Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma.

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice.

The sphingolipid ceramide is a bioactive signaling lipid that is thought to play important roles in modulating synaptic activity, in part by regulating the function of excitatory postsynaptic receptors. However, the molecular mechanisms by which ceramide exerts its effects on synaptic activity remain largely unknown. We recently demonstrated that a rapid generation of ceramide by neutral sphingomyelinase-2 (nSMase2; also known as "sphingomyelin phosphodiesterase-3") played a key role in modulating excitatory postsynaptic currents by controlling the insertion and clustering of NMDA receptors (Wheeler et al. [2009] J. Neurochem. 109:1237-1249). We now demonstrate that nSMase2 plays a role in memory. Inhibition of nSMase2 impaired spatial and episodic-like memory in mice. At the molecular level, inhibition of nSMase2 decreased ceramide, increased PSD-95, increased the number of AMPA receptors, and altered the subunit composition of NMDA receptors. Our study identifies nSMase2 as an important component for efficient memory formation and underscores the importance of ceramide in regulating synaptic events related to learning and memory.

LGD-5552, an antiinflammatory glucocorticoid receptor ligand with reduced side effects, in vivo.

Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.

Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers.

This study was designed to determine the safety, tolerability, pharmacokinetics and effects on cognitive function of GTS-21 in healthy, male volunteers. A total of 18 subjects were randomized to GTS-21 (25, 75 and 150 mg) or placebo administered three times daily (first 4 days, once on Day 5) for three, 5-day sessions. GTS-21 was well tolerated up to doses of 450 mg/day, with no clinically significant safety findings. C(max) and the area under the plasma concentration of GTS-21 and the metabolite 4-OH-GTS-21 increased in a dose-related fashion; although considerable intersubject variability occurred, it decreased with continued dosing. GTS-21 showed statistically significant enhancement of three measures of cognitive function (attention, working memory, episodic secondary memory) compared to placebo. A relationship between exposure to GTS-21 and the magnitude of the cognitive response was apparent, with maximal effect approached for doses between 75 and 150 mg three times a day. These data indicate that GTS-21 may represent a novel treatment for dementia.

The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).

A large decrease in brain nicotinic receptor levels occurs in Alzheimer's disease, relative to muscarinic and other receptors. Neurons possessing high affinity nicotinic receptors seem particularly vulnerable. The low affinity nicotinic receptors which selectively bind alpha-bungarotoxin are not significantly affected. The major nicotinic receptor subtype which binds this toxin is a homo-oligomer composed of alpha7 subunits. Due to its exceptionally high calcium ion selectivity, this particular receptor can be considered as a ligand-gated calcium channel. Alpha7 receptors are found in regions of the brain which are important for cognition, including cerebral cortex and hippocampus. Hippocampal receptors are largely confined to GABAergic interneurons. Alpha7 receptors seem less likely than alpha4-beta2 receptors to be up-regulated in number and down-regulated in function as a result of chronic agonist exposure. A family of nicotinic agonists based upon the marine animal toxin anabaseine have been synthesized and investigated. One of these compounds, DMXBA [3-(2,4-dimethoxybenzylidene)-anabaseine; code name GTS-21] has displayed promising characteristics during phase I clinical tests. In the rat DMXBA is selectively agonistic upon alpha7 nicotinic receptors. In addition it is a moderately potent antagonist at alpha4-beta2 receptors. DMXBA enhances a variety of cognitive behaviors in mice, monkeys, rats and rabbits. It also displays neuroprotective activity upon cultured neuronal cells exposed to beta-amyloid or deprived of NGF. The compound is much less toxic than nicotine and does not affect autonomic and skeletal muscle systems at doses which enhance cognitive behavior. Phase I clinical tests indicate that large doses can be safely administered orally without adverse effects. Psychological tests on healthy young male subjects indicate a positive effect of DMXBA on some measures of cognition. While DMXBA is a much weaker partial agonist on human alpha7 receptors than upon rat alpha7 receptors, its 4-hydroxy metabolite has been shown to have excellent efficacy on both receptors. Thus, some of the physiological and behavioral effects of GTS-21 may be due to the actions of this primary metabolite.

Zilascorb(2H), a low-toxicity protein synthesis inhibitor that exhibits signs of anticancer activity in malignant melanoma.

Zilascorb(2H) is a benzaldehyde derivative giving rise to strong protein synthesis inhibition. It has shown antitumor activity against human malignant melanoma grown as xenografts in nude mice. The effect was manifest only after prolonged daily treatment and was quickly reversible when treatment was stopped. Drug-induced fever was the dose-limiting toxicity observed during clinical phase I studies of zilascorb(2H). The object of the present study was to assess antitumor activity, safety and tolerability of the drug in melanoma patients. Sixteen patients with disseminated malignant melanoma were included, all presenting with WHO performance status 0-2 and adequate organ functions. Previous chemo- or radiotherapy was accepted, while patients with known CNS metastases were excluded. Due to its low solubility and quickly reversible activity, zilascorb(2H) 1400 mg was infused by the patients twice daily through a venous access port for up to 12 weeks. Induction of tumor regression was demonstrated in one patient, who was, however, withdrawn from treatment after 2 weeks because of recurrent fever and fatigue. All the 12 patients evaluable for antitumor activity had progressive disease. Zilascorb(2H) was well tolerated, except for fever reactions and reversible liver toxicity. Most patients learned quickly how to handle a venous access port, but daily self-administration of i.v. infusions became too cumbersome to justify further patient inclusion despite the tumor regression observed. We conclude that zilascorb(2H) seems to have the potential for antitumor activity in metastatic malignant melanoma and is well tolerated. Daily self-administration of drug infusions is not desirable for long periods and zilascorb(2H) tablets have been developed. Because of its favorable toxicity profile, especially compared to other protein synthesis inhibitors, zilascorb(2H) may be particularly interesting for combinations with other anticancer drugs.

Sulindac. Trials of a new anti-inflammatory drug.

Trials in patients with rheumatoid arthritis and osteoarthritis showed sulindac to be an analgesic with anti-inflammatory properties and at least as effective as aspirin. It was effective within 24 hours in doses of 300-400 mg daily. It had the advantages of twice daily administration and a lower incidence of gastric side effects than aspirin. Constipation, usually mild, occurred in 20-30% of cases. Like other anti-inflammatory drugs, it was effective in only a proportion of the patients.

Comparison of sulindac and aspirin in rheumatoid arthritis.

Thirty-one out-patients with rheumatoid arthritis took part in a 10 week double-blind comparison of sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulphinyl)-benzylidene]-indene-3-acetic acid) 200 mg twice daily and aspirin 3.6 g daily, with a 2-week placebo control period. Both drugs were superior to placebo. The incidence of side-effects was approximately the same on the two drugs, but there was a higher drop-out rate due to side-effects on aspirin.

Intestinal blood loss after a new anti-inflammatory drug, sulindac.

Sulindac was tested for fecal blood loss in 40 healthy male subjects whose red cells had been labeled with Na2 51 CrO4. Two daily dose levels of 240 mg and 400 mg were compared with 4.8 gm of aspirin and placebo for 2 wk. At day 15, aspirin-induced blood loss was greater than that of both dose levels of sulindac and of placebo (p less than 0.05). There were no significant differences between the two sulindac groups and the placebo group. Aspirin caused more adverse reactions than sulindac, 240 mg (p less than 0.05), 400 mg (p less than 0.05), and placebo (p less than 0.05).

[Sulindac: Clinical test of a new antiinflammatory agent in rheumatoid arthritis (author's transl)]. / Sulindac: Klinische Prüfung eines neuen Antiphlogisticums bei der chronischen Polyarthritis

Sulindac, a new non steroidal antiinflammatory agent has been compared with acetylsalicylic-acid in a six week controlled double blind study in 28 patients with rheumatoid arthritis. In continuation of this study all patients have been treated with Sulindac up to 18 months. Sulindac has proved to be statistically significant superior to acetylsalicylic-acid as regarding the achieve of pain during the day, of morning stiffness, of gripping of the right hand and evaluation of patients response to the drug. Moreover markedly fewer adverse reactions especially of the gastrointestinal tract were seen. During the following long term study, when 19 patients were treated with Sulindac, a further statistically significant improvement of all controlled parameters up to the complete relief of complaints was observed. A reduction of the daily dose could be established. Laboratory evaluations as well as controlls of EKG and blood pressure showed no evidence of any organ toxicity of this drug.

Vulpinic acids as potential antiinflammatory agents. 1. Vulpinic acids with substituents in the aromatic rings.

The preparation of a series of vulpinic acids, substituted in either or both of the aromatic rings, is described. The compounds were found to be active in the adjuvant arthritis test in rats. High activity combined with an acceptable therapeutic ratio was confined to analogs with electron-withdrawing substituents in the meta positions of the rings.