pasireotide and Liver-Diseases

Clinical trials have shown that in patients with polycystic liver disease (PLD), short-term treatment with somatostatin analogues (SAs) reduces liver volumes by 4.5%-5.9%, compared with placebo. However, the effects of SA therapy vary among individuals. We collected data from individual patients with PLD to identify subgroups that benefit most from SA therapy.. We analyzed data from 107 patients with PLD from 3 randomized placebo-controlled trials (67 received SAs, 52 received placebo). We used multiple linear regression analysis to determine the effects of SAs based on patients' age, sex, baseline liver volume, and diagnosis (autosomal dominant polycystic liver or kidney disease). The primary outcome was change in liver volume after 6-12 months of treatment.. The effects of SA therapy did not differ significantly among patients with different diagnoses or baseline liver volumes; the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001). Among subjects given placebo, young women (48 years old or younger) had the greatest increase in polycystic liver volume (4.8%; 95% confidence interval: 2.2%-7.4%), and mean liver volumes did not increase in older women and men. Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women (a reduction in liver volume of 4.1% compared with placebo; P = .022).. Based on a pooled analysis of data from individual patients with PLD, treatment with somatostatin analogues is equally effective for patients with autosomal dominant polycystic kidney disease or polycystic liver disease; efficacy does not depend on size of the polycystic liver. Young female patients appear to have the greatest benefit from 6-12 months of SA therapy, which might avert the progressive course of the disease in this specific group.

Topics: Adult; Aged; Cysts; Female; Humans; Linear Models; Liver; Liver Diseases; Male; Middle Aged; Octreotide; Organ Size; Peptides, Cyclic; Polycystic Kidney, Autosomal Dominant; Randomized Controlled Trials as Topic; Somatostatin; Treatment Outcome

To assess whether quantitative assessment of symptom reduction is a better outcome parameter than cyst volume reduction for treatment success in patients treated by aspiration sclerotherapy.. We included patients with symptomatic, large (> 5 cm), hepatic cysts from a randomized controlled trial (NCT02048319). At baseline and 6 months after treatment, symptoms were assessed with the polycystic liver disease questionnaire (PLD-Q) and we measured cyst volume using ultrasonography. Patient-reported change in health was assessed on a 5-point Likert scale (much worse to much better) after 6 months. We tested whether PLD-Q scores and cyst volumes changed after aspiration sclerotherapy (responsiveness). Changes in PLD-Q scores and cyst volume were compared with change in health as a measure of treatment success (discriminative ability). As secondary analysis, we compared baseline characteristics between responders (improved) and non-responders (not improved).. We included 32 patients. Six months after treatment, 23 patients (72%) improved. Both PLD-Q score and cyst volume significantly decreased (median 38 to 18 points, p < 0.001, and 479 to 68 mL, p < 0.001). Larger improvement in PLD-Q score was associated with a positive change in health (p = 0.001), while larger proportional reduction in cyst volume was not significantly associated with health improvement after treatment (p = 0.136). Responders had larger baseline cyst volumes compared to non-responders (median 624 mL [IQR 343-1023] vs. 322 mL [IQR 157-423] p = 0.008).. Cyst diameter reduction does not reflect treatment success in aspiration sclerotherapy from patients' perspective, while symptoms measured with the PLD-Q can be used as a reliable outcome measure.. • Cyst diameter reduction poorly reflects treatment success in aspiration sclerotherapy. • Symptoms measured by the polycystic liver disease questionnaire (PLD-Q) is a better outcome measure than cyst volume reduction for treatment success after aspiration sclerotherapy. • Particularly patients with larger cysts (≥ 529 mL) benefit from aspiration sclerotherapy.

Topics: Adult; Aged; Cysts; Double-Blind Method; Female; Humans; Liver Diseases; Male; Middle Aged; Patient Reported Outcome Measures; Sclerosing Solutions; Sclerotherapy; Somatostatin; Suction; Surveys and Questionnaires; Treatment Outcome; Ultrasonography, Interventional

We tested whether complementary use of the somatostatin analogue pasireotide would augment efficacy of aspiration sclerotherapy of hepatic cysts.. We conducted a double-blind, placebo-controlled trial in patients who underwent aspiration sclerotherapy of a large (>5 cm) symptomatic hepatic cyst. Patients were randomized to either intramuscular injections of pasireotide 60 mg long-acting release (n = 17) or placebo (sodium chloride 0.9 %, n = 17). Injections were administered 2 weeks before and 2 weeks after aspiration sclerotherapy. The primary endpoint was proportional cyst diameter reduction (%) from baseline to 6 weeks. Secondary outcomes included long-term cyst reduction at 26 weeks, patient-reported outcomes including the polycystic liver disease-questionnaire (PLD-Q) and safety.. Thirty-four patients (32 females; 53.6 ± 7.8 years) were randomized between pasireotide or placebo. Pasireotide did not improve efficacy of aspiration sclerotherapy at 6 weeks compared to controls (23.6 % [IQR 12.6-30.0] vs. 21.8 % [9.6-31.8]; p = 0.96). Long-term cyst diameter reduction was similar in both groups (49.1 % [27.0-73.6] and 45.6 % [29.6-59.6]; p = 0.90). Mean PLD-Q scores improved significantly in both groups (p < 0.01) without differences between arms (p = 0.92).. In patients with large symptomatic hepatic cysts, complementary pasireotide to aspiration sclerotherapy did not improve cyst reduction or clinical response.. • Complementary pasireotide treatment does not improve efficacy of aspiration sclerotherapy. • Cyst fluid reaccumulation after aspiration sclerotherapy is a transient phenomenon. • Aspiration sclerotherapy strongly reduces symptoms and normalizes quality of life.

Topics: Adult; Cysts; Double-Blind Method; Drug Administration Schedule; Female; Hormones; Humans; Injections, Intramuscular; Liver Diseases; Male; Middle Aged; Quality of Life; Sclerosing Solutions; Sclerotherapy; Somatostatin; Treatment Outcome

Aspiration sclerotherapy is an effective therapeutic option for large symptomatic hepatic cysts. However, incomplete cyst reduction following aspiration sclerotherapy is frequently reported. Strong post-procedural cyst fluid secretion by cholangiocytes, which line the epithelium of the hepatic cyst, seems to be associated with lower reduction rates. Previous studies showed that somatostatin analogues curtail hepatic cyst fluid production. This trial will evaluate the effect of aspiration sclerotherapy combined with the somatostatin analogue pasireotide on cyst reduction. By combining treatment modalities we aim to improve cyst reduction leading to greater symptomatic relief and reduced rates of cyst recurrence.. This single center, randomized, double-blind, placebo-controlled clinical trial evaluates the additional effect of pasireotide when combined with aspiration sclerotherapy in patients with a large (>5 cm) symptomatic hepatic cyst. A total of 34 participants will be randomized in a 1:1 ratio. In the active arm, patients will receive pasireotide (long-acting release, 60 mg injection) two weeks prior to and two weeks following aspiration sclerotherapy. Patients in the control arm will receive placebo injections at corresponding intervals. The primary outcome is proportional cyst diameter reduction four weeks after aspiration sclerotherapy compared to baseline measurements, obtained by ultrasonography. As secondary outcomes, proportional volume reduction, recurrence, symptomatic relief and improvement of health-related quality of life will be assessed. Furthermore, safety and tolerability of the combination of pasireotide and aspiration sclerotherapy will be evaluated.. This trial aims to improve efficacy of aspiration sclerotherapy by a combined approach of two treatment modalities. We hypothesize that pasireotide will decrease fluid re-accumulation after aspiration sclerotherapy, leading to effective hepatic cyst reduction and symptomatic relief.. This trial is registered with ClinicalTrials.gov (identifier: NCT02048319 ; registered on 6 January 2014) and EudraCT (identifier: 2013-003168-29; registered on 16 August 2013).

Topics: Clinical Protocols; Combined Modality Therapy; Cysts; Double-Blind Method; Humans; Liver Diseases; Netherlands; Recurrence; Remission Induction; Research Design; Sclerotherapy; Somatostatin; Suction; Time Factors; Treatment Outcome

Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 µg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 µg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 µg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.

Topics: Adolescent; Adult; Aged; Area Under Curve; Case-Control Studies; Female; Humans; Liver Diseases; Male; Middle Aged; Severity of Illness Index; Somatostatin; Young Adult

Polycystic liver disease (PLD) is a group of genetic disorders with limited treatment options and significant morbidity. Hepatic cysts arise from cholangiocytes exhibiting a hyperproliferative phenotype. Considering that hyperproliferation of many cell types is associated with alterations in autophagy, we hypothesized that autophagy is altered in PLD cholangiocytes, contributes to hepatic cystogenesis, and might represent a potential therapeutic target. We employed functional pathway cluster analysis and next-generation sequencing, transmission electron microscopy, immunofluorescence confocal microscopy, and western blotting to assess autophagy in human and rodent PLD cholangiocytes. A three-dimensional culture model was used to study the effects of molecular and pharmacologic inhibition of autophagy on hepatic cystogenesis in vitro, and the polycystic kidney disease-specific rat, an animal model of PLD, to study the effects of hydroxychloroquine, a drug that interferes with the autophagy pathway, on disease progression in vivo. Assessment of the transcriptome of PLD cholangiocytes followed by functional pathway cluster analysis revealed that the autophagy-lysosomal pathway is one of the most altered pathways in PLD. Direct evaluation of autophagy in PLD cholangiocytes both in vitro and in vivo showed increased number and size of autophagosomes, lysosomes, and autolysosomes; overexpression of autophagy-related proteins (Atg5, Beclin1, Atg7, and LC3); and enhanced autophagic flux associated with activation of the cAMP-protein kinase A-cAMP response element-binding protein signaling pathway. Molecular and pharmacologic intervention in autophagy with ATG7 small interfering RNA, bafilomycin A. Autophagy is increased in PLD cholangiocytes, contributes to hepatic cystogenesis, and represents a potential therapeutic target for disease treatment. (Hepatology 2018;67:1088-1108).

Topics: Animals; Autophagy; Bile Ducts; Blotting, Western; Cell Proliferation; Cells, Cultured; Cluster Analysis; Cysts; Disease Models, Animal; Enzyme Inhibitors; Epithelial Cells; Female; Fluorescent Antibody Technique; High-Throughput Nucleotide Sequencing; Humans; Hydroxychloroquine; Liver; Liver Diseases; Male; Microscopy, Electron, Transmission; Rats; Rats, Sprague-Dawley; Signal Transduction; Somatostatin

Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide. We also assessed effects of ACY-1215 and pasireotide alone and in combination on cell proliferation, cAMP production, and expression of acetylated α-tubulin in vitro in cultured cholangiocytes and the length of primary cilia and the frequency of ciliated cholangiocytes in vivo in PCK rats. Panobinostat and all three HDAC6 inhibitors decreased hepatorenal cystogenesis in PCK rats. ACY-1215 was more effective than other HDAC inhibitors and was chosen for combinational treatment. ACY-1215 + pasireotide combination synergistically reduced cyst growth and increased length of primary cilia in PCK rats. In cultured cystic cholangiocytes, ACY-1215 + pasireotide combination concurrently decreased cell proliferation and inhibited cAMP levels. These data suggest that the combination of drugs that inhibit HDAC6 and cAMP may be an effective therapy for PLD.

Topics: Acetylation; Animals; Bile Ducts; Cell Proliferation; Cilia; Cyclic AMP; Cysts; Disease Models, Animal; Drug Synergism; Female; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Hydroxamic Acids; Liver Diseases; Male; Panobinostat; Pyrimidines; Rats; Receptors, Somatostatin; Somatostatin; Tubulin

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5. TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Proliferation; Cyclic AMP; Cysts; Drug Evaluation, Preclinical; Drug Therapy, Combination; GTP-Binding Protein alpha Subunits, Gs; Humans; Liver Diseases; Mice; Oleanolic Acid; Polycystic Kidney Diseases; Primary Cell Culture; Pyrimidines; Rats; Receptors, G-Protein-Coupled; Somatostatin

In the polycystic liver diseases (PLD), genetic defects initiate the formation of cysts in the liver and kidney. In rodent models of PLD (i.e., the PCK rat and Pkd2(WS25/-) mouse), we have studied hepatorenal cystic disease and therapeutic approaches. In this study, we employed zebrafish injected with morpholinos against genes involved in the PLD, including sec63, prkcsh, and pkd1a. We calculated the liver cystic area, and based on our rodent studies, we exposed the embryos to pasireotide [1 μM] or vitamin K3 [100 μM] and assessed the endoplasmic reticulum (ER) in cholangiocytes in embryos treated with 4-phenylbutyrate (4-PBA). Our results show that (a) morpholinos against sec63, prkcsh, and pkd1a eliminate expression of the respective proteins; (b) phenotypic body changes included curved tail and the formation of hepatic cysts in zebrafish larvae; (c) exposure of embryos to pasireotide inhibited hepatic cystogenesis in the zebrafish models; and (d) exposure of embryos to 4-PBA resulted in the ER in cholangiocytes resolving from a curved to a smooth appearance. Our results suggest that the zebrafish model of PLD may provide a means to screen drugs that could inhibit hepatic cystogenesis.

Topics: Animals; Antineoplastic Agents; Calcium-Binding Proteins; Cysts; Disease Models, Animal; DNA Helicases; Gene Expression Regulation, Neoplastic; Glucosidases; Humans; Intracellular Signaling Peptides and Proteins; Larva; Liver Diseases; Morpholinos; Phenylbutyrates; Polycystic Kidney, Autosomal Dominant; Somatostatin; TRPP Cation Channels; Vitamin K 3; Zebrafish

In polycystic liver (PLD) and kidney (PKD) diseases, increased cyclic adenosine monophosphate (cAMP) levels trigger hepatorenal cystogenesis. A reduction of the elevated cAMP by targeting somatostatin receptors (SSTRs) with octreotide (OCT; a somatostatin analog that preferentially binds to SSTR2) inhibits cyst growth. Here we compare the effects of OCT to pasireotide (PAS; a more potent somatostatin analog with broader receptor specificity) on: (1) cAMP levels, cell cycle, proliferation, and cyst expansion in vitro using cholangiocytes derived from control and PCK rats (a model of autosomal recessive PKD [ARPKD]), healthy human beings, and patients with autosomal dominant PKD (ADPKD); and (2) hepatorenal cystogenesis in vivo in PCK rats and Pkd2(WS25/-) mice (a model of ADPKD). Expression of SSTRs was assessed in control and cystic cholangiocytes of rodents and human beings. Concentrations of insulin-like growth factor 1 (IGF1) and vascular endothelial growth factor (VEGF) (both involved in indirect action of somatostatin analogs), and expression and localization of SSTRs after treatment were evaluated. We found that PAS was more potent (by 30%-45%) than OCT in reducing cAMP and cell proliferation, affecting cell cycle distribution, decreasing growth of cultured cysts in vitro, and inhibiting hepatorenal cystogenesis in vivo in PCK rats and Pkd2(WS25/-) mice. The levels of IGF1 (but not VEGF) were reduced only in response to PAS. Expression of SSTR1 and SSTR2 (but not SSTR3 and SSTR5) was decreased in cystic cholangiocytes compared to control. Although both OCT and PAS increased the immunoreactivity of SSTR2, only PAS up-regulated SSTR1; neither drug affected cellular localization of SSTRs.. PAS is more effective than OCT in reducing hepatorenal cystogenesis in rodent models; therefore, it might be more beneficial for the treatment of PKD and PLD.

Topics: Animals; Cell Cycle; Cyclic AMP; Cysts; Humans; Liver Diseases; Mice; Octreotide; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Rats; Receptors, Somatostatin; Somatostatin