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The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.

WX-UK1 (the active metabolite of upamostat) was originally developed as an inhibitor of the serine protease urokinase (uPA) with a Ki ~1 uM. To identify more sensitive targets, we performed a bioinformatic analysis of the ~200 human trypsin-like serine proteases, many of which play crucial roles in homeostasis and disease. Among these we selected a subset for biochemical analysis based on an inspection of modelled 3D structures of WX-UK1:protease complexes and sequence alignment of binding site residues. Samples of the selected proteases were prepared and characterized for their binding to WX-UK1; enzymatically with respect to inhibition constant (Ki) and by surface plasmon resonance with respect to dissociation constant (kd). We now report that WX-UK1 is a potent and specific inhibitor of five human serine proteases (trypsin-3, trypsin-2, trypsin-1 and matriptase-1 and trypsin-6), with Ki's down to the low nanomolar range, 19 nM for trypsin-3. Several of these serine proteases are known to be associated with cancer progression and metastasis. As a compound with an established clinical safety profile, targeted use of upamostat in oncology and extension to non-oncology indications may be assessed. Citation Format: Emil Oldenburg, Christine R. Schar, Eva Lange, Terry F. Plasse, Danielle T. Abramson, Reza Fathi, Eric M. Towler, Mark Levitt, Jan K. Jensen. New potential therapeutic applications of WX-UK1, as a specific and potent inhibitor of human trypsin-like proteases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4200.

OBJECTIVE: The objective of this investigation was to report the pharmacokinetic properties of misoprostol administered intravaginally to women at term via a controlled-release hydrogel polymer insert. METHODS: This open-label, dose escalation trial consisted of 31 nulliparous women at term who were treated intravaginally in cohorts of six with inserts containing reservoirs from 25 through 300 μg (7 at 200 μg) of misoprostol. Inserts remained intravaginally until the patient went into labor, developed adverse events, or completed 24 hours of treatment. Complete data about residual drug in the inserts and plasma concentrations of misoprostol acid were gathered for 27 and 25 patients, respectively. RESULTS: Misoprostol was released at a constant rate (5.1% total dose per hour) with the amount absorbed being directly proportional to the dose reservoir. For the 25-, 50-, 100-, 200-, and 300-μg reservoir doses, the maximum median plasma concentrations were 6.4, 11.3, 21.7, 40.8, and 74.2 pg/mL, respectively, and the area under the curve until drug removal was 39, 117, 223, 269, and 477 pg h/mL. Regardless of dose, the peak plasma concentration occurred at approximately 7 hours after insertion and the elimination half-life of the misoprostol acid was 0.55 hours (95% confidence interval, 0.36 to 1.32 hours). CONCLUSIONS: Misoprostol is released from the vaginal insert in a controlled manner and is eliminated rapidly after removal. Pharmacokinetic parameters are proportional to the reservoir dose.

WX-UK1, a multi-serine protease inhibitor, was believed to function primarily as a synthetic small-molecule inhibitor of urokinase (uPA). We now reveal that WX-UK1 is a potent and rather specific inhibitor of human trypsin-2 and human trypsin-3, and propose that these new molecular targets offer potential for new indications in oncology and other diseases. Initially, we performed a bioinformatic analysis of the ~200 human trypsin-like serine proteases, most of which play crucial roles in homeostasis and disease. Among these we selected a subset for biochemical analysis based on an inspection of modeled 3D structures of WX-UK1:protease complexes and sequence alignment of binding site residues. Samples of the selected proteases were prepared and characterized biochemically with respect to inhibitory constant (Ki) of inhibition by WX-UK1-1 and dissociation constant (Kd). The Ki values were determined from enzymatic activity assays (37°C), and Kd values (affinity) by surface plasmon resonance (BIACORE) (25°C). Serine protease(human)Ki (nM)Mean ± SD (n)Kd (nM)Mean ± SD (n)Urokinase (uPA)874 ± 95 (3)720 ± 300 (3)Trypsin(-1)190 ± 10 (6)74 ± 18 (3)Trypsin-275 ± 3 (6)N.D.Trypsin-319 ± 4 (6)6 ± 4 (11) While previously described as an inhibitor of bovine trypsin, we now show WX-UK1 to be a specific competitive inhibitor of both human trypsin-2 and human trypsin-3 with Ki of 75 and 19 nM, respectively. With a Kd of 6 nM, WX-UK-1 binds human trypsin-3 with a >100-fold binding specificity relative to most other trypsin-like serine proteases tested so far, including uPA, and 10-fold over the classical human trypsin. WX-UK1 (and its oral prodrug, upamostat) was originally developed as an inhibitor of uPA and other members of the S1 family of trypsin-like serine proteases, essential to aspects of tissue remodeling associated with tumor invasion and metastasis. However, with the identification of human trypsin-3 and human trypsin-2 as high-affinity molecular targets, new disease indications on top of oncology indications may be feasible. As a low-nanomolar inhibitor of human trypsin-3, WX-UK1 may have potential utility in the treatment of inflammatory digestive diseases, including irritable bowel syndrome, inflammatory bowel disease, and pancreatitis, for the latter of which there are currently no approved therapies. Furthermore, WX-UK1, as a human trypsin-2 inhibitor, could potentially be used in the treatment of inflammatory lung diseases, including acute respiratory distress syndrome, acute lung injury, α-1 antitrypsin deficiency, and chronic obstructive pulmonary disease (COPD)–a major unmet medical need. Citation Format: Emil Oldenberg, Christine R. Schar, Eva L. Lange, Terry F. Plasse, Danielle T. Abramson, Mark L. Levitt, Reza Fathi, Jan K. Jensen. New potential therapeutic applications of WX-UK1 as a specific and potent inhibitor of human trypsin-2 and human trypsin-3 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B055.

We studied the effects of long-term (12 months) dronabinol in 94 late-stage acquired immunodeficiency syndrome (AIDS) patients (mean CD4 count of 45/mm3) who previously participated in a 6-week study (placebo versus dronabinol). All patients received dronabinol orally-2.5 mg twice daily (90%) or 2.5 mg once daily (10%). Appetite was measured using a visual analogue scale for hunger (VASH). Dronabinol was associated with consistent improvement in mean appetite. Patients previously treated with dronabinol continued to show improvement in VASH (percent change from baseline of 6-week trial: 48.6-76.1% at each month), whereas those previously treated with placebo exhibited substantial improvement in mean appetite, particularly during the initial 4 months of treatment (48.5-69.9%). Thereafter, dronabinol was associated with a VASH change at least twice baseline. Patients tended toward stable body weight for at least 7 months. Adverse events were primarily related to known central nervous system effects of dronabinol. These data support long-term, safe use of dronabinol for anorexia associated with weight loss in patients with AIDS.

The effects of dronabinol on appetite and weight were evaluated in 139 patients with AIDS-related anorexia and > or = 2.3 kg weight loss in a multi-institutional study. Patients were randomized to receive 2.5 mg dronabinol twice daily or placebo. Patients rated appetite, mood, and nausea by using a 100-mm visual analogue scale 3 days weekly. Efficacy was evaluable in 88 patients. Dronabinol was associated with increased appetite above baseline (38% vs 8% for placebo, P = 0.015), improvement in mood (10% vs -2%, P = 0.06), and decreased nausea (20% vs 7%; P = 0.05). Weight was stable in dronabinol patients, while placebo recipients had a mean loss of 0.4 kg (P = 0.14). Of the dronabinol patients, 22% gained > or = 2 kg, compared with 10.5% of placebo recipients (P = 0.11). Side effects were mostly mild to moderate in severity (euphoria, dizziness, thinking abnormalities); there was no difference in discontinued therapy between dronabinol (8.3%) and placebo (4.5%) recipients. Dronabinol was found to be safe and effective for anorexia associated with weight loss in patients with AIDS.

OBJECTIVE:To examine the effect of dronabinol (delta-9-tetrahydrocannabinol) on appetite and nutritional status in patients with symptomatic HIV infection and weight loss.DESIGN:Double-blind, randomized, placebo-controlled, crossover trial with two five-week treatment periods separated by a two-week washout period. Patients received dronabinol 5 mg twice daily before meals or placebo.SETTING:A university-based HIV/AIDS clinic and a large infectious disease private practice largely devoted to care of patients with HIV.PARTICIPANTS:Twelve HIV-infected patients who had had at least a 2.25-kg weight loss participated in the study. Five patients completed the protocol, and seven withdrew (two because of drug intolerance, two because of disease progression, two because of noncompliance, and one because of experimental antiretroviral therapy).MAIN OUTCOME MEASURES:Main outcome measures included caloric intake, weight, percent body fat, serum prealbumin, and symptom distress.RESULTS:During dronabinol treatment, subjects experienced increased percent body fat (one percent, p=0.04); decreased symptom distress (p=0.04); and trends toward weight gain (0.5 kg, p=0.13), increased prealbumin (29.0 mg/L, p=0.11), and improved appetite score (p=0.14).CONCLUSIONS:In a selected group of HIV-infected patients with weight loss, short-term treatment with dronabinol may result in improvement in nutritional status and symptom distress.

Topical recombinant alpha-2 interferon treatment of recurrent genital herpes was studied in a randomized, double-blind, placebo controlled clinical trial. Three hundred and eighty-seven patients were treated at eight study centers with either interferon gel or placebo four times daily for four days. Interferon therapy caused a 26% decrease in the duration of viral shedding. For male patients, there were also significant decreases in the time to crusting (17%) and duration of pain (34%) and itching (21%). For patients with recurrent genital herpes, treatment with topical interferon was found to be effective in decreasing the duration of viral shedding and, for males, pain, itching and time to crusting.

Dronabinol, delta-9-tetrahydrocannabinol in sesame oil, has been used for several years as an antiemetic for patients receiving cancer chemotherapy. In combination studies with prochlorperazine, enhancement of efficacy, as measured by duration of episodes of nausea and vomiting and by severity of nausea, has been found. The incidence of psychotropic effects from dronabinol appears to be decreased by concomitant administration of prochlorperazine. In open pilot studies, dronabinol caused weight gain in seven of ten patients with symptomatic HIV infection. In both HIV and cancer patients, dronabinol improved appetite at a dose which was well tolerated for chronic administration.

Dronabinol (Marinol, Roxane Laboratories, Columbus, OH) and prochlorperazine were tested alone and in combination in a randomized, double-blind, parallel group, multicenter study. Patients were randomized to receive either 1) dronabinol 10 mg every 6 hr plus placebo; 2) placebo plus prochlorperazine 10 mg every 6 hr; or 3) dronabinol and prochlorperazine, each 10 mg every 6 hr. Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy; all was given orally. Only 29% of patients in group 3 versus 47% in group 1 and 60% in group 2 experienced nausea after chemotherapy. In addition, the median duration per episode and severity of nausea were significantly less with combination therapy. Vomiting occurred after chemotherapy in 41%, 55%, and 35% of patients in groups 1, 2, and 3, respectively. The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2. Side effects, primarily CNS, were more common in group 1 than in group 2; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent. The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting.

Nineteen patients receiving cancer chemotherapy were randomized in a double-blind fashion to receive either (a) dronabinol, 10 mg plus placebo q.i.d.; (b) prochlorperazine, 10 mg plus placebo q.i.d.; or (c) dronabinol plus prochlorperazine, each 10 mg q.i.d. There were six evaluable patients in each of the two single-agent groups and five in the combination group. The median duration and severity per episode of nausea was significantly greater in the group receiving prochlorperazine alone versus the other two groups. The median duration per episode of vomiting was also significantly greater in the prochlorperazine group than in the other two groups. The proportion of patients vomiting was the same in all groups; however, only one patient in the combination group versus three each in the single-agent groups experienced nausea (p = NS). The majority of side effects were associated with the CNS, including somnolence, dizziness, and confusion. Side effects were somewhat more common in both groups receiving dronabinol, though they were not statistically different from the side effects in the group receiving prochlorperazine as a single agent. Efficacy, as measured by duration of nausea and vomiting and by severity of nausea, was significantly greater in both groups receiving dronabinol.

Objective The purpose of this study was to identify the maximum tolerable dose and to determine the efficacy of different misoprostol dose reservoirs in an intravaginal controlled-release hydrogel polymer. Study design Nulliparous women at ≥37 weeks' gestation requiring cervical ripening and induction of labor were treated with misoprostol in a controlled-release, retrievable hydrogel polymer vaginal insert. Sequential cohorts of 6 patients were to be treated with escalating dose reservoirs of 25, 50, 100, 200, and 300 μg. The insert was to be removed upon onset of active labor, at 24 hours, or earlier if treatment-related adverse events occurred. The safety end point was determination of the maximum tolerable dose (MTD) based on occurrence of hyperstimulation syndrome. Our primary efficacy end point was time to vaginal delivery. Results Increasing reservoir doses of misoprostol up to 100 μg produced more rapid increases in modified Bishop scores, less need for oxytocin, and a shorter time to vaginal delivery. Doses above 100 μg did not further enhance cervical ripening or shorten time to vaginal delivery. The median time to vaginal delivery was 14.2 hours using the 100 μg dose. Uterine hyperstimulation and adverse fetal heart rate effects occurred with the 200 and 300 μg inserts. Conclusion The 100 μg vaginal insert resulted in successful cervical ripening and rapid vaginal delivery with an acceptable safety profile for future randomized clinical trials.

To the Editor.— Pressure sores, or decubitus ulcers, are a major cause of morbidity in elderly patients with impaired mobility. Occlusive and semiocclusive dressings have been found to enhance healing.1One of the most widely used of the latter is the hydrocolloid dressing (DuoDERM2, Conva-Tec Division, ER Squibb & Sons, Princeton, NJ). Polyhydroxyethyl methacrylate (poly-hema) dissolved in polyethylene glycol (Hydron Wound Dressing, Acme/Chaston Division, National Patient Development Corp, Dayville, Conn), initially used to treat burns3has also been applied to treatment of decubiti. We compared the safety and efficacy of the two products on treatment of pressure sores in patients at an academic skilled nursing facility caring for an elderly population, the Parker Jewish Geriatric Institute, New Hyde Park, NY. Patients were eligible for the study if they had stage 2 (inflammatory reaction extending through the dermis) or stage 3 (ulceration extending into the subcutaneous fat) pressure

Concurrent Cloning Efficiencies (CE) of both ascites and solid tumor samples from 36 patients with ovarian carcinoma were studied using the soft agar assay. The CE of both were highly variable (range, 0-1.234% and 0-0.802%, respectively). There was marked intrapatient and interpatient heterogeneity in the CE. Of the 36 tested, comparative CE were evaluable in 29. CE was 0 in both solid tumor and ascites in one patient. CE was 0 in four other ascites samples from four patients. In other 24, the relative CE of solid tumor/ascites from each patient ranged from 0.066 to 435. In the 29 patients with samples of ascites and a solid tumor evaluable for concurrent CE, the median colony counts of solid tumors was more than tenfold higher than ascites. The solid tumors obtained from 31 patients had a significantly higher CE than tumor cells obtained from ascites samples from 32 patients. Solid tumors were significantly better than ascites for in vitro testing based on the data that 75% (27/36) of solid tumors and only 31% (11/36) of ascites formed greater than or equal to 30 colonies. The drug sensitivity profiles of tumor cells from a solid tumor and ascites of the same patient appear similar. Based on these observations, it may be more cost and labor effective to do soft agar in vitro chemotherapy assays using a solid tumor than ascites in ovarian carcinoma.

Author(s): Salmon, SE; Alberts, DS; Meyskens, FL; Moon, TE; Aapro, MS; Eliason, JR; Umbach, GE; Spitzer, G; Hug, V; Atkinson, EN; Plasse, TF; Weisenthal, LM; Balk, S; Selby, P; Buick, R; Tannock, I | Abstract: To the Editor: Since our group first reported on the potential clinical applications of the human tumor stem-cell, or clonogenic, assay in the Journal,1 we think some comment from us is warranted regarding the recent article by Selby et al.2 and the editorial by Von Hoff.3 We clearly agree that it is important to plate good single-cell suspensions, that drug-sensitivity criteria are still in the developmental stages,4 that some drugs may require the evaluation of various exposure times, that inappropriate drug concentrations may be misleading, that drugs requiring bioactivation present special problems, that radiation-survival curves with plateaus at. © 1983, Massachusetts Medical Society. All rights reserved.

Fifty-seven adult patients receiving chemotherapy were treated with a total of 133 infusions using portable user-worn infusion pumps, the Autosyringe AS*2F, Cormed ML6-4, and two earlier versions of the latter, the Sigmamotor ML6-2 and ML6-3. Ninety-eight infusions were given on an ambulatory basis. Fourteen infusions were given through peripheral venous catheters, 115 through central venous catheters, and four intra-arterially. Of 127 evaluable infusions, 65 were completed within 5% and 87 within 10% of the planned rate; results are similar for both inpatient and outpatient infusions. The Cormed ML6-4 pump was equal to the Autosyringe AS*2F in reliability but superior to the latter in patient preference. There were no instances of dangerously rapid administration of the drug. The only serious catheter complications were a pneumothorax after insertion of a subclavian catheter in one patient and cellulitis in a leukopenic patient with a Broviac catheter. All but three patients preferred outpatient therapy to hospitalization. Outpatient therapy costs about $300 per day less than in-hospital treatment. Cancer 50:27-31, 1982.

Twenty-seven patients with squamous cell carcinoma of the head and neck were treated with bleomycin 7.5 U/m2/day continuous infusion X 3 days (days 1-4, 8-11), followed by cyclophosphamide 300 mg/ in2, methotrexate 30 mg/m2 and 5-fluorouracil 300 mg/m2 on days 5 and 12 (bleo-CMF). Treatment was repeated every 28 days. All but two had a performance status of 0-2 and all but 3 patients had received prior surgery, radiotherapy, and/or chemotherapy. Of 24 evaluable patients, 1 had a complete remission (1.9 months) and 4 had partial remissions (3.7,3.9,3.9,4.1 months, respectively) for an overall response rate of 21%. If one excludes 7 patients with prior chemotherapy, the response rate is 5 of 17 (29%). All responders had received both radiotherapy and surgery. The median survival was 4.4 months for the responders and 3.5 months for the nonresponders. Marked hematologic toxicity occurred in eight patients, and contributed to the death of two. Severe pulmonary toxicity occurred in two patients and caused the death of one. Bleo-CMF did not produce a higher response rate than historical single-agent trials and caused significant toxicity. Furthermore, there was no important difference in the survival of responders and nonresponders. Cuncer 53:841-843, 1984. DVANCED SQUAMOUS CELL carcinoma of the head