Macroscopic, Microscopic, Preliminary Analytical Evaluation and Quality Assessment of The Seeds of Quercus Leucotrichophora

Doxycycline is the most second generation bacteriostatic antibiotic used to treat various infectious agents including intracellular pathogens. It is effective against gram positive pathogens like Staphylococcus aureus and gram negative pathogens like treptococcus pneumoniae.(1) It is inexpensive and multi- purpose drugs used commonly to treat bacterial infections and it also shows therapeutic benefit in treatment of cancer, Alzheimer’s disease, malaria and cardiovascular disease. Drug reposition is one of the approach to treat viral infections hence antibiotics like macrolides, glycopeptides, tetracyclines and beta-lactams  have been approved by regulatory authorities to fight against viral infections.(2) Doxycycline inhibits replication of wide range of viruses including enveloped and non-enveloped viruses, but its use is restricted in children younger than 8 years of age due to its potential side effects.(3) One such example is use of doxycycline in treatment of SARS-CoV-2 and in-vitro based studies revealed that this drug is effective even at low concentrations and it works by inhibiting viral replication of IHUMI-3 and IHUMI-6 strains.(4) Doxycycline is generally well tolerated when compared to minocycline and adverse effects include esophagitis, mediastinitis. It may have the ability to induce photosensitivity reactions and anaphylactic reactions. Long term use leads to bone deformities and teeth discoloration and reduced contraceptive efficacy in women.(5) There is an intricate relation between Chikungunya and post viral arthritis that lead to our present case report focussing on doxycycline induced urticaria. CHIKV is an arbovirus spread by Aedes aegypti mosquitoes and this disease is characterized by high fever, headache, rash, myalgia and severe joint pain. Usually these symptoms resolve over 2 weeks and if not it usually requires medical attention.(6) A series of events led to development of urticaria in the patient and drug induced urticaria can occur alone or associated with other symptoms such as angioedema and anaphylaxis. It is reported that 1-3% of drug reactions are cutaneous that are precipitated through either IgE mediated pathway or circulating immune complex reactions or pseudo-allergic reactions. From a retrospective study it is found that doxycycline accounts for 0.7%  of total ADRs making it rare but requires timely medical attention.(7)Regardless of the time course of urticarial symptoms usually range from pink to pale plaques with erythematous flare ups, the plagues are usually in round, oval with few millimeters to few centimeters in size. These are usually not painful and are mostly pruritic.(8) The present case report discusses adverse drug reaction due to doxycycline, its anticipated pathophysiology, differential diagnosis and the effective therapeutic management strategies employed to treat urticaria in the patient.

Case Presentation:

A female patient of age 28 years presented to OPD with chief complaints of generalized body pains more intense in upper limbs and back since 10 days. The patient was also presented with generalized body weakness since 5 days accompanied by fever(low grade). The patient has no history of CAD, CVA, HTN and T2DM. Laboratory investigations like CBP, confirmatory diagnostic tests for malaria, typhoid, dengue and viral marker analysis was also performed. Based on subjective and objective evidence the diagnosis was made as viral arthritis (suspected CHIKV) and the patient was put on symptomatic treatment consisting of pain medicine like T. Ultracet(BD) composed of tramadol(37.5mg) and acetaminophen(325mg); antibiotic like doxycycline 100mg(BD) and as patient had chief complaint of fever she was prescribed with T. Dolo composed of paracetamol 650mg (SOS) and for generalized weakness patient was prescribed with T.Zincovit composed of vitamin-A,D3,E,   niacinamide, copper ,zinc and manganese.

Medical history related to present ADR:

After 5 days patient was again admitted in the hospital with chief complaints of redness and swelling of face and edema on both lower and upper limb since 3 days accompanied by severe pain. On physical examination erythema and edema was seen on both arms and legs associated with itching and bruising all over the skin especially on face. Upon patient interview she revealed that she has only taken all the prescribed medications for only one day as there were no more symptoms, and doxycycline 100mg(BD) was the only medication she was taking regularly since 5days and on the 5^th day she had an intense itching associated with pain along with increased puffiness of face and angioedema on lips, genital areas and around eyes. The patient had no prior known history of drug and non-drug allergies, no familial history and was found to be non-compliant with medications.

Figure 1. Erythematous wheals accompanied by angioedema, puffiness and purplish bruising

Examination:

Patient was found to be afebrile, conscious and reciprocating to doctors instructions. The vitals noted as PR-92bpm, RR- 22/min; BP-100/70mm hg; Sp02: 98%; CVS-S1, S2+; RS: BAE+ and RBS were found to be 160mg/dl. The abnormal laboratory investigations are as follows:

Table1.  Abnormal Lab Investigations Seen in Patient During Hospitalization

After the patient was stabilized in the ER she was shifted to General medicine department and appropriate treatment was given. On second day of hospitalization patient was advised for thyroid profile and results were within normal range. The reticulocyte count is increased(1.9%) indicating chances of hemolytic anaemia that need to be ruled out once the patient is recovered from the ADR. The 24 hours urine proteins were found to be exceeding the normal range (297mg/day). The Ultrasound scan of abdomen had shown increased echogenicity of liver along with hepatomegaly giving the impression of Grade-II fatty liver.

Figure2. USG scan of abdomen showing Grade-II fatty liver

Management of ADR:

Upon evaluation of lab data, presenting symptoms and existing medical history the patient is reported with drug induced urticaria secondary to doxycycline classified  under drug induced hepatitis post viral arthritis. Tabet Doxycycline was completely withdrawn and the dechallenge was found to be positive where the patient had shown slight improvement I the symptoms and no rechallenge was performed as it was a serious ADR. The patient was put on symptomatic treatment and was monitored constantly. Patient was put on systemic corticisteroid therapy with inj.Dexamethasone 8mg(BD) to treat urticaria and inj.lasix composed of furosemide(20mg) a loop diuretic was adminstered twice in a day intravenously. To treat the reaction patient was prescribed with tab.Montek LC composed of montelukast(10mg) and levocetirizine(5mg) at night and tab.bilastine(20mg) in the morning.This case was referred to dermatology department and patient was prescribed with Triben B cream composed of cotrimoxazole(1%W/W) and beclomethasone(0.025%W/W) suggested for topical application twice in a day especially at the itchy affected areas of the body. Patient was prescribes with tab.Udiliv composed of ursodeoxycholic acid(300mg) OD that acts as a hepatoprotective preventing further damage to liver.

DISCUSSION:

Drug induced urticaria is a skin reaction caused mainly due to NSAID’S  and antibiotics characterised by swelling on skin and deeper in the skin termed as angioedema. In outpatient depatments it affects 9% of patients more prevalent in adults and children. This case report is validated based on the probability assessment of ADR by Naranjo’s Scale.

Table 2. Naranjo Scale: Probability assessment of Doxycycline induced urticaria.