Dose-limiting Adverse Effects Research Articles

Peripherally restricted cannabinoid and mu-opioid receptor agonists synergistically attenuate neuropathic mechanical hypersensitivity in mice.

Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors (Cnr1 and Oprm1) is coexpressed across different neuron clusters. Myc-CB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain.

Clinical pharmacology and tolerability of REC-994, a redox-cycling nitroxide compound, in randomized phase 1 dose-finding studies.

Cerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC-994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC-994 in healthy volunteers. Single- and multiple-ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18-55). SAD study participants received an oral dose of REC-994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC-994 or matching placebo, once daily for 10 days. Thirty-two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increased in proportion to REC-994 dose after single doses of 50-800 mg and after 10 days of dosing over the 16-fold dose range of 50-800 mg. Median Tmax and mean t1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. REC-994 was well tolerated. Treatment-emergent adverse effects across both studies were mild and transient and resolved by the end of the study. REC-994 has a favorable safety profile and was well tolerated in single and multiple doses up to 800 mg with no dose-limiting adverse effects identified. Data support conducting a phase 2 clinical trial in patients with symptomatic CCM.

Cytomegalovirus Treatment in Solid Organ Transplantation: An Update on Current Approaches.

The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation. Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded. After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations. Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV. Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration.

Prevention of colistin-induced neurotoxicity: a narrative review of preclinical data.

Polymyxin E or colistin is an effective antibiotic against MDR Gram-negative bacteria. Due to unwanted side effects, the use of this antibiotic has been limited for a long time, but in recent years, the widespread of MDR Gram-negative bacteria infections has led to its reintroduction. Neurotoxicity and nephrotoxicity are the significant dose-limiting adverse effects of colistin. Several agents with anti-inflammatory and antioxidant properties have been used for the prevention of colistin-induced neurotoxicity. This study aims to review the preclinical studies in this field to prepare guidance for future human studies. The data was achieved by searching PubMed, Scopus, and Google Scholar databases. All eligible pre-clinical studies performed on neuroprotective agents against colistin-induced neurotoxicity, which were published up to September 2023, were included. Finally, 16 studies (ten in vitro and eight in vivo) are reviewed. Apoptosis (in 13 studies), inflammatory (in four studies), and oxidative stress (in 14 studies) pathways are the most commonly reported pathways involved in colistin-induced neurotoxicity. The assessed compounds include non-herbal (e.g., ascorbic acid, rapamycin, and minocycline) and herbal (e.g., curcumin, rutin, baicalein, salidroside, and ginsenoside) agents. Besides these compounds, some other measures like transplantation of mitochondria and the use of nerve growth factor and mesenchymal stem cells could be motivating subjects for future research. Based on the data from experimental (in vitro and animal) studies, a combination of colistin with neuroprotective agents could prevent or decrease colistin-induced neurotoxicity. However, well-designed randomized clinical trials and human studies are essential for demonstrating efficacy.

Lysosomal-Cleavable Peptide Linkers in Antibody-Drug Conjugates.

Antibody-drug Conjugates (ADCs) are a powerful therapeutic modality for cancer treatment. ADCs are multi-functional biologics in which a disease-targeting antibody is conjugated to an effector payload molecule via a linker. The success of currently used ADCs has been largely attributed to the development of linker systems, which allow for the targeted release of cytocidal payload drugs inside cancer cells. Many lysosomal proteases are over expressed in human cancers. They can effectively cleave a variety of peptide sequences, which can be exploited for the design of ADC linker systems. As a well-established linker, valine-citrulline-p-aminobenzyl carbamate (ValCitPABC) is used in many ADCs that are already approved or under preclinical and clinical development. Although ValCitPABC and related linkers are readily cleaved by cathepsins in the lysosome while remaining reasonably stable in human plasma, many studies have shown that they are susceptible to carboxylesterase 1C (Ces1C) in mouse and rat plasma, which hinders the preclinical evaluation of ADCs. Furthermore, neutropenia and thrombocytopenia, two of the most commonly observed dose-limiting adverse effects of ADCs, are believed to result from the premature hydrolysis of ValCitPABC by human neutrophil elastase. In addition to ValCitPABC, the GGFG tetrapeptidyl-aminomethoxy linker is also cathepsin-cleavable and is used in the highly successful ADC drug, DS8201a. In addition to cathepsin-cleavable linkers, there is also growing interest in legumain-sensitive linkers for ADC development. Increasing plasma stability while maintaining lysosomal cleavability of ADC linkers is an objective of intensive current research. This review reports recent advances in the design and structure-activity relationship studies of various peptide/peptidomimetic linkers in this field.

Individualized chemotherapy drug dose escalation in dogs with multicentric lymphoma.

This study was performed to determine the ability to escalate drug doses in a 15-week CHOP protocol in dogs with multicentric lymphoma. We hypothesized that at least 50% of dogs could successfully be escalated in at least 1 drug. Secondary aims were to establish objective response rate (ORR), progression-free interval (PFI), and overall survival time (OST). Thirty dogs with newly diagnosed multicentric lymphoma were prospectively treated with a 15-week CHOP protocol. This was a prospective cohort study. Drug doses that did not cause dose-limiting adverse effects (AEs) were increased using a standardized escalation protocol. AEs and response were assessed using VCOG criteria. Serial blood samples were collected after the first dose of each drug for pharmacokinetic analysis. Of the 23 dogs with the opportunity to dose escalate, at least 1 drug was successfully escalated in 18 (78%). Vincristine was successfully escalated to 0.8 mg/m2 or higher in 11 dogs, cyclophosphamide to 300 mg/m2 or higher in 16 dogs, and doxorubicin to 35 mg/m2 or 1.4 mg/kg or higher in 9 dogs. Three of the 23 dogs (13%) were hospitalized at least once because of drug-induced AEs. Neutropenia was the most common dose-limiting toxicosis for all drugs. Peak doxorubicin concentrations were significantly lower in dogs where doxorubicin was successfully escalated. The objective response rate was 100%. The median progression free interval was 171 days. The median overall survival time was 254 days. Drugs in the CHOP protocol can often be escalated safely with manageable AEs.

#3722 CARBAPENEM-RESISTANT ENTEROBACTERIACEAE URINARY TRACT INFECTION IN RENAL TRANSPLANT RECIPIENTS: ROLE OF A NOVEL ANTIBIOTIC REGIMEN

Abstract Background and Aims Urinary tract infection (UTI), the most common bacterial infection among renal transplant recipients (RTRs), remains a challenge, particularly given the increased incidence of MDR organisms, including Carbapenem-resistant Enterobacteriaceae (CRE). CRE infections were associated with inferior patient and graft outcomes compared to other bacterial infections. Paradoxically, there have been no guidelines on managing CRE in RTRs besides multiple challenges, including the bacteriostatic nature, poor urinary concentration, and dose-limiting adverse effects of various antibiotics. The current study designed and assessed the outcomes of protocol-based therapy consisting of high-dose Meropenem in combination with other antibiotics followed by prolonged oral administration. Method This is a single-centre retrospective study conducted in the department of Nephrology and Renal transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, India, between 1st August 2016 till 31st July 2022. All the RTRs aged $ \ge $ 18 years admitted between 1st August 2016 and 31st July 2018 with symptomatic UTI and a urine culture positive for CRE were included in the study. Patients who received various antibiotics conventionally based on the treating physician's decision from August 2016 to July 2017 were considered under the Best available treatment (BAT) group, while the Standardized Therapeutic Antibiotic Regimen (STAR) group included patients treated from August 2017 to July 2018. The treatment of the STAR group consists of a therapeutic phase for at least six weeks (IV therapeutic phase for two weeks total or one week after the clinical recovery, whichever is later + Oral Therapeutic phase for four weeks) followed by an oral chemoprophylaxis phase for three months. Following the treatment of index UTI episodes due to CRE, follow-up both groups’ follow-up data until a minimum of four years were collected. Appropriate statistical tools were applied, and analyses were performed by SPSS software, version 25. Results A total of 37 patients fulfilling the inclusion criteria were included in the study, of which 13 patients were under the BAT group, and 24 were treated by the STAR-based protocol. The mean age of the study population was 37.6 $ \pm \ $12.3 years, and all were males. Most patients (70.2%) had the UTI due to CRE within one-month post-transplant, and the median duration of UTI post-transplant was 6.1 days (IQR: 4.5 – 33). The primary outcome, recurrence rates of UTI at 48-month follow-up among the patients in the STAR group, was significantly lower than those in the BAT group (30.4% vs 77.8%, p = 0.01). The death-censored graft survival was also significantly better among the STAR group than the BAT group (100% vs 75%, p = 0.03) after 48 months. Graft function at 48 months was also better in the STAR group (Serum creatinine- 1.4 ± 0.8 mg/dl vs 2.9 ± 2.2 mg/dl, p = 0.007). The patient survival, however, was similar among the two groups (95.8% vs 88.9%, p = 0.47). Conclusion Prolonged and combination antibiotic therapy followed by long-term antibiotic prophylaxis significantly reduced the recurrence of UTI due to CRE among the RTRs. Graft function and death-censored graft survival were also considerably better. Hence, the current study may pave the path for future RCTs based on combination antibiotic therapy as a solution to combat the challenge of CRE in RTRs.

Rational Design of Chemically Controlled Antibodies and Protein Therapeutics.

Protein-based therapeutics, such as monoclonal antibodies and cytokines, are important therapies for various pathophysiological conditions such as oncology, autoimmune disorders, and viral infections. However, the wide application of such protein therapeutics is often hindered by dose-limiting toxicities and adverse effects, namely, cytokine storm syndrome, organ failure, and others. Therefore, spatiotemporal control of the activities of these proteins is crucial to further expand their application. Here, we report the design and application of small-molecule-controlled switchable protein therapeutics by taking advantage of a previously engineered OFF-switch system. We used the Rosetta modeling suite to computationally optimize the affinity between B-cell lymphoma 2 (Bcl-2) protein and a previously developed computationally designed protein partner (LD3) to obtain a fast and efficient heterodimer disruption upon the addition of a competing drug (Venetoclax). The incorporation of the engineered OFF-switch system into anti-CTLA4, anti-HER2 antibodies, or an Fc-fused IL-15 cytokine demonstrated an efficient disruption in vitro, as well as fast clearance in vivo upon the addition of the competing drug Venetoclax. These results provide a proof-of-concept for the rational design of controllable biologics by introducing a drug-induced OFF-switch into existing protein-based therapeutics.

Characteristics and outcomes for participants with congenital ichthyosis who responded to treatment with the topical isotretinoin formulation TMB-001: Results from the Phase 2b CONTROL study.

Emollients and keratolytics are frequently used to manage symptoms of congenital ichthyosis (CI). Systemic retinoid treatment is complicated by teratogenicity and dose-limiting adverse effects. This analysis from the randomised Phase 2b CONTROL study investigated the characteristics of participants who responded to treatment with TMB-001, a novel topical isotretinoin ointment formulation. Participants ≥9 years with genetically confirmed CI and ≥2 (out of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥3 scaling score were randomised 1:1:1 to TMB-001 0.05%:TMB-001 0.1%:vehicle twice daily for 12 weeks. Efficacy end points included the proportion of participants with ≥50% reduction vs baseline in VIIS-scaling (VIIS-50) and ≥2-grade reduction in Investigator Global Assessment (IGA)-scaling score vs baseline. Changes in body surface area (BSA) involvement, Dermatology Life Quality Index (DLQI) scores, and Itch-Numeric Rating Scale (I-NRS) scores were assessed. Of the 33 participants (TMB-001 0.05% [n = 11], 0.1% [n = 10], and vehicle [n = 12]), median age was 29 years, and most were male (64%) and White (79%). Baseline demographics were generally similar among participants who did or did not achieve TMB-001 treatment success. Participants who had lower mean BSA involvement and higher DLQI and I-NRS scores at baseline were more likely to achieve VIIS-50. Similarly, higher baseline DLQI and I-NRS scores were associated with IGA response; BSA involvement was similar for IGA responders vs nonresponders. Higher DLQI and I-NRS scores at baseline were associated with participants achieving treatment success by VIIS-50 and IGA response. Lower BSA involvement was associated with VIIS-50 success.

Combination analgesic development for enhanced clinical efficacy (the CADENCE trial): a double-blind, controlled trial of an alpha-lipoic acid-pregabalin combination for fibromyalgia pain.

Drug therapy for fibromyalgia is limited by incomplete efficacy and dose-limiting adverse effects (AEs). Combining agents with complementary analgesic mechanisms-and differing AE profiles-could provide added benefits. We assessed an alpha-lipoic acid (ALA)-pregabalin combination with a randomized, double-blind, 3-period crossover design. Participants received maximally tolerated doses of ALA, pregabalin, and ALA-pregabalin combination for 6 weeks. The primary outcome was daily pain (0-10); secondary outcomes included Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. The primary outcome of daily pain (0-10) during ALA (4.9), pregabalin (4.6), and combination (4.5) was not significantly different (P = 0.54). There were no significant differences between combination and each monotherapy for any secondary outcomes, although combination and pregabalin were both superior to ALA for measures of mood and sleep. Alpha-lipoic acid and pregabalin maximal tolerated doses were similar during combination and monotherapy, and AEs were not frequent with combination therapy. These results do not support any additive benefit of combining ALA with pregabalin for fibromyalgia. The observation of similarly reached maximal tolerated drug doses of these 2 agents (which have differing side-effect profiles) during combination and monotherapy-without increased side effects-provides support for future development of potentially more beneficial combinations with complementary mechanisms and nonoverlapping side effects.

Interleukin gene delivery for cancer gene therapy: In vitro and in vivo studies.

Cytokine-mediated cancer therapy has the potential to enhance immunotherapeutic approaches and cancer elimination plans through the endowing of the immune system by providing improved anticancer immunity. Despite the encouraging pioneer studies on interleukins (ILs), the influence of ILs-originated therapeutics is still restricted by a class of potent immunoregulatory cytokines, systemic dose-limiting toxicities, ILs pleiotropy, and administration issues. During previous years, the area of transferring genes encoding immunostimulatory ILs was fundamentally widened to overcome these challenges and expedite ILs-based tumor regression. Numerous viral and non-viral delivery systems are currently available to act as crucial elements of the gene therapy toolbox. Moreover, cell-based cancer therapies are recruiting MSCs in the role of versatile gene delivery platforms to design one of the promising therapeutic approaches. These formulated gene carrier systems can provide possible alternatives to diminish dose-limiting adverse effects, promote administration, and enhance the therapeutic activity of ILs-derived treatment modalities in cancer treatment. This review provides a discussion on the advances of ILs gene delivery systems while focusing on the developing platforms in preclinical cancer immunogene therapy studies.

OR03-2 Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus

Abstract Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN). Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM). Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction. GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist. Pharmacodynamic studies demonstrated that GFB-024 protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN. In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of GFB-024 in up to 56 healthy overweight and obese (BMI 25–40 kg/m2) participants. A total of 38 subjects have completed 5 cohorts in the SAD, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects. PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on four different in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested. In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing. Presentation: Saturday, June 11, 2022 11:45 a.m. - 12:00 p.m.

Nicotinamide Riboside Alleviates Cisplatin-Induced Peripheral Neuropathy via SIRT2 Activation

<h3>Purpose/Objective(s)</h3> Chemotherapy-induced peripheral neuropathy represents a major impairment to the quality of life of cancer patients and is one of the most common dose-limiting adverse effects of cancer treatment. Despite its prevalence, no effective treatment or prevention strategy exists. We have previously provided genetic evidence that the NAD+-dependent deacetylase, SIRT2, protects against cisplatin-induced peripheral neuronal cell death and neuropathy by enhancing nucleotide excision repair. In this study, we aimed to examine whether pharmacologic activation of SIRT2 would provide effective prevention and treatment of cisplatin-induced peripheral neuropathy (CIPN) without compromising tumor cell cytotoxic response to cisplatin. <h3>Materials/Methods</h3> Using von Frey tests, we studied the use of nicotinamide riboside (NR) to prevent and treat CIPN in WT and <i>Sirt2</i>-KO mouse models. We also performed cell survival assays to investigate the effect of NAD+ supplementation on cisplatin toxicity in neuronal and cancer cells. <h3>Results</h3> We show that NR, an NAD+ precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD+ mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD+ may, in fact, further sensitize certain cancer cell types to cisplatin. <h3>Conclusion</h3> Together, our results identify SIRT2-targeted activity of nicotinamide riboside as a potential therapy to alleviate the debilitating and potentially permanent toxicity, CIPN.

Computational Design of Phosphatidylinositol 3-Kinase Inhibitors.

One of the most sought-after therapeutic targets for treating human cancers is the phosphoinositide 3-kinase; PI3k is an integral part of the PI3K/protein kinase B signaling arcade. This pathway is frequently activated in malignancies. Drug resistance and dose-limiting adverse effects are currently associated challenges with the existing anticancer chemotherapy. Therefore, in this research, a series of pyrimidine derivatives were designed and evaluated against human PI3K by using molecular docking analysis. The docking results were further verified by molecular dynamic simulation, which analyzed the strength of the macromolecular complex with respect to time. Compounds IV and XIV were found to be the most potent inhibitors of the human PI3K receptor with a high degree of stability within the active site of the target receptor for a timeframe of 50 ns. Thus, both of these compounds could be important drug candidates for the development of PI3K inhibitors as a prospective anticancer agent.

392-P: Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus

Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN) . Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM) . Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction. GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist that protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN. In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK) , and immunogenicity of GFB-024 in 38 healthy overweight and obese (BMI 25 - 40 kg/m2) participants, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects. PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested. In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing. Disclosure G.Gaich: Consultant; 89 bio, Inc., Employee; Goldfinch Bio, Inc. S.Bilic: Consultant; Goldfinch Bio, Inc. Y.Dagon: Employee; Goldfinch Bio, Inc. T.Gustafson: Employee; Goldfinch Bio, Inc., Janssen Pharmaceuticals, Inc. J.Lawler: Employee; Goldfinch Bio, Inc. L.Johnson: Employee; Goldfinch Bio, Inc. L.Rudolph-owen: Employee; Goldfinch Bio, Inc.

Targeting the M1 muscarinic acetylcholine receptor in Alzheimer's disease.

Alzheimer’s disease (AD) remains a major cause of morbidity and mortality worldwide, and despite extensive research, only a few drugs are available for management of the disease. One strategy has been to up-regulate cholinergic neurotransmission to improve cognitive function, but this approach has dose-limiting adverse effects. To avoid these adverse effects, new drugs that target specific receptor subtypes of the cholinergic system are needed, and the M1 subtype of muscarinic acetylcholine receptor (M1-mAChR) has been shown to be a good target for this approach. By using several strategies, M1-mAChR ligands have been developed and trialled in preclinical animal models and in human studies, with varying degrees of success. This article reviews the different approaches to targeting the M1-mAChR in AD and discusses the advantages and limitations of these strategies. The factors to consider in targeting the M1-mAChR in AD are also discussed.

Targeted Osmotic Lysis: A Novel Approach to Targeted Cancer Therapies.

The conventional treatment of cancer has been based on the delivery of non-selective toxins and/or ionizing energy that affect both the cancer and normal tissues in the hope of destroying the offending disease before killing the patient. Unfortunately, resistance often develops to these treatments and patients experience severe, dose-limiting adverse effects that reduce treatment efficacy and compromise quality of life. Recent advances in our knowledge of the biology of tumor cells and their microenvironment, the recognition of surface proteins that are unique to specific cancers and essential to cell growth and survival and signaling pathways associate with invasion and metastasis have led to the development of targeted therapies that are able to identify specific cellular markers and more selectively deliver lethal treatment to the invading cancer thus improving efficacy and limiting adverse effects. In the context of targeted approaches to cancer therapy, we present targeted osmotic lysis as a novel and fundamentally different approach for treating advanced-stage carcinoma that exploits the conserved relationship between voltage-gated sodium channels and Na+, K+-ATPase and has the potential to increase survival without compromising quality of life in a broad spectrum of highly malignant forms of cancer.

Nicotinamide riboside alleviates cisplatin-induced peripheral neuropathy via SIRT2 activation.

BackgroundChemotherapy-induced peripheral neuropathy represents a major impairment to the quality of life of cancer patients and is one of the most common dose-limiting adverse effects of cancer treatment. Despite its prevalence, no effective treatment or prevention strategy exists. We have previously provided genetic evidence that the NAD+-dependent deacetylase, SIRT2, protects against cisplatin-induced peripheral neuronal cell death and neuropathy by enhancing nucleotide excision repair. In this study, we aimed to examine whether pharmacologic activation of SIRT2 would provide effective prevention and treatment of cisplatin-induced peripheral neuropathy (CIPN) without compromising tumor cell cytotoxic response to cisplatin.MethodsUsing von Frey and dynamic hot plate tests, we studied the use of nicotinamide riboside (NR) to prevent and treat CIPN in a mouse model. We also performed cell survival assays to investigate the effect of NAD+ supplementation on cisplatin toxicity in neuronal and cancer cells. Lewis lung carcinoma model was utilized to examine the effect of NR treatment on in vivo cisplatin tumor control.ResultsWe show that NR, an NAD+ precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD+ mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD+ may, in fact, further sensitize certain cancer cell types to cisplatin.ConclusionsTogether, our results identify SIRT2-targeted activity of NR as a potential therapy to alleviate CIPN, the debilitating and potentially permanent toxicity.

Correlation between the secondary structure and surface activity of β-sheet forming cationic amphiphilic peptides and their anticancer activity

Cancer is one of the main causes of death worldwide. The current cancer treatment strategies often lack selectivity for cancer cells resulting in dose-limiting adverse effects and reduced quality of life. Recently, anticancer peptides (ACPs) have emerged as an alternative treatment with higher selectivity, less adverse effects, and lower propensity for drug resistance. However, most of the current studies on the ACPs are focused on α-helical ACPs and there is lack of systematic studies on β-sheet forming ACPs. Herein we report the development of a new series of rationally designed short cationic amphiphilic β-sheet forming ACPs and their structure activity relationship. The peptides had the general formula (XY1XY2)3, with X representing hydrophobic amino acids (isoleucine (I) or leucine (L)), Y1 and Y2 representing cationic amino acids (arginine (R) or lysine (K)). The cytotoxicity of the designed ACPs in HCT 116 colorectal cancer, HeLa cervical cancer and human dermal fibroblast (HDF) cells was assessed by MTT test. The physicochemical properties of the peptides were characterized by various techniques including RP-HPLC, LC-MS, and Circular Dichroism (CD) spectroscopy. The surface activity of the peptides at the air-water interface and their interaction with the lipid monolayers as models for cell membranes were studied by Langmuir trough. The peptides consisting of I with R and K had selective anticancer activity while the combination of L and R diminished the anticancer activity of the peptides but rendered them more toxic to HDFs. The anticancer activity of the peptides was directed by their surface activity (amphiphilicity) and their secondary structure in hydrophobic surfaces including cancer cell membranes. The selectivity of the peptides for cancer cells was a result of their higher penetration into cancer cell membranes compared to normal cell membranes. The peptides exerted their anticancer activity by disrupting the mitochondrial membranes and eventually apoptosis. The results presented in this study provide an insight into the structure-activity relationship of this class of ACPs which can be employed as guidance to design new ACPs with improved anticancer activity and lower toxicity against normal cells.

Safety and efficacy of a ribose-cysteine supplement to increase erythrocyte glutathione concentration in healthy dogs.

To evaluate the safety of oral administration of a d-ribose-l-cysteine (RibCys) supplement to dogs and the effect of this supplementation on erythrocyte glutathione (GSH) concentration. 24 healthy adult dogs. In a randomized, double-blinded, controlled trial, dogs received 500 mg of a RibCys supplement or placebo (n = 12/group), PO, every 12 hours for 4 weeks. Dogs were evaluated weekly by means of a physical examination, CBC, serum biochemical analysis, urinalysis, and owner-completed quality-of-life questionnaire. Erythrocyte GSH concentration was measured on day 0 (ie, the day before treatment began) and weekly during supplementation. No dose-limiting adverse effects were noted in any dog. Two dogs in each group had mild, self-limiting diarrhea and anemia. No significant increase in erythrocyte GSH concentration was noted in either group at any time point. Two dogs in the RibCys group had improved skin and coat health and improved clinical signs of osteoarthritis. No clinical or owner-perceived improvements were noted in the placebo group. The RibCys supplement was safe and well tolerated in all dogs. Owners reported improvements in dermatologic and orthopedic conditions in some dogs in the RibCys group. No significant differences were observed in erythrocyte GSH concentration before or after RibCys treatment. This lack of significant differences may have been attributable to the use of healthy dogs, which would not be expected to have depleted GSH concentrations. Given the observed safety profile of RibCys, additional research is warranted to explore the potential usefulness of RibCys supplementation in dogs with cancer and those undergoing treatment for cancer.