Fangchinoline inhibits SARS-CoV-2 and MERS-CoV entry.

The COVID-19 pandemic caused by SARS-CoV-2, lead to mild to severe respiratory illness and resulted in 6.9 million deaths worldwide. Although vaccines are effective in preventing COVID-19, they may not be sufficient to protect immunocompromised individuals from this respiratory illness. Moreover, novel emerging variants of SARS-CoV-2 pose a risk of new COVID-19 waves. Therefore, identification of effective antivirals is critical in controlling SARS and other coronaviruses, such as MERS-CoV. We show that Fangchinoline (Fcn), a bisbenzylisoquinoline alkaloid, inhibits replication of SARS-CoV, SARS-CoV-2, and MERS-CoV in a range of in vitro assays, by blocking entry. Therapeutic use of Fcn inhibited viral loads in the lungs, and suppressed associated airway inflammation in hACE2. Tg mice and Syrian hamster infected with SARS-CoV-2. Combination of Fcn with remdesivir (RDV) or an anti-leprosy drug, Clofazimine, exhibited synergistic antiviral activity. Compared to Fcn, its synthetic derivative, MK-04-003, more effectively inhibited SARS-CoV-2 and its variants B.1.617.2 and BA.5 in mice. Taken together these data demonstrate that Fcn is a pan beta coronavirus inhibitor, which possibly can be used to combat novel emerging coronavirus diseases.

Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Thalidomide-Revisited: Are COVID-19 Patients Going to Be the Latest Victims of Yet Another Theoretical Drug-Repurposing?

The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the "cytokine storm" that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.

Acyclovir is not effective in pityriasis rosea: Results of a randomized, triple-blind, placebo-controlled trial.

BACKGROUND: Acyclovir is considered to be an effective treatment for pityriasis rosea but randomized, blinded, placebo-controlled trials have not been performed. AIMS: To test the efficacy of acyclovir in pityriasis rosea in a randomized, triple-blind, placebo-controlled trial. METHODS: Twenty seven patients with pityriasis rosea were randomly allocated to receive placebo (n = 13) or acyclovir (800 mg five times daily for one week) (n = 14). The severity of disease was assessed by the pityriasis rosea area and severity index. Cure was defined as the absence of erythema, with no or minimal scaling. RESULTS: The number of days (mean ± standard deviation) taken for cure was not significantly different between the two groups (placebo 26.54 ± 9.14 days versus acyclovir 33.29 ± 9.49 days; P = 0.0720, t-test; 95% confidence interval of difference -0.65 to 14.14 days). LIMITATIONS: The sample size for the present study was calculated using data from an earlier study. As the standard deviation was not mentioned in that article, a common standard deviation of fifteen days was assumed. A study with a larger sample size may be more effective in detecting minor treatment differences between acyclovir and placebo, if they exist at all. CONCLUSION: Acyclovir is not an effective treatment for pityriasis rosea.

Use of rituximab in pemphigus patients with chronic viral hepatitis: report of three cases.

Use of rituximab in patients with chronic viral hepatitis can worsen pre-existing hepatitis or reactivate occult infection. There are no reports of use of rituximab in pemphigus patients with co-existing viral hepatitis. Herein, we report three pemphigus patients with co-existing chronic viral hepatitis (hepatitis C (n = 2), hepatitis B (n = 1)), who were treated successfully with rituximab under close supervision and concurrent antiviral drug administration. There was no derangement of the liver function tests or increase in viral load in any of the patients. By incorporating good collaboration with a hepatologist and close follow-up, such patients can be managed successfully with biologic therapies when the conventional treatment modalities have failed.

Rabies, tetanus, leprosy, and malaria.

The developing world is still endemic to rabies, tetanus, leprosy, and malaria. Globally more than 55000 people die of rabies each year, about 95% in Asia and Africa. Annually, more than 10 million people, mostly in Asia, receive postexposure vaccination against the disease. World Health Organization estimated tetanus-related deaths at 163000 in 2004 worldwide. Globally, the annual detection of new cases of leprosy continues to decline and the global case detection declined by 3.54% during 2008 compared to 2007. Malaria is endemic in most countries, except the US, Canada, Europe, and Russia. Malaria accounts for 1.5-2.7 million deaths annually. Much of the disease burden related to these four infections is preventable.

Mononeuritis multiplex and painful ulcers as the initial manifestation of hepatitis B infection.

Hepatitis B virus infection leads to multisystem manifestations owing to involvement of kidney, skin, vasculature, haematopoietic and nervous system. The hepatitis B infection can cause neuropathy either to vasculitis associated with polyarteritis nodosa or immune-mediated neural damage. In this submission, we report a young woman, who presented with mononeuritis multiplex and painful ulcerations as the first manifestation of chronic hepatitis B virus infection. The antiviral therapy along with steroids led to remarkable recovery. The clinical settings of hepatitis B virus infection should not be ignored in the presentation of mononeuritis multiplex with ulcers, although the commonest cause is leprosy in the Indian sub-continent.

Leprosy and HIV coinfection: a critical approach.

An increase in leprosy among HIV patients, similar to that observed in patients with TB, was expected approximately 20 years ago. Studies conducted in the 1990s together with those reported recently seemed to indicate that a coinfection with HIV did not alter the incidence and the clinical spectrum of leprosy and that each disease progressed as a single infection. By contrast, in countries with a high seroprevalence of HIV, TB was noted to increase. Explanations may be provided by the differences in the incubation time, the biology and toxicity of Mycobacterium leprae and Mycobacterium tuberculosis. After the introduction of HAART the leprosy-HIV coinfection manifested itself as an immune reconstitution inflammatory syndrome (IRIS), typically as paucibacillary leprosy with type 1 leprosy reaction. The incidence of leprosy in HIV-infected patients has never been properly investigated. IRIS-leprosy is probably underestimated and recent data showed that the incidence of leprosy in HIV patients under HAART was higher than previously thought.

Newer trends in the management of genital herpes.

Management of genital herpes is complex. Apart from using the standard antivirals, an ideal management protocol also needs to address various aspects of the disease, including the psychological morbidity. Oral acyclovir, valacyclovir or famciclovir are recommended for routine use. Long-term suppressive therapy is effective in reducing the number of recurrences and the risk of transmission to others. Severe or disseminated disease may require intravenous therapy. Resistant cases are managed with foscarnet or cidofovir. Genital herpes in human immunodeficiency virus-infected individuals usually needs a longer duration of antiviral therapy along with continuation of highly active anti retroviral therapy (HAART). Genital herpes in late pregnancy increases the risk of neonatal herpes. Antiviral therapy and/or cesarean delivery are indicated depending on the clinical circumstance. Acyclovir appears to be safe in pregnancy. But, there is limited data regarding the use of valacyclovir and famciclovir in pregnancy. Neonatal herpes requires a higher dose of acyclovir given intravenously for a longer duration. Management of the sex partner, counseling and prevention advice are equally important in appropriate management of genital herpes. Vaccines till date have been marginally effective. Helicase-primase inhibitors, needle-free mucosal vaccine and a new microbicide product named VivaGel may become promising treatment options in the future.

The impact of treatment with tumour necrosis factor-alpha antagonists on the course of chronic viral infections: a review of the literature.

Biologics that antagonize the biological activity of tumour necrosis factor (TNF)-alpha, namely infliximab, etanercept and adalimumab, are increasingly used for treatment of immune-mediated inflammatory diseases, including psoriasis, worldwide. TNF-alpha antagonists are known to increase the risk of reactivation and infection, particularly of infections with intracellular bacteria such as Mycobacterium tuberculosis. More frequently these agents are given to patients with viral infections. Viral hepatitis and human immunodeficiency virus infections are often present in these patients, with a considerable geographical variation. Other concomitant viral infections such as herpes, cytomegalovirus and varicella zoster virus may occur much more frequently than tuberculosis or leprosy. General recommendations about the management related to possible problems associated with anti-TNF-alpha treatment and these viral infections are lacking. This short review will give an overview of the most recent data available on the effects of anti-TNF-alpha therapy on viral infections with a particular focus on patient management and screening recommendations.

Clinical, immunological and histological aspects of an uncommon type II reaction in patients with lepromatous leprosy.

This study reports three cases of an unusual leprotic reaction characterized by superficial bullous ulcerative cutaneous lesions associated with high fever, malaise and oedema in patients with leprosy. Two patients responded to thalidomide treatment, with regression of the symptoms and skin ulcers. The third patient responded to thalidomide plus prednisone. Analysis of the ulcerated skin lesions showed dermal oedema with mononuclear cell infiltrate enriched for gammadelta-positive T lymphocytes and an increased number of Mycobaterium leprae bacilli within capillary endothelium. In contrast, gammadelta+ cells were decreased in or absent from the blood. Tumour necrosis factor-alpha and interleukin-6 were raised in the serum of the patients at the onset of the reaction. After the episode, cytokine levels and the percentage of gammadelta+ cells in the blood returned to normal. These cases characterize an uncommon leprotic reaction with clinical similarities to type II reaction and may indicate a significant role for gammadelta+ T cells in its pathogenesis.

Mini outbreak of Kaposi's varicelliform eruption in skin ward: a study of five cases.

BACKGROUND: Kaposis varicelliform eruption (KVE) represents widespread cutaneous herpes simplex virus (HSV) infection in patients with preexisting dermatoses. Occasionally, this infection can present as a nosocomial infection in skin wards, if adequate bed-spacing and barrier nursing methods are not followed. We are reporting five cases of KVE; four cases acquired the infection in a makeshift ward after admission of the first case in May 2005, due to the renovation work of the regular skin ward. AIM: The purpose of this study is to create clinical awareness about this uncommon dermatologic entity and to stress upon the importance of bed-spacing and barrier nursing in skin wards. METHODS: Five cases of KVE, three females and two males with different primary dermatoses (pemphigus foliaceus--one, pemphigus vulgaris--two, paraneoplastic pemphigus--one and toxic epidemal necrolysis--one) were included in this study. Diagnosis was made clinically and supported with Tzanck smear and HSV serology. All the cases were treated with oral acyclovir. RESULTS: Four out of five cases of KVE recovered with treatment, one case of extensive pemphigus vulgaris with KVE succumbed to death. CONCLUSION: Mini outbreaks of KVE can occur in skin wards with inadequate bed-spacing and overcrowding of patients. Therefore adequate bed-spacing, barrier nursing and isolation of suspected cases are mandatory to prevent such life-threatening infections.

Kaposi's varicelliform eruption.

Kaposi's varicelliform eruption (eczema herpeticum) is the name given to a distinct cutaneous eruption caused by herpes simplex and certain other viruses that infect persons with preexisting dermatosis. Most commonly it is associated with atopic dermatitis. We report a case of a three-year-old atopic child who presented with extensive vesicular eruption suggestive of Kaposi's varicelliform eruption. There was history of fever, malaise and extensive vesicular eruptions. Diagnosis was made based on clinical features and Tzanck smear examination. Patient responded adequately to oral acyclovir therapy.