Palatin Technologies (United States)

Wettability and fluid transport mechanisms in unconventional rocks have been a matter of continued debate, with broad implications on oil production from these reservoirs. The presence of microstructural heterogeneities makes the characterization of these rocks complicated. In this paper, the fluid transport properties in a tight sandstone and a silicaceous microfractured mudstone from the Permian Basin are quantified through spatial NMR imaging experiments on spontaneous imbibition of dodecane and water. The tight sandstone sample has a relatively homogeneous pore structure with mixed-wet pores and wettability features similar to conventional sandstones, leading to fluid transport governed by the fractional flow model. In contrast, the mudstone sample has bedding-parallel microfractures that are oil-wet due to the presence of organic matter, while the rock matrix is mixed-wet. The presence of these microfractures leads to nontrivial fluid transport features that require more advanced analysis. The microfractures enhance the transport of hydrocarbon fluids into the matrix by facilitating their movement along bedding planes. Hydrocarbon imbibition occurs along bedding planes, as well as normal to bedding planes from oil-wet microfractures to the matrix. In contrast, a similar transport normal to the bedding planes is not observed for water imbibition. Finally, transport rates along bedding planes are higher, implying anisotropy in transport parallel and perpendicular to the bedding planes.

Introduction: The effect of PL8177, a melanocortin 1 receptor-specific agonist, on inflammation, cell population composition, and gene and protein expression was investigated in colons from a dextran sulfate sodium (DSS)–induced rat model of colitis. Methods: Colitis was induced by 5% DSS in drinking water. Rats received vehicle control (placebo) capsules, oral PL8177 capsules (20, 50, and 100 μg per animal), or mesalazine (positive control). Colons were harvested on day 8. Samples were analyzed for cytokines, and by single nuclei RNA-seq and data-independent acquisition tandem mass spectrometry. Colitis was assessed by diarrhea and rectal bleeding, colon length shortening, colon weight gain, and histopathology. Total colitis index assessed inflammatory damage. Results: PL8177 50 μg showed a significant (P< 0.05) improvement in colon weight (53% reduction), stool consistency, and fecal occult blood score vs vehicle, and there was significant improvement in the total colitis index for the PL8177 100-μg group vs vehicle. All PL8177 cohorts showed greater improvement in the total colitis index than mesalazine. Mesalazine produced a marked reduction in colon length, but only moderate improvement (35%) in colon weight. Single nuclei RNA-seq showed that in the PL8177 100-µg group, relative cell populations and key gene expression levels were closer to those of healthy controls. Subclustering analysis revealed significant differences between PL8177 100-µg and vehicle populations. Although both showed the presence of macrophages, vehicle-treated colons were primarily M1 macrophages involved in inflammation. In PL8177 100 µg–treated colons, macrophages were primarily pro-resolution M2. Proteomic analysis showed that PL8177-treated colons are more similar to sham colons than to vehicle colons. Also after treatment with PL8177, a protein known to promote intestinal homeostasis and a blood-based biomarker protein showed expression similar to that seen in the sham group, a result not seen in vehicle-treated colons. Conclusion: Oral PL8177 treatment showed significant improvement in anatomical markers of colitis vs the vehicle and mesalazine control groups, supporting the aim of treating inflammatory bowel disease (IBD). Transcriptomics and proteomics data show that oral PL8177 treatment causes diseased colons to move toward the healthy state and to resolve inflammation. Resolving inflammation—rather than blocking it—provides the possibility of efficacy coupled with safety in treating IBD.

IntroductionPL8177 is a potent and selective agonist of the melanocortin 1 receptor (MC1R). PL8177 has shown efficacy in reversing intestinal inflammation in a cannulated rat ulcerative colitis model. To facilitate oral delivery, a novel, polymer-encapsulated formulation of PL8177 was developed. This formulation was tested in 2 rat ulcerative colitis models and evaluated for distribution, in vivo, in rats, dogs, and humans. MethodsThe rat models of colitis were induced by treatment with 2,4-dinitrobenzenesulfonic acid or dextran sulfate sodium. Single nuclei RNA sequencing of colon tissues was performed to characterize the mechanism of action. The distribution and concentration of PL8177 and the main metabolite within the GI tract after a single oral dose of PL8177 was investigated in rats and dogs. A phase 0 clinical study using a single microdose (70 µg) of [14C]-labeled PL8177 investigated the release of PL8177 in the colon of healthy men after oral administration.ResultsRats treated with 50 µg oral PL8177 demonstrated significantly lower macroscopic colon damage scores and improvement in colon weight, stool consistency, and fecal occult blood vs the vehicle without active drug. Histopathology analysis resulted in the maintenance of intact colon structure and barrier, reduced immune cell infiltration, and increased enterocytes with PL8177 treatment. Transcriptome data show that oral PL8177 50 µg treatment causes relative cell populations and key gene expressions levels to move closer to healthy controls. Compared with vehicle, treated colon samples show negative enrichment of immune marker genes and diverse immune-related pathways. In rats and dogs, orally administered PL8177 was detected at higher amounts in the colon vs upper GI tract. [14C]-PL8177 and the main metabolite were detected in the feces but not in the plasma and urine in humans. This suggests that the parent drug [14C]-PL8177 was released from the polymer formulation and metabolized within the GI tract, where it would be expected to exert its effect. ConclusionCollectively, these findings support further research into the oral formulation of PL8177 as a possible therapeutic for GI inflammatory diseases in humans.

Introduction: Melanocortin-1 receptors (MC1Rs), found in many tissues including the colon, promote the resolution of inflammation. High potency and no detected systemic absorption make the MC1R agonist PL8177 a promising candidate for oral gut restricted ulcerative colitis (UC) treatment. Methods: Oral PL8177 capsules were tested in 2 rat UC models and evaluated for distribution, in vivo, in rats, dogs, and humans. UC was induced in rats by dinitrobenzene sulfonic acid (DNBS) or dextran sulfate sodium (DSS). BID doses of 10, 20, 50, 100 or 200 µg PL8177 were compared with vehicle control (placebo) in DNBS and DSS rats. Colitis was assessed by diarrhea and rectal bleeding, and by changes in colon length and weight, and histopathological assessment on termination. Distribution of PL8177 within the GI tract after a single PL8177 dose was investigated in rats and dogs. A phase 0 study using a single oral microdose (70 µg) of [14C]-labeled PL8177 investigated the release of PL8177 in the colon of healthy men. A phase 2 double-blind, placebo-controlled, study will evaluate the safety, tolerability and efficacy of oral PL8177 in adults with UC. Results: Rats treated with 10-200 µg oral PL8177 demonstrated lower macroscopic colon damage scores and improvement in colon weight, stool consistency, and fecal occult blood vs the vehicle. Histopathology analysis showed PL8177 treatment resulted in the maintenance of intact colon structure and barrier, and reduced immune cell infiltration. In rats and dogs, PL8177 was detected at higher amounts in the colon vs upper GI tract. [14C]-PL8177 and the main metabolite were not detected in human plasma and urine, suggesting that the parent drug [14C]PL8177 was released from the polymer formulation and metabolized within the GI tract. The most efficacious doses (P< 0.05 vs vehicle) in the rat studies were 20 and 50 µg, which provide the basis for estimating suitable doses for the phase 2 trial. Colonic surface area for humans is ∼3,000 greater than rat. Considering species-specific MC1R receptor sensitivity differences and other variables, such as GI transit time, pH, and proteolytic enzyme activity, a dose of 20 mg/day was estimated to be the best choice for observation of efficacy in the phase 2 trial. Conclusion: Collectively, these findings support further development of PL8177 as a treatment option for GI inflammatory diseases in humans. This will be further examined in the phase 2 trial in humans with UC.

Background and ObjectivePL8177 is a selective melanocortin 1 receptor agonist in development for the treatment of various immunologic and inflammatory conditions. Here we describe the pharmacokinetics of PL8177 after subcutaneous (sc) delivery in animals and humans.MethodsMice, rats, and dogs were administered sc PL8177 at single doses of 1.0 and 3.0 mg/kg (mice); 1.0, 5.0, and 25.0 mg/kg/day (rats); or 1.5, 8.0, and 40.0 mg/day (dogs). Blood was collected over 24 h (mice) or 28 days (rats and dogs). Safety and pharmacokinetics of single and multiple sc doses were also examined in human volunteers. Two dose levels were tested in two dosing cohorts of 1.0 and 3.0 mg/day for 7 days. Blood samples were collected through Day 1 and on Days 2 to 6 at peak and trough times based on analysis of the first two single-dose cohorts.ResultsIn mice, 3 mg/kg PL8177 resulted in an area under the plasma concentration–time curve from 0 to infinity (AUC∞) of 1727 ng·h/mL, a maximum plasma concentration (Cmax) of 2440 ng/mL, an elimination half-life (t½) of 0.5 h, and a time to maximum concentration (tmax) of 0.25 h. Results for the 1-mg/kg dose were generally proportional. In rats, mean tmax values were independent of dose and ranged from 0.25 to 1.0 h for single and multiple dosing. Cmax values ranged from 516 to 695 ng/mL (1-mg/kg dose) and from 666 to 1180 ng/mL (25-mg/kg dose). In dogs, mean tmax values ranged from 0.4 to 1.3 h for single and multiple dosing. Values for tmax decreased with increasing dose and mean plasma Cmax increased less than dose proportionally (96–129 ng·h/mL [1.5 mg], 275–615 ng·h/mL [8.0 mg], and 633–1280 ng·h/mL [40.0 mg]). In humans, PL8177 was observed in the plasma within 15 min after a single dose and persisted for up to 48 h at higher doses. The tmax was 30–45 min (single dose) and 15–45 min (multiple doses). In multiple-dose studies, maximum steady-state plasma concentration (Cmax,ss) and AUC∞ increased with dose. Geometric mean Cmax,ss values were 20.1 ng/mL (1.0 mg) and 57.2 ng/mL (3.0 mg). AUC∞ values were 54.3 ng·h/mL (1.0 mg) and 199 ng·h/mL (3.0 mg). Unchanged PL8177 excreted in the urine was ≤ 1%, and accumulation was minimal.ConclusionPL8177 administration resulted in a consistent pharmacokinetic profile. The measured exposure levels resulted in pharmacologically active PL8177 concentrations at the targeted MC1R. Rapid absorption was seen in healthy volunteers, and multiple-dose administration over 7 days resulted in pharmacokinetic characteristics similar to those observed after single-dose administration. Results support the continued development of PL8177 to treat immunologic and inflammatory conditions.

BackgroundThe Elements of Desire Questionnaire (EDQ) is a patient-reported outcome (PRO) measure developed to evaluate sexual desire and was included in two identically designed phase 3 clinical trials (RECONNECT) as an exploratory endpoint. The EDQ was developed based on a literature review, qualitative research with patients with hypoactive sexual desire disorder (HSDD), and input from clinical experts. This instrument is intended to be used to collect efficacy data in clinical trials evaluating potential treatments for HSDD. The objective of this study was to evaluate the measurement properties of both the monthly and daily recall versions of the EDQ during the RECONNECT trials.MethodsParticipants completed the EDQ daily version for 7 consecutive days prior to selected monthly clinic visits. The monthly recall version was completed at each monthly clinic visit. The analysis population consisted of all subjects with Female Sexual Function Index (FSFI) data at baseline and ≥ 1 follow-up visit.ResultsAt baseline, 1144 and 676 subjects completed the monthly and daily recall EDQs, respectively. The EDQ scores had good internal consistency and test-retest reliability. Monthly and daily recall EDQ scores were correlated with FSFI-desire domain scores at baseline and month 3. Scores from the monthly and daily recall versions were also correlated. After 6 months, there was a significantly greater improvement for bremelanotide versus placebo in both the monthly and daily recall versions (both P < 0.0001).ConclusionsThe results demonstrated that EDQ exhibited good reliability, validity, and sensitivity to change. Consistent with other validated PRO measures of sexual desire, the EDQ provides additional insights into sexual desire.Trial registrationNCT02338960 and NCT02333071 (RECONNECT studies).

Business rule management is the task of storing and maintaining company-specific decision rules and business logic that is queried frequently by application users. These rules can impede efficient query processing when they require the business rule engine to resolve semantic hierarchies. To address this problem, this work discusses hierarchical indexes that are performance and storage-conscious. In the first part of this work, we develop a tree-based hierarchical structure that represents client-defined semantic hierarchies as well as two variants of this structure that improve performance and main memory allocation. The second part of our work focuses on selecting the top rules out of those retrieved from the index. We formally define a priority score-based decision scheme that allows for a conflict-free rule system and efficient rule ranking. Additionally, we introduce a weight-based lazy merging technique for rule selection. All of these techniques are evaluated with real world and synthetic data sets.