Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro.

Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO.

Vaccine-Induced Pityriasis Rosea and Pityriasis Rosea-Like Eruptions: A Review of Literature and a Case Report of COVID-19 Vaccine-Induced Pityriasis Rosea

Pityriasis rosea (PR) is frequently proposed to result from a viral etiology. In line with the current pandemic, COVID-19 vaccines are noticed to trigger PR development. Our patient is a 23-year-old female who developed an itchy skin rash following the Pfizer-BioNTech COVID-19 vaccine. Examination showed one erythematous plaque on the left shoulder and multiple small scaly plaques of similar appearance distributed over the trunk and proximal extremities. The patient was clinically diagnosed, educated, reassured, prescribed topical mometasone ointment and oral chlorpheniramine, and was given a follow-up appointment. We report this case to increase awareness on COVID-19 vaccines as potential triggers of PR. Copyright © 2022 Journal of Dermatology and Dermatologic Surgery.

A Comparative Study of Topical Antifungal Therapy in COVID-19-Associated Mucormycosis (CAM): A New Hope?

Introduction: COVID-19-associated mucormycosis (CAM) is an ongoing epidemic that adds to COVID-19 woes in several countries. Mucormycosis is a fulminant angioinvasive fungal disease for which surgical debridement with systemic antifungal therapy is advocated. The efficacy of using topical antifungal therapy in the form of lipid-based amphotericin B gel and povidone-iodine is compared in the trial. Method(s): This is a multiarm, parallel randomized control trial. Microbiologically and histologically proven cases of mucormycosis in patients who underwent open or endoscopic surgical debridement were included in the study. The trial was conducted in the in-patient ear, nose, throat department of a tertiary care referral hospital in eastern India, All India Institute of Medical Sciences, Bhubaneswar, from May to December 2021. The postoperative cavity was treated according to the intervention arm in the form of lipid-based amphotericin B gel, povidone-iodine ointment, or saline nasal douching according to the allotted group. The aim was (1) to compare the efficacy of 0.1% w/w liposomal amphotericin B gel with 10% w/w povidone-iodine and saline nasal douching in preventing revision surgery in patients with CAM and (2) to develop the AIIMS Bhubaneswar Endoscopic Scoring System (AMESS) to quantify response to treatment. The requirement of revision surgery in postoperative cases of CAM was assessed. Result(s): Fifteen participants were analyzed in each group. The control arm's risk of revision surgery was 4.50 (95% CI, 1.16-17.44) times than the lipid-based amphotericin B gel arm and 1.50 (95% CI, 0.71-3.16) times than povidone-iodine arm. The difference was statistically significant (P=.02) for amphotericin but not for povidone-iodine. The absolute risk reduction of applying amphotericin gel is 46.7%, and number needed to treat is 2.14. Conclusion(s): Topical amphotericin B gel application in the postoperative cavity can decrease the need for revision surgery and help in early recovery. However, long-term studies with greater sample size are required to confirm our findings.

ACUTE HEPATITIS AND RASH LINKED THROUGH EPSTEIN-BARR VIRUS

Epstein-Barr virus (EBV) hepatitis is well established, and most cases involves asymptomatic liver enzyme abnormalities. Albeit rare, viruses such as EBV have been reported to induce generalized pustular psoriasis (GPP);and exanthems such as GPP have been associated with acute hepatitis. This case describes a unique case of cholestatic hepatitis due to EBV, followed by a diffuse pustular rash suggestive of GPP. After complete resolution of the cholestatic hepatitis, the patient returned over a year later with concurrent hepatitis and diffuse pustular rash. Case: An obese 26 year-old African-American female presented to the hospital on three separate occasions over a 15 month span with slightly varying symptoms. At the index hospitalization she presented with fatigue and jaundice. Liver chemistries revlead a mixed pattern liver injury, see Table 1. Extensive serological evaluation was unremarkable, though antinuclear antibody and anti-smooth muscle antibody were mildly and non-specifically elevated, but IgG was normal. A liver biopsy was performed revealing portal and lobular inflammation with predominantly lymphocytic moderate micro-vesicular steatosis (Figure 1). EBV PCR returned positive at 20,737 IU/mL yielding a diagnoses of EBV-induced hepatitis. She returned to the hospital one week later due to a diffuse pruritic and painful rash. She had scleral icterus and diffuse erythematous plaques with tiny pustules dispersed over the body sparing the palms, soles, and mucosal surfaces. Laboratory values were overall improved as noted in Table 1. Punch biopsy of the right arm was suggestive of EBV induced GPP. She rapidly stabilized and was discharged the following day with triamcinolone 0.1% ointment. The patient had an uneventful convalescence and liver chemistries returned to normal. Approximately 15 months after her initial hospitalization, she presented with both recurrent hepatitis and a pustular, pruritic, erythematous rash with perioral and periorbital swelling. She denied taking any new medications or supplements. Labs revealed recurrent, though now primarily cholestatic liver injury, see Table 1. Results of a repeat thorough serological evaluation were negative, including for EBV-PCR and COVID-19. Abdominal ultrasound revealed a 16 cm hepatic length. Pustules, spongiosis, and edema were found on repeat skin biopsy, suggestive of GPP. She recovered quickly with systemic steroids. Awareness of GPP induced hepatitis can guide a judicious assessment of abnormal liver chemistries. Furthermore, unnecessary healthcare utilization can be avoided by providing appropriate and timely pharmacotherapy (i.e., corticosteroid taper) for on demand flares. (Figure Presented) (Table Presented) (Figure Presented)

Cutaneous thrombosis associated with skin necrosis following Oxford/AstraZeneca COVID-19 vaccination: a case report

A 73-year-old man presented with left shin ulceration two weeks after receiving his first dose of the Oxford-AstraZeneca vaccine. Within 24 h of vaccination, the patient became generally unwell with fever and headache. On the third day after vaccination, he developed left shin erythema and blistering, which rapidly ulcerated. This formed two superficial ulcers with a necrotic base and a violaceous edge on the lateral aspect of his left shin, measuring approximately 2 cm × 3 cm. He had a background of atrial fibrillation and ischemic cardiomyopathy, and had been on several longstanding medications including apixaban. Blood tests revealed normal clotting, full blood count, liver and renal function. The differential diagnosis included pyoderma gangrenosum, vasculitic ulceration, and a cutaneous adverse drug reaction to vaccination. A punch biopsy was obtained from the edge of an ulcer, which revealed microthrombi within blood vessels, an ischemic epidermis, and fat necrosis of subcutaneous tissue. The patient experienced slow healing of ulceration with topical clobetasol propionate 0.05%, neomycin sulphate and nystatin ointment, and compression bandaging treatment. To our knowledge, this is the first reported case of cutaneous thrombosis associated with skin necrosis following Oxford/AstraZeneca vaccination. Recently there have been concerns related to reports of thrombotic events at atypical sites (including cerebral and splanchnic vascular beds) associated with thrombocytopenia following Oxford/ AstraZeneca vaccination (Greinacher A, Thiele T, Warkentin TE et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021;384: 2092-101). These findings extend the range of atypically located thromboses associated with COVID-19 vaccination and reinforce the necessity for physicians to be vigilant for signs and symptoms related to thromboses at atypical sites in recently vaccinated patients.

Sarcoid-like immune reaction following COVID-19 infection presenting with COVID toes and dactylitis

A 21-year-old woman presented with a 5-month history of swollen, painful, purple discolouration of her toes and fingers, which began 6 weeks after COVID-19 infection. This was refractory to ibuprofen and clobetasol 0.05% w/w ointment. She reported no other associated symptoms. On examination she had erythematous mottling of the tips of the toes and nail folds of the right foot and sausage-shaped deformities of the left second and fourth toes, consistent with dactylitis. Her blood work-up for COVID toes revealed a raised serum angiotensin- converting enzyme (ACE) level (64 U L-1) with no other abnormalities. Her chest X-ray was unremarkable. Plain radiographs of the feet showed soft tissue swelling and lacelike bony appearances with discrete areas of lucency, particularly affecting the middle phalanx of the left second toe. This pattern has been described in sarcoid arthropathy. Magnetic resonance imaging of the left foot demonstrated features of inflammatory arthropathy, including subarticular bone marrow oedema, periarticular soft tissue oedema and flexor tendon tenosynovitis. The findings were consistent with COVID toes;however, some features of the dactylitis extended beyond the expected presentation of a vascular manifestation of COVID-19. She displayed overlap features seen in sarcoid-related pathologies, including raised ACE levels and a lace-like bony appearance. We believe this to be a sarcoid-like immune reaction to COVID-19 presenting with COVID toes and dactylitis. A sarcoid-like immune reaction to COVID-19 with granulomatous skin lesions rather than dactylitis has been reported. Viral infections are a documented trigger for sarcoid- like immune reactions. This case suggests that COVID-19 can trigger sarcoid-like immune reactions, albeit with a more discrete presentation.

Acute localized deterioration in pemphigoid gestationis following COVID-19 vaccination

Pemphigoid gestationis is a rare autoimmune blistering disorder which typically presents in the second and third trimester of pregnancy. We present an interesting case of a localized flare of the condition following COVID-19 vaccination. A 33- year-old woman presented 2 weeks post partum with an acute onset bullous rash. This had started at week 35 of gestation, one day prior to the onset of labour. A pruritic rash developed on her right arm before becoming widespread, with urticated erythematous plaques and tense bullae. There was no mucous membrane involvement and the infant was unaffected. Skin biopsy showed a prominent perivascular infiltrate with numerous eosinophils, suggestive of pemphigoid gestationis. Uncharacteristically, direct immunofluorescence was negative. Her symptoms improved with 30 mg oral prednisolone and topical clobetasol propionate ointment. She received the first dose of the Pfizer SARS-CoV-2 vaccine 5 weeks after the onset of the rash and within days developed a flare of her rash around the inoculation site. To our knowledge, this is the first report of a flare of pemphigoid gestationis following COVID-19 vaccination. There are case reports of other autoimmune bullous disorders (bullous pemphigoid and pemphigus vulgaris) flaring and occurring de novo following mRNA COVID-19 vaccinations. COVID -19 vaccination has been rapidly rolled out and side-effects in patients with rare conditions are only becoming apparent as these patients are exposed to the vaccine. Knowledge of this side effect will enable us to anticipate it, counsel and treat our patients more effectively, and could help maintain vaccine uptake in this vulnerable patient group. (Figure Presented) .

Reactive infectious mucocutaneous eruption in children diagnosed with COVID-19

We describe the cases of two immunocompetent children who developed mucositis with oral, ocular and genital involvement during acute COVID-19 illness. Patient 1 was a 17-year-old male and patient 2 was a 14-year-old male. Both patients presented approximately one week following onset of fever and cough, and subsequent positive SARS-CoV-2 polymerase chain reaction (PCR) test. They each developed conjunctivitis and ulceration of oral mucosa, and erythematous circumferential erosions of the glans penis, with no other cutaneous findings within 10 days of initial systemic symptoms. No other intercurrent infections, including herpes simplex virus 1/2 PCR viral swabs or new medications, were identified, suggesting that COVID-19 was causative. Following dermatology consultation, both patients were diagnosed with SARS-CoV-2-associated reactive infectious mucocutaneous eruption (RIME). Both patients were treated with intravenous hydrocortisone, betamethasone valerate 0.1% ointment once daily, analgesia and intravenous hydration. Both patients noted improvement with systemic corticosteroid therapy. Patient 1 was discharged after 4 days and Patient 2 after 14 days as his severe mucosal ulceration was impacting his oral intake. He had complete resolution of mucositis one week after discharge. The term RIME describes the clinical presentation of significant mucositis (oral, ocular, and anogenital) that is absent to sparse cutaneous involvement, typically occurring as a late manifestation of exposure to Mycoplasma and other infectious agents. The combination of recent PCR-confirmed SARS-CoV-2 infection, absence of other contemporaneous laboratory- confirmed infections and prominent mucositis suggests SARS-CoV-2 as an infectious trigger for RIME in both patients. Clinicians should be aware that SARS-CoV-2 can precipitate RIME and that systemic corticosteroids may provide benefit.

Bullous pemphigoid onset following Pfizer-BioNTech COVID-19 vaccine (COMIRNATY®): coincidence or a new emerging adverse effect?

We report the case of a 61-year-old man referred to the dermatology clinic with a new onset of itchy rash with blisters within 2 weeks following the first dose of the Pfizer-BioNTech COVID-19 vaccine (COMIRNATY®). After the second dose of the same vaccine within 72 h, he developed a widespread rash with tense blisters with oral mucosal involvement. His medical history included obesity (body mass index 47.8 kg m-2), type 2 diabetes mellitus, hypertension and hypothyroidism. His regular medications included alogliptin (established for 3 years) and levothyroxine. There were no recent changes or additions to his drugs reported. On examination, he had extensive erythematous plaques with tense bullae and oral ulcers. Skin anti-epi basement membrane antibodies were positive, and anti-epidermal intercellular antibodies were negative. We considered the diagnosis of bullous pemphigoid (BP) on the clinical picture and indirect immunofluorescence studies. Topical treatment started with 50: 50 white soft paraffin, clobetasol propionate ointment and systemic oral prednisolone with doxycycline with reasonable disease control within 4 weeks. We were faced with a diagnostic conundrum. We postulated two possibilities: new-onset BP coincidental and unrelated to vaccination or BP secondary to the vaccine as suggested by the time-dose relationship. As the patient was established on alogliptin for 3 years, we considered it unlikely this drug had contributed to the disease onset. Case reports are now emerging of BP following vaccination with other COVID- 19 vaccines. This phenomenon has implications for future inoculation with the booster vaccine, requiring careful consideration and discussion with our patients. This case is registered on the Yellow Card scheme (Pérez-López I, Moyano- Bueno D, Ruiz-Villaverde R. Bullous pemphigoid and COVID-19 vaccine. Med Clin (Engl Ed) 2021;157: e333-4;Agharbi F, Eljazouly M, Basri G et al. Bullous pemphigoid induced by the AstraZeneca COVID-19 vaccine. Ann Dermatol Venereol 2022;149: 56-7).

NEW ONSET OF NAIL PSORIASIS AFTER MRNA COVID-19 VACCINE: A CASE REPORT

Currently in Bulgaria the two messenger RNA vaccines used to vaccinate the population against COVID-19 are Pfizer-BioNTech COVID-19 Vaccine (COMIRNATY) and Moderna COVID-19 Vaccine. We present a case of a patient with palmoplantar form of psoriasis (in remission in the last 2 years), who has an attack of psoriasis of the nails, which began two weeks after the second dose of Pfizer-BioNTech COVID-19 Vaccine. Within the next two months, onychopathy of the nails of the ten fingers developed with the manifestation of almost all known psoriatic changes in the nail bed and nail matrix. The toenails are not affected. Topical therapy with calcipotriol/betamethasone ointment under occlusive dressings was prescribed for two months. The monitoring continues.

Cinnamomum camphora: A long history for epidemics control

Camphor (C10H16O) is a white crystalline solid exist in enantiomeric form R and S camphor. It is a terpenoid obtained from turpentine oil. Synthetically it is synthesized by catalytic process as alpha pinene. Naturally camphor is obtained by steam distillation of woods of Cinnamomum camphora tree, also known as Camphor tree, camphor laure and camphor wood. Camphor has many pharmacological properties. It acts as antiviral, anticancerous, antimicrobial, insecticidal, anticoccidial, anti-nociceptive and antitussive drug. In addition, it can be used as skin penetrating enhancer. Camphor gives a soothing and cooling effect, which helps to reduce pain. The reason behind its soothing effect is camphor act as a counter-irritant by activating heat sensitive transient receptor potential vanilloid subtype 1 and transient receptor potential vanilloid subtype 3 receptors and inhibits the transient receptor potential melastatin-subfamily member 8 receptor. As a result, these receptors provide a sensation of scalding heat and pain (nociception) and could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue such as in osteoarthritis. Camphor has a history of epidemics cure. During leishmaniosis (kala-azar) pandemic in 14th century, camphor was used as fumigant to control the spread of plague in European countries. In 19th century when cholera, small pox and influenza spreads, camphor was used as mothballs in Indian subcontinent as a (cough reliever) agent. During 18th century Russian influenza “flu pandemic” founder of Homeopathy Hahnemann in 1831, published his research work on camphor and suggested camphor as a “divine remedy” for influenza given in extremely small doses. In the same year, several companies launched to sell menthol rub as natural rub ointment consisting camphor as prevention measures for spread of influenza. As the recent epidemic of COVID-19 arises, prevention and control of spread of disease is an alarming issue. This article covered the glimpse of uses and importance of camphor in the history of epidemic cure.

On relevance of excipients allergies

Background: Polyethylene glycols (PEGs), also called macrogols, are molecules that cause allergic reactions in individuals who are sensitized to them. Their relevance lies in their popularity as they are usually found in many drugs and skin products such as laxatives, cosmetics, antibiotics, corticoids, contrast dyes, vitamin complexes These compounds have recently attained certain prominence due to their presence in several vaccines developed against the global pandemic of SARS-CoV2. Allergic to these substances individuals cannot be vaccinated, as PEGs or polysorbate 80 (which cross-reacts with PEGs) may be included in the vaccine. This research presents a clinical case of a 57-year man who had had several local skin reactions with associated itching, caused by different cosmetic products and Betadine® (povidone-iodine ointment) in gel. He also developed a similar clinical picture, as well as wheezing, by means of Moviprep® (a laxative), but the same day he tolerated another laxative, Casenglicol®. Additionally, he suffered a reaction to Vincigrip® (paracetamol/pseudoephedrine hydrochloride/chlorpheniramine maleate), but tolerated paracetamol alone Method: The tests have been practised on this patient are standard patch-tests, photopatch testing with sunscreen lotions, prick-tests and intra dermo-reaction (1:100) with PEGs, and controlled exposure test with laxatives Citraflett® and Vincigrip® (both of them without PEGs). Results: All these tests cast negative results but the intra dermoreaction test. In this case, the patient developed facial and oropharynx itchiness, scattered wheals, and dyspnoea, which decreased after administrating adrenaline, corticoids, and antihistamines. The patient was diagnosed allergy to PEG and has been advised from receiving any SARS-CoV2 vaccine at all. Conclusion: It is of great relevance to diagnose allergic to PEG patients, for two main reasons. First, due to the frequent presence of PEGs in medicaments and cosmetics. Many times they may be overlooked as they are included only in some formulations or brands of a same product. Thus, in consequence, these patients cannot be administrated some vaccines against SARS-CoV2 containing PEG or polysorbate.