Craving likely represents a more proximal determinant of alcohol use than stimulation and sedation, which are shown to indirectly influence alcohol self-administration through craving . An additional exploratory aim was to test whether a characteristic of AUD severity, withdrawal-related dysphoria, moderated ibudilast’s effects on daily alcohol-induced changes in mood and craving. Notably, we found that individuals without a reported history of withdrawal-related dysphoria who were treated with ibudilast showed attenuation of alcohol-induced changes in craving, urge, and positive mood when compared to placebo. This tempering of alcohol’s effects may reflect ibudilast’s enhancement of antiinflammatory and neurotrophic factors suspected to impact dopaminergic signaling in rewards regions, such as the nucleus accumbens, where PDE4 and PDE10 are highly expressed . However, individuals who endorsed this withdrawal-dysphoric profile did not appear to benefit from treatment via this mechanism, such that ibudilast did not significantly blunt acute rewarding and reinforcing effects of alcohol. Although intriguing, these moderation findings should be interpreted with caution given the limited sample size, particularly the subgroup of individuals reporting experiences with withdrawal-related dysphoria . Despite these findings, preliminary analyses from this two-week RCT show that withdrawal dysphoria did not moderate clinical response to ibudilast regarding rates of heavy drinking or drinks per drinking day. Notably, these subjective response results are somewhat in contrast to what might be expected for individuals with a history of withdrawal and experiencing the “dark side of addiction”,cannabis indoor grow system such that these individuals may potentially show greater dysfunction of the immune system and thus may be predicted to have better response to an anti-inflammatory treatment, such as ibudilast.
However, it is suspected that other mechanisms may be central to the maintenance of AUD among individuals with withdrawal dysphoria, beyond the enhancing effects of alcohol. Namely, these individuals may primarily drink to feel ‘normal’ and alleviate physiological or psychological distress, particularly during early abstinence , which was not the focus on the current study. The present findings also differ somewhat from our laboratory’s initial efficacy trial of ibudilast, in which individuals with higher levels of depression showed attenuation of alcohol-induced increases in positive mood and ‘wanting’ during intravenous alcohol administration . A relevant difference between these studies is that participants enrolled in the efficacy trial were likely in a state of early abstinence, as they were asked to refrain from drinking for safety reasons; yet those enrolled in the present trial were not asked to change their drinking behaviors and consumed alcohol on roughly 60% of trial days and around 6 DPDD on average. In preclinical models, withdrawal increases the expression of innate immune markers in brain regions regulating autonomic and emotional states and while speculative, may thus represent a unique condition with the potential to impact ibudilast’s therapeutic effects. For instance, ibudilast reduced opioid withdrawal symptoms among individuals with heroin dependence and another PDE4 inhibitor, rolipram, diminished withdrawal-induced behaviors indicative of negative affect in rodents . Future research evaluating the impact of withdrawal states on immune signaling in larger clinical samples is needed to advance understanding of these complex processes and immune intervention. These findings should be considered in the context of the study’s strengths and limitations. One limitation is that DDAs were reported retrospectively once daily, which is less temporally accurate than EMA designs.
As such, items on subjective response and drinking were reported by participants concurrently the morning following a drinking episode and did not capture one’s subjective response level at a specific BrAC or blood alcohol curve limb. As such, this weakens our ability to draw a causal link between the effect of subjective response on alcohol intake and may introduce recall bias. Next, participants with more non-drinking days and incomplete DDAs during the trial are suspected to have greater error variance in their data given the lower number of observations with subjective response data. The lack of daily pre-drinking data on stimulation and sedation prevented us from examiningdaily changes in these variables, such that we could not account for pre-drinking levels. The sample was comprised of non-treatment seeking individuals with moderate AUD on average and the majority did not fall in the withdrawal-related dysphoria category. Future work with ibudilast in more diverse and treatment-seeking samples with more significant experiences of withdrawal-related dysphoria is needed. This study’s strengths include a clinical AUD sample enrolled in a rigorous double-blind RCT testing a promising novel pharmacotherapy. This trial displayed strong medication adherence rates and tolerability. Further, DDAs had high completion rates and the data comprise a substantial number of drinking episodes . Morning reports are also less likely to be affected by the intoxicating effects of alcohol that may lend to reporting errors, as could be seen with EMA or nightly reports. Finally, to our knowledge, this is the first study on the effect of immune modulation on subjective alcohol response in the natural environment. In closing, this daily diary study complements findings from our previous reports of ibudilast treatment for AUD by examining medication effects on subjective response during real-world drinking episodes.
The nuanced nature of the findings, including the distinction among those with and without withdrawal-related dysphoria and within vs. between person subjective response effects, speak to the heterogeneity of AUD and dynamic mechanisms maintaining alcohol use. Ibudilast’s effects on subjective alcohol responses, such as positive mood and craving, appear to be nuanced and perhaps most salient for individuals drinking for positive reinforcement as opposed to normalizing. Treatment with ibudilast potentiated the within-person relations between stimulation/ sedation and alcohol intake in this trial, such that an individual’s quantity of consumption on a given day appears to be more tightly connected to subjective response. The ecologically valid nature of these DDA, through retrospective reports of past day drinking and subjective responses to alcohol, provide a clinically useful window into how individuals experience and recall alcohol’s effects while taking ibudilast, compared to placebo. Novel medications and novel biological targets call for careful assessment of mechanisms beyond the “usual suspects”, such as changes in mean levels of subjective response and alcohol craving. Ultimately, the combination of multiple scientific approaches, including human laboratory, DDAs, neuroimaging, and biomarker assessment, offer complementary and clinically useful findings that can inform the development of ibudilast, and immune treatments for AUD more broadly.In 2021, an estimated 66,570 women in the United States will be diagnosed with uterine cancer and 21,410 will be diagnosed with ovarian cancer.Within each of these diseases, the worst outcomes are among patients with the rarest forms: uterine carcinosarcoma and ovarian carcinosarcoma . Although only 5% of uterine cancers are UCS,this aggressive disease causes 15% of all uterine cancer deaths.Similarly, between 1% and 4% of ovarian cancers are OCS, and patients with OCS have a shorter 5-year survival than those with other ovarian cancers .In part, these poor outcomes are because these patients often present at a late stage. For example,cannabis equipment more than half of patients with UCS present with regional or distant metastases,and 5-year disease-free survival is shortest in those with the latest stage disease . Outcomes are often poor even in those diagnosed with early-stage UCS; more than 50% of such patients experience disease recurrence, leading to death.Standard treatment for patients with UCS and OCS is surgery , peritoneal washings, and retroperitoneal lymph node assessment.Developing and testing treatments for these diseases has been hampered, as historically, UCS was treated with other sarcomas. However, recent evidence indicates that the carcinomatous components dictate tumor behavior,and molecular studies demonstrated that the sarcomatous components are derived from the carcinomatous components through metaplastic transformation.Thus, in 2009, the International Federation of Gynecology and Obstetrics mandated that UCS should be staged as an endometrial carcinoma.A 2013 Cochrane review of both published and unpublished data from the large phase III trials in UCS evaluated the efficacy of adjuvant radiotherapy, paclitaxel and ifosfamide , cisplatin, ifosfamide, and mesna, or ifosfamide alone. The review concluded that patients in the PI and cisplatin, ifosfamide, and mesna arms had longer overall survival and progression-free survival than those in the radiotherapy or ifosfamide-alone arms, but those in the cisplatin, ifosfamide, and mesna arm experienced greater toxicity than those in the PI or ifosfamide-alone arms. Thus, PI was established as the evidence-driven standard for treating UCS.
However, this regimen has three important limitations. First, it is difficult to administer, requiring 3 days of infusion. Second, it requires the use of growth factor support. Third, it is associated with a greater risk for central neurologic toxicity than other chemotherapy regimens, especially for older patients. Paclitaxel and carboplatin has been a standard regimen for epithelial ovarian carcinoma since the late 1990s and became the standard for endometrial carcinomas with the results of GOG-209.This regimen has been evaluated in small studies of patients with both OCS and UCS. For example, among 28 patients with OCS treated with PC, 16 had a complete response and six had a partial response, and the median OS for all patients was 27 months. Thus, PC was recommended for all stages of OCS.GOG-0232 evaluated 55 patients with UCS treated with PC and found that 13% of patients had confirmed complete response and 41% had partial response. The total overall response rate was 54% , which compared favorably with earlier ifosfamide-based regimens for similar patients.Given the limitations of PI noted above, the efficacy of PC in ovarian carcinomas, and the findings of small studies evaluating PC in patients with OCS and UCS, PC could be a good alternative to PI. Here, we tested the null hypothesis that PC was inferior to PI for patients with all stages of UCS and OCS.The study accrued 637 women between August 17, 2009, and March 24, 2014, at 176 sites across the United States and Korea. As of February 18, 2019, the median follow-up time was 61 months. Ninety-eight patients deemed ineligible on central review were distributed equally across treatment arms as shown in the CONSORT diagram . Of all eligible patients enrolled, 24 were never treated and 20 withdrew consent to continuous follow-up. Of the 449 eligible patients enrolled with uterine primary disease , 21 were never treated with protocol-assigned treatment . Select patient and tumor characteristics of the patients with UCS are shown in Table 1, and additional details are given in Appendix Table A1 . For characteristics of the patients with OCS, see Appendix Table A2 . Most participants were between the age 50 and 79 years and non-Hispanic or White and had a stage I or III uterine primary disease. More than 60% of patients completed all planned treatment, and the median time on treatment was 16 weeks from random assignment. Thirteen percent of participants discontinued treatment because of progression, 9% refused some or all treatment, and 13% discontinued treatment early because of AEs or death. Similar numbers of cycles of therapy were given to eligible patients in both regimens; 69% received four-six cycles of PC, and 70% received four-six cycles of PI. Major protocol violations occurred more commonly in the PI arm than in the PC arm and were often due to the complex dosing adjustments required in response to nadir blood counts.This open-label, randomized, phase III therapeutic non-inferiority clinical trial shows that PC is not inferior to PI in terms of OS and PFS and significantly increases PFS duration for patients with UCS. Findings were similar but not statistically significant in the smaller OCS cohort. Overall, the toxicity and patient-reported quality-of-life profiles were similar for the two drug regimens. These results establish that PC should be used as a standard regimen for patients with UCS and should be considered for treating patients with OCS. These findings are important because PC is easier to administer than is PI. Moreover, patients with UCS could be considered for inclusion in clinical trials for patients with the more common epithelial sub-types of uterine cancer treated with PC. Similarly, it may be reasonable to combine OCS patients with other epithelial subtypes in ovarian cancer trials. Both UCS and OCS have significant racial and age disparities in risk and outcome. For example, UCS occurs up to three times more frequently in Black women than in White women, and this disparity appears to be increasing. In addition, carcinosarcomas are most common in older women; the mean age at diagnosis is 68 years.In part, this is because tamoxifen and previous radiation therapy are likely risk factors.