A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma.

Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5-3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of 13C10 kynurenine vs endogenous kynurenine was 75% vs 24%. PF-06840002 CSF-to-plasma ratio was 1.00. Disease control occurred in eight patients (47%). Mean duration of stable disease (SD) was 32.1 (12.1-72.3) weeks. Two patients with SD discontinued the study at 450 and 561 days and continued PF-06840003 on compassionate use. Conclusion PF­06840003 up to 500 mg BID was generally well tolerated with evidence of a pharmacodynamic effect and durable clinical benefit in a subset of patients with recurrent malignant glioma. ClinicalTrials.gov, NCT02764151, registered April 2016.

Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives.

Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT-29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected.

Symptoms and course of intoxication with mesuximide--a case report.

We report on a 31-year-old, female patient who presented with somnolence due to an intoxication by the antiepileptic drug, mesuximide (MSM). The serum concentration of its metabolite n-desmethyl-mesuximide (85.7 mg/L) was above the so-called therapeutic range (10-40 mg/L) but below the concentration range that led to an impairment of consciousness in previous cases according to the German SPC (>150 mg/L). The symptoms remitted quickly under hemodialysis. In somnolent patients treated with MSM, the treating physicians should be aware of drug intoxication as a possible etiology. Therefore, the serum concentration should be measured early. Due to the, often, long latency until the results are available, treatment initiation may be necessary based on suspicion.

Synthesis and anticonvulsant properties of new mannich bases derived from 3,3-disubstituted pyrrolidine-2,5-diones. Part IV.

A library of 21 new N-Mannich bases of 3,3-diphenyl- (5a-g), 3-methyl-3-phenyl- (6a-g), and 3-ethyl-3-methylpyrrolidine-2,5-diones (7a-g) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The acute neurological toxicity was determined applying the rotarod screen. The results in mice showed that 13 compounds were effective in the MES or/and scPTZ screen. From these, seven molecules were tested in the MES seizures after oral administration in rats. The quantitative studies showed that N-[{4-(2-hydroxyethyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6c) and N-[(4-benzylpiperidin-1-yl)-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6f) revealed higher protection in the MES and scPTZ tests than valproic acid or ethosuximide which were used as reference antiepileptic drugs. Four compounds (5c, 6c, 6e, 6f) showed high effectiveness in the 6-Hz psychomotor seizure model of partial and therapy resistant epilepsy.

Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood.

The efficacy and safety of methsuximide (MSM) was evaluated in children with intractable epilepsies in a prospective uncontrolled study. MSM was added to the therapeutic regimen of 112 children with intractable epilepsy under inpatient conditions, all of whom were therapeutically refractory to various first-line antiepileptic drugs (AED) or combinations of other AED. Titration of MSM was performed following a uniform protocol. Administration of MSM resulted in a 50% or greater reduction in seizure frequency in 40 patients after a short-term observation period (mean 9.1 weeks). After a mean of 3.7 years, the rate of seizures and side effects were re-evaluated in 39 patients who were still receiving MSM as part of their antiepileptic regimen. Twenty two of these patients derived long-term benefit from MSM. In patients with good seizure control, fasting plasma levels of N-desmethylmethsuximide, the principal active metabolite of MSM, were 25.3-44.7 mg l(-1)(mean 36.0 mg l(-1)). Thus effective plasma levels of N-desmethylmethsuximide in children were found to be higher than previously described. Forty one of 112 patients (28.9%) developed side effects during MSM treatment. No serious or irreversible side effects were seen. Our study demonstrates the value of MSM as an 'add-on' drug in intractable epilepsies.

[Side effects of anticonvulsants in the treatment of idiopathic generalized epilepsy]. / Pobochnye éffekty antikonvul'santov pri lechenii idiopaticheskoi generalizovannoi épilepsii.

This investigation was ainced on detection of frequency and main features of side effects of anticonvulsants in therapy of idiopathic generalized epilepsy. There were observed 190 patients aged 5-29 years suffering from different forms of idiopathic generalized epilepsy. Side effects were revealed in 48.4% of patients as a result of the investigation. Almost half of patients (49.0%) who were administered valproic acid developed side effects. Neuroendocrine dysfunctions and digestive disturbances were the most frequent. Side effects were revealed within the first two months after administration of valproats. Only in 13.2% of cases the treatment and to be stopped at the expense of severeness of side effects. Barbiturates caused side effects in 39.6% of cases. Toxic damage of CNS was the most significant. Hyperkinetic syndrome with lack of attention was observed 37.9% of cases. Succinimides caused side effects in 37.9% of cases. Toxic damage of CNS was the most frequent--in 22.4% of cases, digestive disturbances was in 15.5% of cases. There are no really effective means for correction of above mentioned side effects.

Cholinergic drugs as diagnostic and therapeutic tools in affective disorders.

The hypothesis of a significant involvement of the cholinergic system in the pathogenesis of affective disorders still lacks strong experimental support. This is mainly because of missing specific peripheral markers of the central nervous activity of the cholinergic system and the lack of specific cholinergic agonists and antagonists without severe peripheral side effects. As the direct cholinergic agonist RS 86 seems to be more suitable because of its minor side effects, long half-life and oral applicability, it was tested for its antimanic property and its effect on the hypothalamo-pituitary adrenal system and the rapid eye movement (REM) sleep-generating system. RS 86 exhibited antimanic and REM sleep-inducing properties, but failed to stimulate the cortisol system.

An immunotoxin for the treatment of T-acute lymphoblastic leukemic meningitis: studies in rhesus monkeys.

Monoclonal antibody WT1 (anti-CD7), conjugated to ricin A chain, was administered intrathecally to rhesus monkeys to test its suitability for use in the therapy of leukemic meningitis. The WT1-SMPT-dgRTA conjugate was cytotoxic to CEM (T-lymphoblastic leukemia) cells in vitro with an ID50 of 53 pM. Immunoperoxidase testing showed no binding of WT1 to normal human tissues other than lymph nodes. Thirteen animals received one or more intrathecal 60-micrograms doses of WT1-SMPT-dgRTA. All monkeys receiving repeated doses developed a cerebrospinal fluid (CSF) pleocytosis (primarily eosinophils), which was generally resolving by 3-4 weeks after therapy. Pharmacokinetic studies showed a half-life of 99 min, consistent with CSF clearance by bulk flow. Peak CSF immunotoxin concentrations exceeded the ID50 for CEM cells by more than 2 log units and a concentration exceeding the ID50 was maintained for as long as 24 h. All eight monkeys receiving repeated doses of immunotoxin developed serum antibodies against both WT1 and ricin A chain. In six of these monkeys antibodies were also present in the CSF. Both anti-WT1 and anti-(ricin A chain) antibodies were able to inhibit in vitro cytotoxicity of the immunotoxin for CEM cells; however, only anti-WT1 antibodies could block immunotoxin binding to the cell surface. No monkey developed anti-immunotoxin antibodies fewer than 7 days after the initiation of therapy, suggesting that repeated doses could be administered for up to 1 week without inhibition of clinical activity.

RS 86 in the treatment of Alzheimer's disease: cognitive and biological effects.

Twelve patients who met Research Diagnostic Criteria for Alzheimer's disease (AD) completed a double-blind crossover study comparing oral RS 86, a long-acting and specific muscarinic agonist, with placebo. Cognitive and noncognitive effects were assessed with the Alzheimer's Disease Assessment Scale (ADAS). RS 86 was found to improve ADAS test scores consistently (both cognitive and noncognitive subscales) in seven patients, with a clinically obvious improvement in only two patients. RS 86 produced a significant increase in peak nocturnal cortisol levels, and this increase correlated with improvement on ADAS testing. Similarly, there was a 38% increase in amplitude of the P300 evoked potential with RS 86. The biological findings suggest that RS 86 was effective only to the extent that it enhanced central cholinergic activity.

Ames Salmonella/mammalian-microsome testing of peptides and peptide synthesis reagents.

The Ames Salmonella/mammalian-microsome assay was used to evaluate the bacterial mutagenicity of 6 bioactive peptides and of 11 chemical reagents used in peptide synthesis. Samples of 2 reagents, bis(2-oxo-3-oxazolidinyl)phosphinic chloride and fluoren-9-ylmethyl chloroformate, showed mutagenic activity with strains TA100 and TA1535, and with TA1537, respectively. No mutagenic activity was found with the bioactive peptides or with the other 9 peptide synthesis reagents.

Efficacy of second line antiepileptic drugs in the treatment of patients with medically refractive complex partial seizures.

The efficacy of second-line antiepileptic drugs (AEDs) was evaluated in the treatment of 66 patients with complex partial seizures who had previously failed first-line AEDs. Methsuximide, valproate, or clorazepate had eliminated seizures in 11% of the patients at the end of the study. However, these good results deteriorated on longer follow-up and were not expected to be permanent. It is recommended that suitable patients with partial epilepsy be referred for surgical evaluation after failing the first-line AEDs, and that second-line AEDs be reserved for nonsurgical candidates.

Effect of a cholinomimetic drug (RS 86) in tardive dyskinesia and drug-related parkinsonism.

RS 86, a specific muscarinic agonist, was evaluated in a blind, placebo-controlled, single-dose trial in 10 psychiatric patients with stable tardive dyskinesia (TD). RS 86, 0.5-4 mg orally, produced no significant effects in TD, although 4 mg caused a minimal aggravation in parkinsonism. Side effects of the highest dose (4 mg) included hypersalivation (eight patients), nausea (6), sweating (3), and vomiting (3). It is concluded that treatment with RS 86 and probably other cholinomimetics has no or only limited beneficial effect in TD.

Clinical trials with the cholinergic drug RS 86 in Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT).

The muscarinic agonist RS 86 was administered to patients with Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT) in a series of controlled clinical trials. Daily doses were up to 3.0 mg orally for a maximum duration of 18 weeks. RS 86 produced typical peripheral cholinergic effects, but appeared to be better tolerated than similar drugs, such as physostigmine and arecoline. Positive clinical changes with regard to cognitive functions, mood, and social behavior were seen in a minority of AD and SDAT patients. Psychometric tests suggested improvement of functions entailing a speed component. RS 86 is a suitable drug for further clinical experiments in AD and SDAT.

Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions.

Methsuximide (MSM; Celontin) was administered for 8 weeks to 26 patients with complex partial seizures (CPS) refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction in CPS frequency was obtained in eight patients. MSM therapy was continued chronically in these eight patients, and five continued to have a 50% or greater reduction in CPS frequency after 3 to 34 months of follow-up. Drowsiness, gastrointestinal disturbance, hiccups, irritability, and headache were the common side effects of MSM. No serious toxicity occurred. N-desmethylmethsuximide was the principal substance detected in plasma and had the following pharmacokinetic values: accumulation half-life, 49.7 hours; time to steady state, 10.4 days; elimination half-life, 72.2 hours; therapeutic range of plasma concentration, 10 to 30 mg per liter. Plasma concentrations of phenytoin and phenobarbital derived from primidone rose significantly (p less than 0.05) after addition of MSM.

[Effect of drugs used for the prevention of urinary calculi recurrence on the growth and metabolism of young experimental animals]. / Der Einfluss verschiedener in der Harnsteinmetaphylaxe verwendeter Medikamente auf das Wachstum und den Stoffwechsel junger Versuchstiere.

In the animal experiment should be made clear whether several medicaments which stood the test in the prevention of relapses of urinary calculi may be used without any danger also in the infantile carrier of concrements. For this purpose young rabbits high doses of diuretics, kation exchangers, aluminium oxide, extracts of the root of rubia tinctorum, succinimide and diphosphonate were given. Growth and development of the animals were negatively influenced by the medicaments, with the exception of the kation exchanger and the extracts of the root of rubia tinctorum. Numerous animals died under the administration of duiretics. The results of the examinations of metabolism only partly allow general conclusions. The medicamentous long-term metaphylaxis of the urolithiasis in childhood is also to be used like dietetic restrictions under strong indication and permanent control.