Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir.

The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chemistry offers a means to mitigate the risk associated with handling large amounts of hazardous reagents and to better control the reaction parameters. A case study describing the cyanation of a glycoside using continuous flow chemistry toward the synthesis of the drug candidate remdesivir is presented.

[A clinical case of lactic acidosis development in a diabetic patient taking metformin].

Metformin is a biguanide. Due to its effects in decreasing the hepatic production of glucose and in increasing insulin sensitivity in peripheral tissues, such as adipose tissue and skeletal muscle, the agent is used in metabolic syndrome and type 2 diabetes mellitus and, in which insulin resistance is especially pronounced. Eighty-one-year old male patient was admitted to the emergency unit with sudden vertigo, tiredness, dyspnea, cyanosis, and lethargy. He had had type 2 diabetes mellitus for 10 years and was taking glargin 12 U/kg once daily and metformin (glucophage) 850 mg thrice daily. The patient showed no cooperation and orientation. Metabolic acidosis, hypoxemia, and hypercapnea were detected in arterial blood gases (ABG). The patient was transferred to an intensive care unit of the hospital; endotracheal intubation was applied and mechanic ventilation was started. On the following day, his ABG got better; he was disconnected and weaning was applied. Lung X-ray study revealed no signs of pneumonia or pulmonary edema. On the same day, extubation was ended and O2 was given by mask at a rate of 4 L/min. After the patient's vital signs, blood sugar, and lactate levels were stabilized; his treatment regimen was arranged again and the patient was discharged on day 4 of his admission. Dyspnea, acidosis, and hypoxia seen in the patient were thought to be due to lactic acidosis which may rarely occur when metformin is used.

[A clinical case of development of lactic acid acidosis in a diabetic patient taking metformin].

Metformin is a biguanide. Due to its effects in suppressing the hepatic production of endogenous glucose and in increasing insulin sensitivity in adipose tissue and skeletal muscle, the agent is used particularly in type 2 diabetes mellitus and metabolic syndrome, in which insulin resistance is especially pronounced. Lactic acidosis is one of the most important side effects of metformin. A male patient, born in 1923, was admitted to the emergency unit of our hospital for sudden vertigo, weakness, dyspnea, cyanosis, and lethargy. His history data showed that the patient had been suffering from type 2 diabetes mellitus for 10 years and taking Glargin (insulin), 12 U/kg, once daily and Glucophage (metformin), 850 mg thrice daily. The patient's general condition was fair; stupor, time and spatial orientation were absent. Analysis of arterial blood gases showed the presence of metabolic acidosis, hypokalemia, hypoxemia, and hypercapnia. Thereafter the patient was transferred to the intensive care unit of the hospital; intubated and connected to a T-bird ventilation apparatus. On the following day, an analysis of arterial blood gases indicated the proximity of the results to their physiological parameters. Ventilation was stopped; and monitoring of the patient continued by following the T-shape type of ventilation discontinuation. There were no X-ray signs of pneumonia or pulmonary edema. On the same day, the patient was extubated and oxygen inhalation in a dose of L/min was continued through a mask. On day 4 since therapy was initiated, the patient's vital signs, serum sugar and lactate levels became normal. By determining a new treatment regimen, the patient was discharged from the intensive care unit. Dyspnea, acidosis, and hypoxia developed in the patient resulted from lactic acidosis caused by the use of metformin. It should be remembered that dyspnea, acidosis, and hypoxia, which suddenly developed in metformin-treated patients with type 2 diabetes mellitus, may be caused by lactic acidosis.