Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Development of the Commercial Manufacturing Process for Nirmatrelvir in 17 Months.

The advancement of nirmatrelvir, the active ingredient in Paxlovid, from discovery to emergency use authorization was achieved in just 17 months, requiring an unprecedented rate of chemical process development.

Granular cell tumor in a premenstrual female breast.

Granular cell tumor is an exceedingly rare pediatric breast mass, derived from Schwann cells which are most commonly observed in the oral cavity, skin, and subcutaneous tissue. When they occur in the breast, they can mimic intrinsic breast masses. Most cases are benign, but malignant cases have been reported. We present a case of a premenstrual, African-American 9 year old female with a painful right breast mass originally felt to be an epidermal inclusion cyst. An ultrasound was performed 17 months after original presentation which demonstrated a 1 cm well-circumscribed solid ovoid mass. Despite the relatively small size and benign imaging appearance of the mass, surgical resection was performed for symptom relief given the associated pain. This is the first known case of granular cell tumor of the breast in a premenstrual female.

Reversible control of solubility using functionalized nanoparticles.

The paper provides a novel method for the reversible control of solubility by use of functionalized nanoparticles. The nanoparticles are functionalized with functional groups that can act as a co-solvent or anti-solvent and thus can induce either dissolution or crystallization. The process is reversible, as the solution will go back to its original state when the nanoparticles are removed. The use of magnetic nanoparticles facilitates this reversibility. Reductions in solubility (and thus crystallization) were demonstrated for d-mannitol-water, sodium chloride-water and fenofibrate-ethyl acetate systems. An increase in solubility (and thus dissolution) was demonstrated for the benzoic acid-water system and the 4-nitrophenol-water system. Reversible manipulation of solubility can be used to reduce solvent usage in dissolution and crystallization by elimination of the need for an antisolvent or co-solvent.

Self-association during heterogeneous nucleation onto well-defined templates.

We investigated the interplay between self-associates in solution and surface templating by studying the crystallization behavior of isonicotinamide (INA) and 2,6-dihydroxybenzoic acid (DHB) in the presence of self-assembled monolayers (SAM). The end group of the SAM as well as the hydrogen-bonding capabilities of the solvent and self-association of INA and DHB were found to be important in polymorph crystallization on SAMs. In the case of INA in ethanol, both chain and dimer self-associates are present in the solution. In the absence of SAMs the polymorph form II (dimer structure) is the crystallization outcome. In ethanol the 4-mercaptopyridine and 4-mercaptobenzoic acid SAMs organize INA chain associates at the template surface and enable the crystallization of form I while the 16-mercaptohexadecanoic acid SAM results in the crystallization of form II. Raman spectroscopy suggests that molecular interactions between INA and the SAM are responsible for the formation of specific polymorphs. XRPD results in the identification of the orientation of the crystal on the surface that further verified the results obtained by Raman spectroscopy. In nitrobenzene and nitromethane INA associates in solution only as chains and crystallization results in the formation of form IV and form I, respectively (both chain forms). The crystals formed in the bulk solution and on SAMs were the same, which seems to indicate that the self-association in nitrobenzene and nitromethane is not influenced by the presence of templates. In the case of DHB in toluene and chloroform, all three SAMs nucleated only one type of polymorph (stable form 2). In the case of toluene the polymorphic outcome was stable form 2 instead of metastable form 1, which is favored in toluene in the absence of the SAMs. Again, Raman spectroscopy and XRPD suggest that DHB-SAM molecular interactions may be responsible for the formation of form 2.

Isonicotinamide self-association: the link between solvent and polymorph nucleation.

We show that, in a controlled and reproducible way, specific solvents lead to specific polymorphic forms of isonicotinamide. We argue on the basis of Raman and FTIR spectroscopy that the hydrogen bonding in solution kinetically drives the nucleation towards a specific form. This generally may lead to good understanding and control of polymorphism and crystal nucleation.

Arterial complications following anterior lumbar interbody fusion: report of eight cases.

The objective of this study is to report eight cases of arterial complication following anterior lumbar interbody fusion (ALIF) and to analyze the data in order to identify possible risk factors. The authors have encountered six cases of common iliac artery occlusion and two cases of acute vasospasm as a complication of ALIF using two different approaches to spine: hypogastric-midline-transperitoneal approach at one center and minimally invasive muscle-sparing retroperitoneal approach at the other. All cases involved surgery at the L4-L5 level. All patients were smokers, and three had an existing history of vascular disease. The left iliac and common femoral arteries were involved in seven cases, while the right common iliac was involved in one case. Five patients had thromboembolism, one patient had an intimal tear and two had functional vasospasm. Circulation to the lower limb was restored by thrombectomy (five patients) and arterioplasty for the intimal tear (one patient). One of the vasospasm cases was explored (false-positive), while the other was treated conservatively. One of the patients with thrombosis developed rhabdomyolysis resulting in fatal acidosis. All but the first case at each center was diagnosed either intraoperatively or within 2 h of surgery. We believe that awareness of this potentially serious complication will lead to precautionary measures for prevention of the problem as well as early diagnosis and management of the complication if it does occur. Intraoperative monitoring of lower limb blood flow by measuring the toe oxygenation with a pulse oxymeter can prove to be helpful in early diagnosis.

Total disc replacement arthroplasty using the AcroFlex lumbar disc: a non-human primate model.

Using a non-human primate model, the current study was undertaken to investigate the efficacy of the AcroFlex lumbar disc as an intervertebral disc prosthesis, based on biomechanical, histopathologic and histomorphometric analyses. A total of 20 mature male baboons (Papio cynocephalus, mean weight 30 kg) were randomized into two equal groups based on post-operative time periods of 6 (n=10) and 12 months (n=10). Each animal underwent an anterior transperitoneal surgical approach to the lumbar spine, with intervertebral reconstructions performed at L3-L4 and L5-L6 using the following techniques: (1) tricortical iliac autograft and (2) AcroFlex lumbar disc. The two treatments were equally randomized between the non-contiguous operative lumbar levels. Post-mortem analysis included histopathologic assessment of the systemic reticuloendothelial tissues, multi-directional flexibility testing of the operative functional spinal units and quantitative histological analysis of trabecular bone coverage at the prosthesis endplates. Data were statistically compared using a one-way ANOVA with the Student-Newman-Keuls test. All animals survived the operative procedure and post-operative interval without significant intra- or peri-operative complications. Histopathologic analysis of the paraffin-embedded systemic reticuloendothelial tissues indicated no significant pathologic changes at the 6- or 12-month intervals. Plain film radiographic analysis showed no lucencies or loosening of any prosthetic vertebral endplate. Biomechanical testing of the 6-month autograft, reconstructions with AcroFlex lumbar disc and non-operative control (n=10) intact motion segments indicated no significant differences in peak range of motion (ROM) in axial compression. However, axial rotation produced significantly lower ROM for the autograft treatment compared to the intact and AcroFlex groups (P<0.05). The most significant differences in peak ROM were noted between all treatment groups under flexion/extension and lateral bending loading modalities (P<0.05). By 12 months, the intact condition indicated significantly more motion in all bending modes compared to the AcroFlex and autograft treatments, which were not statistically different from each other (P>0.05). Gross histopathologic analysis of the AcroFlex disc prosthesis demonstrated excellent ingrowth at the level of the implant-bone interface, without evidence of fibrous tissue or synovium. BioQuant histomorphometric analysis at the metal-bone interface (bone contact area/total endplate area) indicated the mean ingrowth was 54.59+/-13.24% at 6 months and 56.79+/-5.85% at 12 months. Radiographic analysis showed no lucencies or loosening of the AcroFlex vertebral endplate. Based on multi-directional flexibility testing, motion was preserved in axial rotation, but significantly diminished in the other bending modalities, particularly at the 12-month interval. This effect may be secondary to the limited surface area of device-vertebral endplate contact. Histomorphometric analysis of porous ingrowth coverage at the vertebral bone-metal interface was more favorable for total disc arthroplasty compared to historical reports of cementless femoral components. This project serves as the first comprehensive in vivo investigation into the AcroFlex disc prosthesis, and establishes an excellent research model in the evaluation of total disc replacement arthroplasty.