Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.

Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. EMEND (aprepitant) is the first and only neurokinin-1 (NK-1) receptor antagonist available on the market for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Aprepitant acts centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, EMEND helps improve patients' daily living and their ability to complete multiple cycles of chemotherapy. The development of aprepitant included a novel nanoparticle formulation to optimize oral absorption and innovative chemistry to discover a prodrug form suitable for intravenous administration to improve compliance and convenience for healthcare professionals and cancer patients.

No abstract

Phaeochromocytoma is a tumour of the adrenal medullary cells of chromaffin origin, which, although histologically benign, may be dangerous because of excessive secretion of adrenaline and noradrenaline. The growth may not be confined to the adrenals but may occur wherever chromaffin tissue is found, for example along the sympathetic chain, the para-aortic areas, the aortic bifurcation, the retroperitoneum and even in the bladder.Clinical features, resulting from the release of catecholamines, include hypertension, paroxysmal or continuous, hyperhydrosis, hyperglycaemia, increased oxygen consumption, haemoglobin percentage and haematocrit reading, and an elevated basal metabolic rate.The diagnosis is confirmed by measurement of single 24-hour urinary catecholamine or 3-methoxy, 4-hydroxymandelic acid (VMA) values, by certain radiological techniques, and by the effect of certain pharmacological agents, for example histamine to release stored catecholamines and to raise the blood pressure or phentolamine to lower it. Case reportThe patient, a 32-year-old male weighing 79.5 kg, gave a history of low back pain for 2 years and of attacks of sudden uncontrollable aggressive behaviour during the past 18 months with periodic blurred vision.The family history showed that his father, grandfather and great-grandfather had suffered from similar attacks of aggressive behaviour, and a sister had undergone removal of a phaeochromocytoma.Clinical examination revealed a blood pressure of 215/130 mmHg, and a lumbar disc herniation was found at L4-5 level. The attacks of aggressive behaviour were not controlled by drug therapy. Intravenous pyelography showed no abnormality, but on arteriography a large tumour was demonstrated in the right suprarenal area.

No abstract