Direct One-Pot Synthesis of Propofol from Paracetamol Tablets

The COVID-19 pandemic has affected millions of people in the entire world and caused a shortage of several drugs, including propofol. Therefore, several protocols for propofol synthesis have been published in recent years. Herein, we present a process starting from paracetamol, a very common and abundant active pharmaceutical ingredient. Since the first three steps (Friedel-Crafts double alkylation, acetyl deprotection, and diazotization) are done in acidic media, a one-pot approach was developed. Furthermore, we observed that the extraction of the final product can be simplified by steam-distillation, leading to propofol in 47% isolated yield with high purity. This presented process could be an example of active pharmaceutical ingredient reuse since similar results were observed with commercial paracetamol tablets (with excipients) regardless of expiration date. © 2023 American Chemical Society.

Direct One-Pot Synthesis of Propofol from Paracetamol Tablets

The COVID-19 pandemic has affected millions of people in the entire world and caused a shortage of several drugs, including propofol. Therefore, several protocols for propofol synthesis have been published in recent years. Herein, we present a process starting from paracetamol, a very common and abundant active pharmaceutical ingredient. Since the first three steps (Friedel-Crafts double alkylation, acetyl deprotection, and diazotization) are done in acidic media, a one-pot approach was developed. Furthermore, we observed that the extraction of the final product can be simplified by steam-distillation, leading to propofol in 47% isolated yield with high purity. This presented process could be an example of active pharmaceutical ingredient reuse since similar results were observed with commercial paracetamol tablets (with excipients) regardless of expiration date. © 2023 American Chemical Society.

POSB103 COVID-19 Positive Patients Hospital Management in the Italian Setting: The Economic Impact

Objectives: To investigate the costs related to COVID-19 patients’ hospital management (from positivity confirmation to discharge, including rehabilitation activities), defining overall resources’ absorption with regard to both the COVID-19 per day and the COVID-19 clinical pathway costs, based on the patients’ clinical condition. Methods: A time-driven activity-based costing approach was implemented to define the costs related to the hospital management of COVID-19 positive patients, according to real-word data derived from six Italian Hospitals, in 2020. The average per-day cost and the average most frequent clinical pathways (considering the internal transfers between wards, based on the patient’s clinical improvement or deterioration), were valorised according to: 1) low-complexity hospitalizations;2) medium-complexity hospitalizations, with presence of hospital beds equipped with C-PAP or non-invasive ventilation;3) high-complexity hospitalizations. Results: The higher the complexity of care, the higher the hospitalization cost per day (low-complexity=€475.86;medium-complexity=€700.20;high-complexity=€1,401.65). Focusing on the entire clinical pathway (ER access, ward transfer, and rehabilitation): i) 29% spent 18.6 days between a medium and a low-complexity hospitalization (€10,778);ii) 16% spent 17.7 days between a low and a medium-complexity hospitalization (€13,902);iii) 12% spent 22.6 days between a high and a medium-complexity hospitalization (€25,817);iv) 8% spent 23.4 days between a medium and a high-complexity hospitalization (€32,141) and v) 5% spent 18.4 days between a low and a high-complexity hospitalization (€23,431). 30% of patients did not experience any ward’s transfer: 17% spent 10.2 within a medium-complexity hospitalization, 9% spent 13 days within a low-complexity hospitalization and 4% spent 11 days within a high-complexity hospitalization, requiring on average €10,113, €6,198 and €21,346 respectively for their management. Conclusions: The study reported the economic evaluation of COVID-19 pandemic in Italy, providing real-world data for an adequate healthcare resources’ allocation, being useful for the further development of proper reimbursement tariffs devoted to COVID-19 positive hospitalized patients.

COVID-19 temporally related multisystem inflammatory syndrome (MIS-C): An early window of opportunity is a good treatment strategy The experience of the paediatric covid center in Palermo

Introduction: Multi-system inflammatory syndrome in children (MISC) shows a presentation mimicking Kawasaki Disease (KD), Toxic Shock Syndrome (TSS), Macrophage Activation Syndrome (MAS). Furthermore, many children show respiratory or abdominal symptoms. Objectives: Intravenous immunoglobulin (IVIG) is recommended as first line treatment as in KD, followed by aspirin, steroids and, in IVIGresistant patients, IL-1 or IL-6 blocking agents. Methods: We describe a cohort of 16 Sicilian children (6M;10F;age:1.4-14 years), with MIS-C, with clinical features compatible with classical or incomplete KD, in some cases with MAS and/or TSS. Demographic, clinical, laboratory, echocardiographic and imaging findings, treatment strategy and outcome were collected. Results: Common presenting symptoms included: fever (94%), abdominal pain or vomiting (50%), mucocutaneous rash (50%), conjunctivitis (44%), latero-cervical lymphadenitis (63%), cheilitis/ pharyngeal hyperaemia (81%), hands and feet oedema (13%). Symptoms started 1-8 days before the hospitalization. Nasopharyngeal swab for SARS-CoV-19 was positive in 12/16 patients, with positive serological IgG, negative or grey zone IgM-type antibodies. 2 patients with negative swab had a history of recent infection and positive IgG-type antibodies;2 patients had parents with positive swab. All the patients showed significant increase of C-reactive protein (CRP). AST, ALT, gamma-GT were increased in 25%. Pancreatic amylase and lipase were increased in 13%, 19% showed lymphocytopenia. Pro-BNP was increased (129-3980pg/ml) in 44% and troponin was increased (27.3-246ng/ml) in 31%. In addition, hyponatraemia was found in 100% of cases. Furthermore, 31 % had proteinuria. 50% showed cardiac involvement (3 pericardial effusion;5 mitral insufficiency;2 mitral and aortic insufficiency;1 coronaritis). Pleural, ascitic, pericardial effusion and abdominal adenitis were found in 19%, 25%, 19% and 31% of cases, respectively. IL-6 levels were evaluated in 9/16 patients and 8/9 showed a significant increase (30.2-285pg/ml) with a rapid normalization after steroids and IVIG treatment. Pro-BNP persisted increased for 7-10 days after IVG and steroids treatment. 25% of patients dramatically and rapidly evolved in a MAS-like form, fulfilling the classification criteria for the diagnosis of MAS (ACR/EULAR 2016). High doses of steroids and IVIG were promptly started with a significant improvement of the clinical course. In all the patients, treatment was started within 72 hours of admission, with IVIG (2 g/ Kg/dose), methylprednisolone (2mg/Kg/day in 56% of patients;30 mg/Kg/day for 3 days, followed by 2 mg/Kg/day in 38% of patients). 2 patients were treated with enoxaparin. TSS was described in 2 patients, who received additionally vasoactive drugs, albumin and diuretics. Conclusion: In our series, most of patients received a prompt treatment with IVIG and steroids. This approach could explain the good outcome in all the cases and the rapid restoring of cardiac function also in patients with MAS or TSS. Patients showed a wide spectrum of presenting signs and symptoms;evidence of inflammation with pathological values of CRP, ESR, D-dimer, ferritin, pro-BNP, troponin, transaminase, pancreatic amylase and albumin;a multi-organ involvement was documented in a high percentage of cases, inducing the clinician to perform a multi-specialistic approach.

Acute cardiovascular manifestations in children with multisystem inflammatory syndrome associated with COVID-19 infection in a Sicilian case series

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of COVID-19 infection, typically evidenced 4-6 weeks after the infection. The debated pathogenesis is a dysregulation of inflammatory response to SARS-CoV-2 infection ad a cytokine hyperexpression. Persistent fever, respiratory and gastrointestinal symptoms are the most common manifestations, associated with typical clinical signs described in Kawasaki Disease (KD). Furthermore, pleiomorphic cardiac manifestations are described, including ventricular dysfunction, coronary artery dilation and aneurysms, arrhythmia, conduction abnormalities and pericardial effusion. These manifestations are a strong link with KD, even if in MIS-C they are more frequently documented. Severe cases can present as Toxyc Shock Syndrome (TSS) with vasodilatory or cardiogenic shock, requiring treatment with plasma expanders, inotropic drugs, diuretics, albumin and -in the more severe patients- extracorporeal membrane oxygenation and mechanical ventilation. KD experience guided the clinicians to treat these children with intravenous immunoglobulin (IVIG), steroids, aspirin (ASA) and, in refractory cases, anti-IL-1 monoclonal antibodies. Objectives: Most patients recover within days to a couple of weeks and mortality is rare, although the medium- and long-term sequelae, particularly cardiovascular complications, are not yet known. Methods: We describe the short-term outcome in a case series of 12 Sicilian children (4M;8F;age: 1.4-14 years) with MIS-C and a documented recent or actual infection by SARS-CoV-2 who showed cardiac involvement. Results: The cardiac features were: 3 patients showed pericardial effusion;1 coronaritis;6 transient mitral valve regurgitation;1 Brugada pattern, evidenced when he was febrile;2 showed associated mitral and aortic valve regurgitation). 7/8 patients with valve regurgitation showed a significant increase of pro-BNP, normalized during the follow-up. TSS was described in 2 patients, showing a significant increase of troponin, promptly treated with high dose of methylprednisolone, IVIG, vasoactive drugs, albumin and diuretics. 3 patients (21%), after the resolution of the acute phase, showed bradycardia (heart rate < 50/min), persisting for 7-10 days. The bradycardia was not associated with first-degree AVB, or a pathological PR. 6 patients (42%) showed an altered ventricular repolarization phase, in association with an increase of pro-BNP (129-3980 pg/ml). 4/12 (33%) had increased troponin levels (27.3-246 ng/ml) in the acute phase, with the normalization of troponin after IVIG and steroids treatment. Pro-BNP persisted increased for a longer time, besides the clinical improvement and the normalization of blood chemistry parameters. Conclusion: Generally, pro-BNP and troponin levels in MIS-C are higher than in KD, reflecting vasculopathy and cardiomyocytes damage extent. Persistence of increased levels of pro-BNP, in patients with a normalization of inflammatory parameters, suggests a mechanism of myocardial oedema, persisting besides the intensive care approach useful, however, to limit effects on cardiac function and normalize inflammatory parameters. Patients admitted with MIS-C require close electrocardiogram monitoring during the acute phase and the recovery, even if they do not manifest dyselectroliteemia, coronary lesions, pericardial effusion, myocarditis, shock. This approach can avoid severe arrythmia.