Upamostat: a serine protease inhibitor for antiviral, gastrointestinal, and anticancer indications.

INTRODUCTION: Serine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases and oncology. Upamostat is an orally bioavailable prodrug of WX-UK1, which is most active against trypsins and closely related enzymes. AREAS COVERED: Research over the past two decades suggests several diseases in the three areas noted above which upamostat may be active. Upamostat has been studied clinically against several cancers and for outpatient treatment of COVID-19. Preclinical and clinical pharmacokinetic and metabolism studies demonstrate good bioavailability, sustained tissue levels, and high concentrations of the active moiety, WX-UK1, in stool, potentially important for treatment of gastrointestinal diseases. Clinical studies suggest activity against SARS-CoV-2; results against pancreatic cancer are also encouraging, though studies in both indications are not definitive. The drug was very well tolerated for periods of 2 weeks to several months. EXPERT OPINION: Upamostat is an orally bioavailable serine protease inhibitor with an excellent safety profile and favorable pharmacokinetic properties. It has demonstrated preliminary evidence of efficacy against COVID-19, and nonclinical data suggest potential applicability against other viral illnesses, gastrointestinal diseases, and cancer.

Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia.

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.

Dronabinol as a treatment 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.

Effect of dronabinol on nutritional status in HIV infection.

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.

Recent clinical experience with dronabinol.

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.

1,25-Dihydroxyvitamin D3 receptors in human carcinomas: a pilot study.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] receptor concentration was measured by an accurate immunoradiometric assay in primary tumors from 10 patients with colorectal carcinoma and 11 patients with non-small cell carcinoma of the lung. Measurements were also performed on a noncancerous sample of the same origin as the tumor from each patient. All of the tumors contained receptor with a mean concentration of 123.4 fmol/mg protein for colorectal and 75.1 fmol/mg protein for lung carcinoma. Compared to normal tissue from the same patient, 100% of the lung tumors and 70% of the colorectal tumors had significantly higher levels of the 1,25-dihydroxyvitamin D3 receptor. A correlation was found between well-differentiated colorectal tumors with no or few metastases and high levels of 1,25-dihydroxyvitamin D3 receptor. Receptor concentration was also assayed in metastatic lesions of malignant melanoma from 7 patients. 1,25-Dihydroxyvitamin D3 receptor was present in 85% of the metastases at a mean level of 26 fmol/mg protein. For these patients an inverse correlation was found between receptor level and age. The results obtained in this pilot study suggest that an alteration in 1,25-dihydroxyvitamin D3 receptor regulation may occur in vivo when a cell undergoes malignant transformation.

Dronabinol and prochlorperazine alone and in combination as antiemetic agents for cancer chemotherapy.

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.

Simultaneous soft agar cloning of ascites and solid tumor specimens from patients with ovarian cancer.

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.

Natural interferon alfa for treatment of condylomata acuminata.

The activity of natural (leukocyte) interferon alfa in the treatment of condylomata acuminata was assessed in a randomized, double-blind, placebo-controlled, multicenter trial. Interferon alfa (Alferon N Injection) or placebo was injected into lesions twice weekly for up to eight weeks. Eighty-six patients were given interferon alfa, and 72 were given placebo. Eighty-six percent of interferon alfa-treated patients and 89% of placebo-treated patients had received previous therapy for condylomata acuminata. Side effects, usually flulike symptoms, occurred briefly after the injections; if present, they disappeared before the end of the third week of therapy. Treatment completely eliminated warts in 62% of interferon alfa-treated patients compared with only 21% of placebo-treated patients. Natural interferon alfa given intralesionally is an effective and safe treatment even in patients with recurrent or recalcitrant genital warts.

Bleomycin infusion followed by cyclophosphamide, methotrexate, and 5-fluorouracil in advanced squamous carcinoma of the head and neck.

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/m2, 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.

Effects of physiological oxygen concentration on human tumor colony growth in soft agar.

Cloning efficiencies of 67 fresh human tumor specimens, consisting of 29 ovarian, 10 lung, and 7 each of colon, breast, mesenchymal, and miscellaneous tumors, from 58 patients were studied using the technique of Hamburger and Salmon to evaluate the effect of incubation in a 5% rather than 20% oxygen environment. Under the low-oxygen tension, carcinomas exhibited an average of 170% increase in cloning efficiency (p less than 0.01). The number of carcinomas forming at least 30 colonies/dish increased from 22 to 27. Mesenchymal tumors, however, exhibited a 20% decrease in cloning efficiency (not significant). A mixture of 5% oxygen, 5% carbon dioxide, and 90% nitrogen gives a higher cloning efficiency than 20% oxygen, 5% carbon dioxide, and 75% nitrogen for certain human carcinomas in semisolid agar.