Approach to Study the Efficacy and Safety of New Complementary and Alternative Medicine Formulations: Lesson during COVID-19 from Sri Lanka.

COVID-19 affected Sri Lanka from early 2020, a time of considerable ignorance accompanied by wide media coverage of a devastating epidemic in Italy and Europe. Many were attracted to complementary and alternative medicine (CAM) or traditional medicine (TM) in this desperate situation. Several preparations were claimed to be effective against COVID-19 globally. Dammika Bandara Syrup© was one such preparation promoted for preventing and treating SARS-CoV-2 infection. It was based on bees' honey, pericarp and mace of Myristica fragrans (nutmeg), the seed of Foeniculum vulgare and fresh rhizome of Zingiber officinale, all believed to have anti-viral properties. Following an unpublished clinical study claiming efficacy, Dammika Bandara Syrup© gained wide media publicity and political patronage. The producer claimed of Goddess Kali revealing the formula added an anthropological, cultural, and religious complexity to the issue. The demand for the product increased rapidly as a debate raged both in public and in the parliament on utilizing such products in combating COVID-19. The Department of Ayurveda, which is statutorily responsible for regulating CAM/TM had to respond to the situation. The legislation to regulate such indigenous medicinal products was weak, and the crisis deepened as thousands converged to the production facility, defying mobility restrictions introduced to control COVID-19. This led to the Ministry of Health requesting academics to form a team and conduct a clinical trial to prove its efficacy. This paper outlines the process and issues faced during the regulatory approval for the trial in a polarized political environment. Some health professionals accused the researchers of bowing to political pressure and questioned the scientific justification for the trial. However, the team considered this as an opportunity to streamline a path for research into CAM/TM therapies in situations such as COVID-19. Several processes were identified and addressed, such as the provisional registration of CAM preparations, assessing the potential efficacy of a CAM product, confirmation of authenticity and safety, standardization and supervision of production respecting cultural identities, obtaining approval for human use, choice of comparators, and ethical issues. We believe the study has helped set standards and a benchmark for CAM and TM research in Sri Lanka.

Features of Covid-19 patients detected during community screening: A study from a rural hospital in Sri Lanka.

ABSTRACT: We studied the clinical course and virus shedding of all patients referred to Welikanda Hospital, in one month. There were 53 positives for Covid-19 by PCR. 24 (45%) were male, with an age range of 11-94 years. Of these, 41 (77%) were asymptomatic, 9 had cough, 4 had sore throat and six had fever. Pulse, blood pressure, respiratory rate and capillary oxygen were normal in all. A proportion of them had poor prognostic factors: asthma (n=4), hypertension (n=11), age above 60 years (n=9), and diabetes (n=11). Lymphopenia was seen in 20 and elevated CRP in 14. Viral shedding continued beyond 14 days in several persons and continued in symptomatic patients for a significantly longer time than asymptomatic patients. Covid-19 was an asymptomatic or mild illness in this group of people. Several of them continued to be RT-PCR positive even after 14 days. Such cases are an important source of community spread.

Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia.

The Asia-Pacific Working Group on inflammatory bowel disease (IBD) was established in Cebu, Philippines, under the auspices of the Asian Pacific Association of Gastroenterology with the goal of improving IBD care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in the conjunction with conventional treatments for ulcerative colitis (UC) and Crohn's disease (CD) in Asia. These statements also address how pharmacogenetics influence the treatments of UC and CD and provide guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of IBD workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing and future revisions are likely as new data continue to emerge.

Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia.

The Asia-Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, under the auspices of the Asia-Pacific Association of Gastroenterology with the goal of improving inflammatory bowel disease care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in conjunction with conventional treatments for ulcerative colitis and Crohn's disease in Asia. These statements also address how pharmacogenetics influences the treatments of ulcerative colitis and Crohn's disease and provides guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of inflammatory bowel disease workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing, and future revisions are likely as new data continue to emerge.

Association of Serum Ferritin with Diabetes and Alcohol in Patients with Non-Viral Liver Disease-Related Hepatocellular Carcinoma.

INTRODUCTION: Non-alcoholic fatty liver disease is a leading cause for hepatocellular carcinoma (HCC) in Sri Lanka. Diabetes mellitus, alcohol abuse, and liver inflammation are known to increase the risk of HCC. The present study evaluates serum ferritin levels in a cohort of patients with non-viral HCC (nvHCC). METHODOLOGY: Consecutive patients with nvHCC presenting to the Colombo North Liver transplant Service, Ragama, from January 2012 to July 2013 were investigated. All were negative for hepatitis B and C. At registration, 5 mL of serum was separated into plain tubes, stored at -80°C and analysed for ferritin using an enzyme-linked immunosorbent assay. Correlation between the serum ferritin and patient risk factors, liver status, and tumour characteristics were analysed. RESULTS: There were 93 patients with nvHCC (median age 65 [12-82] years; 82 [88.2%] males). The median ferritin level was 246.2 µg/L, and 38 (40.86%) patients had elevated ferritin. Non-diabetics (median 363.5 mg/L, p = 0.003) and alcohol abusers (median 261.2 mg/L, p = 0.018) had higher ferritin levels. On multiple-variable analysis, being non-diabetic (p = 0.013) and alcoholic (p = 0.046) was significantly associated with high serum ferritin. No association was found with body mass index, tumour stage, size, macrovascular invasion, number of nodules, alpha-fetoprotein, bilirubin, international normalized ratio, and survival. CONCLUSION: In patients with nvHCC, serum ferritin levels are higher in non-diabetics and alcoholics.

Diffuse-Type Hepatoma: A Grave Prognostic Marker.

BACKGROUND: Data on diffuse-type hepatocellular carcinoma (HCC) are rare. HCC in Sri Lanka is rising, and the majority is related to nonalcoholic fatty liver disease. This study was planned to compare nodular- and diffuse-type HCC in this cohort. METHODS: CT scans of 227 patients with HCC negative for infective hepatitis were analyzed and grouped as nodular and diffuse from July 2011 to July 2014. Diffuse-type cancer was defined as a tumor without convex/distinct margin, diffusely infiltrating the hepatic parenchyma. There were 45 (20%) cases. The baseline liver functions, etiology, treatment, and the outcome were compared with nodular-type cancers. Stage III diffuse cancers were matched with 2 stage III nodular cancers looking at the T stage and background liver. RESULTS: There was no difference in the age (63 vs. 62 years, p = 0.937) and gender. Diffuse cancers had a low BMI (24 vs. 22, p = 0.009), a higher alpha fetoprotein (AFP) level (p < 0.001), a higher incidence of major vascular invasion (14 vs. 80%, p < 0.001), and a history of significant alcohol consumption (39 vs. 67%, p = 0.001). The baseline liver functions were similar in diffuse and nodular cancers. A large proportion (27 vs.77%, p < 0.001) of diffuse cancers were not candidates for active treatment. Overall survival was poor in the diffuse type (4.7 vs. 25 months, p < 0.001). Diffuse-type stage III cancers had a poor survival compared to matched nodular cancers (2.5 vs. 15.8 months, p = 0.001). CONCLUSION: HCC without a background of infective hepatitis were common in our cohort. These tumors are associated with high AFP levels, major vascular invasion, and a poor prognosis.

Classic polyarteritis nodosa associated with hepatitis C virus infection: a case report.

INTRODUCTION: Hepatitis C virus has been under-recognized as an etiologic factor for polyarteritis nodosa and the presence of hepatitis C antigenemia in patients with polyarteritis nodosa has been reported as insignificant. In the literature hepatitis C virus-associated polyarteritis nodosa is a rare and controversial entity. CASE PRESENTATION: A 34-year-old Sri Lankan Tamil man presented to our facility with a two-week history of slow-resolving pneumonia of the right mid and lower zones. On physical examination he had panniculitic type tender skin nodules with background livedo reticularis. A skin biopsy was suggestive of a small and medium vessel vasculitis compatible with polyarteritis nodosa. He was tested positive for hepatitis C antibodies. A serum cryoglobulin test was negative but perinuclear antineutrophilic cytoplasmic antibody test was positive. Serum complement levels were reduced. He was diagnosed as having classic polyarteritis nodosa associated with hepatitis C infection. He later developed left-sided radiculopathy involving both upper and lower limbs and an ischemic cardiac event. His hepatitis C infection was managed with polyethylene glycol-interferon 2α combined with oral ribavirin. Simultaneously, his classic polyarteritis nodosa was treated with prednisolone and cyclophosphamide. He made a good recovery. CONCLUSIONS: Hepatitis C virus infection is capable of inducing a fulminant form of vasculitis in the form of polyarteritis nodosa. It may be easily confused early in its course with mixed cryoglobulinemia, which is commonly known to be associated with hepatitis C virus. Awareness of hepatitis C virus-related polyarteritis nodosa helps in diagnosing the condition early so combined immunosuppressive and antiviral treatment can be started as soon as possible.

Comparison of a composite symptom score assessing both symptom frequency and severity with a score that assesses frequency alone: a preliminary study to develop a practical symptom score to detect gastro-oesophageal reflux disease in a resource-poor setting.

BACKGROUND: There is a need for a practical instrument to screen for gastro-oesophageal reflux disease (GORD) in epidemiological studies. OBJECTIVES: To develop a practical score to detect GORD and compare assessment of both symptom frequency and severity with frequency alone. METHODS: One hundred patients with upper gastrointestinal symptoms and 150 volunteers with no such past history faced an interviewer-administered questionnaire assessing seven symptoms, graded for frequency and severity. Two scores were generated. Score 1, the sum of frequency of symptoms and score 2, the sum of products of frequency and severity of each. Internal consistency, test-retest reliability and criterion validity against 24-h pH monitoring were assessed. Cut-off scores were generated by receiver operating characteristic curves using scores of half the volunteers and patients selected randomly and validated on the other half. RESULTS: Cut-off scores and area under the curve for score 1 were >/=10.5 and 0.93, and score 2 were >/=12.5 and 0.93, respectively. The sensitivity and specificity of diagnosing the disease in the remaining participants using score 1 was 89.7 and 92.4% and score 2 was 93.8 and 94.0%, respectively. The instrument had good internal consistency (Cronbach alpha = 0.73) and reliability (intraclass correlation coefficient of scores 1 and 2 were 0.94 and 0.95, respectively). Score 2 showed better correlation with 24-h pH monitoring parameters (Spearman's rank correlation, P = 0.01). CONCLUSION: Our score is valid, reliable and can detect GORD with high sensitivity and specificity. A score assessing both frequency and severity of symptoms correlates better to an objective measure of GORD.

Liquid chromatography-tandem mass spectrometry method for the simultaneous quantitative determination of the organophosphorus pesticides dimethoate, fenthion, diazinon and chlorpyrifos in human blood.

Simultaneous determination of the organophosphorus pesticides dimethoate, fenthion, diazinon and chlorpyrifos in human blood by HPLC-tandem mass spectrometry was developed and validated. The pesticides were extracted by a simple one-step protein precipitation procedure. Chromatography was performed on a Luna C(18) (30mmx2.0mm, 3microm) column, using a step-gradient at a flow rate of 0.4ml/min. The assay was linear from 0.5 to 100ng/ml (r(2)>0.992, n=24) for all pesticides. The inter- and intra-day accuracy and precision for the method was 96.6-106.1% and <10%, respectively. The lower limit of quantification was 0.5ng/ml. In conclusion, the method described displays analytical performance characteristics that are suitable for the quantification of these pesticides in cases of acute poisoning.

Fetal effects of environmental exposure of pregnant women to organophosphorus compounds in a rural farming community in Sri Lanka.

BACKGROUND: The possible deleterious effects of low-grade, chronic environmental and occupational exposure to organophosphorus compounds (OPCs) are not well documented. OBJECTIVE: To investigate the possible effects of low-level, chronic exposure of pregnant mothers to OPCs on the fetus by measuring OPC levels, and using markers of OPC exposure, oxidative stress and oxidative tissue damage. METHODS: Toxicity was assessed by measuring (i) OPC levels in breast milk and plasma from maternal and cord blood using gas chromatography, (ii) maternal and fetal butyrylcholinesterase (BChE) activity using inhibition assays, (iii) antioxidant status of the fetus using superoxide dismutase activity assays, (iv) oxidative stress in the fetus by determining malondialdehyde (MDA) concentrations, and (v) examining for fetal DNA fragmentation using electrophoresis. Samples were obtained from consenting mothers living in a farming community in southern Sri Lanka at the end of the pesticide spray season (study group) and just before the commencement of the spray season (in-between spray season; control group). RESULTS: Organophosphate residues were detected in only two subjects (chlorpyrifos in maternal and cord blood of one during the spray season and dimethoate in breast milk of another during the in between spray season), but the test employed was capable of only detecting concentrations above 0.05 mg/l. However, cord blood obtained during the spray season showed significant inhibition of BChE activity, increased oxidative stress and more DNA fragmentation when compared with cord blood obtained during the in-between spray season. CONCLUSIONS: Inhibition of cord blood BChE activity indicates fetal exposure to organophosphorus compounds during times when there is a high probability of environmental drift. This provides a plausible explanation for the increased oxidative stress and high DNA fragmentation in the fetus. Long-term outcomes of such exposures are unknown.