indicated that there was no correlation between HCQ concentrations in rheumatoid arthritis patients and the occurrence of COVID-19 or its complications.

Neuroinflammation and Its Impact on the Pathogenesis of COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SARS-CoV-2 attacks the CNS directly or through activation of the peripheral immune system and immune cell infiltration. Although the modality of neurological impairments associated with COVID-19 has not been thoroughly investigated, the latest studies have observed that SARS-CoV-2 induces neuroinflammation and may have severe long-term consequences. Here we review the literature on possible cellular and molecular mechanisms of SARS-CoV-2 induced-neuroinflammation. Activation of the innate immune system is associated with increased cytokine levels, chemokines, and free radicals in the SARS-CoV-2-induced pathogenic response at the blood-brain barrier (BBB). BBB disruption allows immune/inflammatory cell infiltration into the CNS activating immune resident cells (such as microglia and astrocytes). This review highlights the molecular and cellular mechanisms involved in COVID-19-induced neuroinflammation, which may lead to neuronal death. A better understanding of these mechanisms will help gain substantial knowledge about the potential role of SARS-CoV-2 in neurological changes and plan possible therapeutic intervention strategies.

Associations of Depression and Anxiety with Stigma in a Sample of Patients in Saudi Arabia Who Recovered from COVID-19.

PURPOSE: The coronavirus disease (COVID-19) outbreak combined with social distancing, isolation, and movement restrictions has had a profound impact on individuals' physical and psychological well-being. The aim of this study was to examine the associations of depression and anxiety with feelings of stigma among patients in Saudi Arabia who have recovered from COVID-19. MATERIALS AND METHODS: A cross-sectional survey was conducted between July and December 2020. Trained healthcare providers contacted and interviewed participants by phone. Depression, anxiety, and stigma were assessed using the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder (GAD-7) questionnaire, and the Explanatory Model Interview Catalogue stigma scale (EMIC). Data on sociodemographic characteristics, comorbidities, and family history of mental illness were also collected. Multiple linear regression models were performed to explore factors associated with depression and anxiety. RESULTS: A total of 174 adult participants (≥18 years old) who had recently recovered from COVID-19 were interviewed. The mean PHQ-9 and GAD-7 scores were 7.53 (±5.04) and 3.77 (±4.47), respectively. About 68% of the participants had at least mild depression (PHQ-9 score of 5-9), whereas only 29.89% had at least mild anxiety (GAD-7 score of 5-9) during their infections with COVID-19. Multiple linear regression showed that females were more vulnerable to depression and anxiety disorders than their male counterparts were (ß=3.071 and ß=1.86, respectively). Notably, participants' stigma scores were significantly associated with higher scores on depression and anxiety. CONCLUSION: These findings highlight the negative consequences of COVID-19 infection on the mental health of recovered patients. Therefore, considerable attention from local and international health authorities is needed to improve the mental well-being of recovered COVID-19 patients.

Impact of the loss of smell on the sleep quality and fatigue level in COVID­19 survivors.

PURPOSE: Patients with Coronavirus disease 2019 (COVID-19) are reported to have symptoms such as shortness of breath, dry cough, headache, fatigue, and diarrhea. Loss of smell is a symptom that some patients have suffered from due to inflammation of olfactory epithelium and neuroinvasion of COVID-19 resulting in damage to the olfactory nerves and olfactory bulb. Losing an important sense such as smell might have unfavorable consequences on the lives of COVID-19 survivors; however, these unfavorable consequences have not been sufficiently investigated. METHODS: This was a cross-sectional descriptive study, 81 COVID-19 survivors (51.85% male) answered the Pittsburgh Sleep Quality Index, Fatigue Severity Scale, and Patient Health Questionnaire. RESULTS: COVID-19 survivors who lost their smell were more likely to have poor sleep quality, high fatigue severity, and depression symptoms compared to others who did not lose their smell. Most COVID-19 survivors who lost their smell were women and had breathing difficulties. CONCLUSION: Our knowledge of this relationship will assist in establishing more efficient treatment regimens that consider both psychological and physiological factors. Future research is needed to investigate the causality relationship between poor sleep quality, increased fatigue, and depression symptoms in COVID-19 survivors who experienced loss of the sense of smell.

Effect of chronic hydroxychloroquine use on COVID-19 risk in patients with rheumatoid arthritis and systemic lupus erythematosus: a multicenter retrospective cohort.

OBJECTIVE: Hydroxychloroquine (HCQ) has been used during the coronavirus disease 2019 (COVID-19) pandemic because of its reported anti-viral activity. This study examined the association of chronic HCQ use with the incidence and complications of COVID-19. METHODS: This retrospective cohort study included adults with rheumatoid arthritis and/or systemic lupus erythematosus who visited rheumatology clinics in three tertiary hospitals in Riyadh, Saudi Arabia between January 2019 and December 2020. Patients were categorized into two groups based on HCQ use. Data were obtained from the electronic health record and by interviews with patients. The primary study objective was the incidence of COVID-19 and its complications from March 2020 to February 2021. RESULTS: Almost 11% of the study cohort was positive for COVID-19, and the incidence of COVID-19 was similar between HCQ users (11.11%) and nonusers (10.86%). Disease complication rates were similar in the study arms, and they mainly included fever, dry cough, fatigue, and breathing difficulty. CONCLUSIONS: This study revealed no significant association between chronic HCQ use and the incidence of COVID-19, and disease complications were similar in the study arms.

Validation and Cultural Adaptation of Explanatory Model Interview Catalogue (EMIC) in Assessing Stigma among Recovered Patients with COVID-19 in Saudi Arabia.

Stigma is a negative feeling affecting many patients with various health conditions, especially the contagious ones such as COVID-19. The Explanatory Model Interview Catalogue (EMIC) is one of the valid and reliable stigma-measuring tools; however, it has not been translated and validated in Arabic. Therefore, the aim of this study was to translate and validate the EMIC in Arabic among a sample of Arabic-speaking adults who recently recovered from COVID-19 in Saudi Arabia. The 12 items of the EMIC scale were forward- and backward-translated and reviewed by all authors to check the face and content validity prior to approving the final version of the Arabic 12-item EMIC. A total of 174 participants aged ≥18 years who contracted COVID-19 and recovered as of 29 July 2020 were interviewed. The Cronbach's alpha of the Arabic version of the 12-item EMIC was 0.79, indicating an acceptable level of internal consistency. Using principal component analysis with varimax rotation, two factors explained more than 60% of the variance of the translated EMIC scale. The mean EMIC score was 5.91, implying a low level of stigma among participants. Married participants (ß = 2.93; 95%CI 0.88 to 4.98, p = 0.005) and those with a family history of mental illness (ß = 2.38; 95%CI 0.29 to 4.46, p = 0.025) were more likely to have higher EMIC scores in comparison to their counterparts who were unmarried and had no family history of mental illness. On the contrary, older adults were less likely to have high EMIC scores (ß = -0.11; 95%CI -0.21 to -0.01, p = 0.03). Future studies with larger samples of patients with COVID-19 and various health conditions should be conducted to examine the validity and reliability of the Arabic version of the EMIC among different patient populations and to unveil the factors that may play a role in patients' feelings of stigmatization in this part of the world.

Association of Healthy Diet with Recovery Time from COVID-19: Results from a Nationwide Cross-Sectional Study.

The world is still in need of an effective therapy to treat coronavirus disease-19 (COVID-19). This cross-sectional study was conducted on COVID-19 survivors in Saudi Arabia to investigate the influence of a healthy diet on the recovery time from COVID-19. A questionnaire was developed to assess participants' dietary habits, based on the 2015 Dutch food-based dietary guidelines. A total of 738 COVID-19 survivors participated in the study, of whom 237 (32.1%) were hospitalized for COVID-19 treatment while 501 (76.9%) were not hospitalized, and 320 (43.4%) were females and 418 (56.6%) were males. Overall, no significant difference was noted in healthy diet score between males and females; however, this score was significantly lower for Saudis compared to non-Saudis. Among the non-hospitalized patients, eating a more healthy diet was associated with a shorter duration of recovery (p < 0.05) and was significantly affected by gender (15.8 ± 9.3 male vs. 12.1 ± 8.9 female; p < 0.001) and marital status (12.1 ± 8.4 singles vs. 13.7 ± 9.3 married vs. 16.1 ± 11.8 divorced; p < 0.05). In contrast, no significant correlation was found with age or BMI. In this study, a more healthy diet was associated with a shorter duration of recovery from COVID-19. However, further studies are needed to thoroughly investigate the relationship between diet and recovery time from COVID-19.

Demographics, comorbidities, and outcomes among young and middle-aged COVID-19 patients in Saudi Arabia.

The impact of different sociodemographic and clinical characteristics on the COVID-19-related morbidity and mortality rates have been studied extensively around the world; however, there is a dearth of data on the impact of different clinical and sociodemographic variables on the COVID-19-related outcomes in Saudi Arabia. This study aimed to identify those at high risk of worse clinical outcomes, such as hospitalization and longer length of stay (LOS) among young and middle-aged adults (18 to 55 years). In this questionnaire-based cross-sectional study, 706 patients with real-time polymerase chain reaction (RT-PCR) confirmed COVID-19 infection were interviewed. Patients' demographic characteristics, dietary habits, medical history, and lifestyle choices were collected through phone interviews. Patients with chronic health conditions, such as diabetes and hypertension, reported a higher rate of hospitalization, ICU admission, oxygen-support needs, and a longer period of recovery and LOS. Multiple logistic regression showed that diabetes, hypertension, and pulmonary disease (e.g., asthma and chronic obstructive pulmonary disease (COPD)) were associated with a higher risk of hospitalization and longer LOS. Multiple logistic regression showed that symptoms of breathlessness, loss of smell and/or taste, diarrhea, and cough were associated with a longer recovery period. Similarly, breathlessness, vomiting, and diarrhea were associated with higher rates of hospitalization. The findings of this study confirm the similarity of the factors associated with worse clinical outcomes across the world. Future studies should use more robust designs to investigate the impact of different therapies on the COVID-19-related morbidity and mortality in Saudi Arabia.

Patients' Behavior Regarding Dietary or Herbal Supplements before and during COVID-19 in Saudi Arabia.

The use of traditional medicinal plants in Saudi Arabia stems mainly from consumers' belief in prophetic medicine. This study was conducted to explore changes in patients' use of dietary or herbal supplements among individuals infected with COVID-19 before and during infection and the association between herbal or dietary supplements and hospitalization. A cross-sectional, questionnaire-based study was conducted enrolling symptomatic patients who had recently recovered from COVID-19. Data were collected through phone interviews, and McNemar's test was used to investigate changes to consumption of dietary or herbal supplements before and during infection. Multivariable logistic regression was used to investigate the association between supplements use during patients' infection and hospitalization. A total of 738 patients were included in this study, of whom 32.1% required hospitalization. About 57% of participants were male with a mean age of 36.5 (±11.9) years. The use of lemon/orange, honey, ginger, vitamin C, and black seed among participants significantly increased during their infection. In contrast, patients using anise, peppermint, and coffee peel before their infection were more likely to stop using them during their infection. In addition, using lemon/orange (p < 0.0001), honey (p = 0.0002), ginger (p = 0.0053), vitamin C (p = 0.0006), black seed (p < 0.0001), peppermint (p = 0.0027), costus (p = 0.0095), and turmeric (p = 0.0012) was significantly higher among nonhospitalized patients than hospitalized ones. However, in the multivariable logistic regression, only use of vitamin C (OR = 0.51; 95% CI 0.33-0.79), peppermint (OR = 0.53; 95% CI 0.31-0.90), and lemon/orange (OR = 0.54; 95% CI 0.33-0.88) was associated with significantly lower odds of hospitalization. The study reveals that patients' consumption of dietary or herbal supplements changed in response to their COVID-19 infection, with hospitalized patients having a lower likelihood of using these supplements. Because some supplements were associated with lower odds of hospitalization, these supplements or their bioactive components should be further investigated as feasible options for COVID-19 treatment.