First-in-Human, Single- and Multiple-Ascending-Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator.

Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC-220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single-dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple-dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3 mg once daily for 28 days, or 1 mg once daily for 7 days with a 7-day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure increased in a dose-proportional manner. Terminal half-life was 9-13 hours after a single dose. Iberdomide decreased peripheral CD19+ B lymphocytes (Emax , 92.4%; EC50 , 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (Emax , 34.8%; EC50 , 0.932 ng/mL). Lipopolysaccharide-stimulated proinflammatory cytokines (IL-1α, IL-1ß) were reduced, but anti-CD3-stimulated IL-2 and interferon-γ were increased. Iberdomide 1 mg once daily partially decreased T-cell-independent antibody responses to PPV23 but did not change tetanus toxoid recall response. Pharmacodynamic data suggest dose-dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated up to 6 mg as a single dose and at 0.3 mg once daily for 4 weeks. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for 21 days; a 7-day drug holiday alleviated neutropenia. Further investigation of iberdomide in autoimmune and hematological diseases is warranted.

An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors.

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.

Synthesis and anticonvulsant evaluation of some N-substituted phthalimides.

Two series of phthalimides--one possessing an N-phenoxyalkyl moiety substituted at position 3 or 4 of the phenyl ring (1-9) and the other of N-alkenyl or alkinyl phthalimides (10-18)--were synthesized, evaluated for anticonvulsant activity and had their in silico lipophilicity estimated using computer programs. The anticonvulsant activity of phthalimides containing an unsaturated substituent at the phthalimide nitrogen was superior to that of the N-phenoxyalkyl phthalimides. Alkinyl derivative 10 emerged as the most active (in MES and ScMet tests) of all the compounds tested. A correlation between anticonvulsant activity and in silico estimated lipophilicity was not observed.

Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.

The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.

Effect of the herbicide flumioxazin on photosynthetic performance of grapevine (Vitis vinifera L.).

Among the herbicides used in vineyards, the pre-emergence soil-applied flumioxazin (fmx) is a recently used molecule that inhibits chlorophyll biosynthesis in weed species. The aim of this work is to further characterize the effects of fmx on the non-target grapevine (Vitis vinifera L. cv. Chardonnay) using cutting as a model. Several photosynthesis parameters were estimated during 25 days after treatment with various fmx concentrations (from 0.5mM to 50mM). Measuring chlorophyll fluorescence it appeared that fmx or a by-product penetrated the plant throughout roots and spread throughout vessels. Besides the initial target, protox, fmx affected other functions related to photosynthesis. Fmx induced a simultaneous drop of both P(n), g(s) and T. Fmx caused stomatal closure, which partially explains the decrease of the net photosynthesis. The decline in F(v)/F(m) indicates that the photochemistry of PSII and its ability to reduce the primary acceptor Q(A) are also affected by fmx in grapevine. Fmx leads to a decrease in the coefficients of both photochemical and non-photochemical quenching. Simultaneous stomatal closure and decrease in the quantum yield of CO(2) assimilation indicate a change in energy metabolism following fmx stress. After ten days of fmx treatment, analyses of the response of net carbon assimilation in leaves to different intercellular CO(2) concentrations have shown a decrease of the maximum carboxylation velocity of RuBP. Stomatal closure, PSII photochemistry, change in energy metabolism and RuBP activity were affected by fmx treatment.

Contact sensitization to N-(cyclohexylthio)phthalimide.

Previous reports revealed relative high sensitization rates to the rubber chemical N-(cyclohexylthio)phthalimide (CTP; CAS-No. 17796-82-6), but the relevance of positive reactions remained unknown. It was discussed whether the test concentration of 1% pet. needed to be changed. The German Contact Dermatitis Research Group (DKG) added CTP in 3 concentrations, i.e. 0.25% pet., 0.5% pet, 1% pet., to the rubber series. From June 1999 to December 2000, 1936 patients in 30 departments of dermatology were tested with CTP. Of the 56 patients with a positive test reaction (2.9%), 52 reacted to CTP 1% pet., 21 to CTP 0.5% pet., and 9 to CTP 0.25% pet. The reaction indices were about the same with all concentrations. 34 patients with a positive reaction to CTP 1% pet. did not react to the lower concentrations. The majority of these reactions are probably false-positive. With CTP 0.25% pet., however, the majority of true allergic reactions to CTP were missed. Analysis of population characteristics and concomitant sensitizations to other rubber chemicals led to the conclusion that a positive reaction to CTP 0.5% pet. was a good indicator of contact allergy to CTP. Thus, the DKG decided to continue patch testing with CTP 0.5% pet. in the rubber series. Manufacturers' information about the use of CTP seem to partly contradict the patients' characteristics seen in this study. So the relevance of positive CTP patch test reactions, and the causative exposures in patients with CTP allergy, still remain to be clarified.

Frequency and relevance of positive patch tests to cyclohexylthiophthalimide, a new rubber allergen.

Cyclohexylthiophtalimide (CTP) is currently the most widely used vulcanization retarder in the rubber industry. Little is known about sensitization to CTP, although positive tests to it do occur in patients exposed to rubber objects. A retrospective study of 350 patients who were patch tested with the standard rubber chemical series was conducted in two departments of dermatology, one in Nancy, France, and one in Leuven, Belgium. Sixteen (4.6%) out of the 350 patients had clear and 6 (1.7%) had doubtful positive reactions to CTP. Cross-sensitivity with other molecules could not be determined. The source of sensitization in most cases seems to have been protective rubber gloves at work. In the other cases, sensitization was suspected to have been caused by rubber shoes, elastic bands in underwear, or other rubber objects. The determination of the relevance of positive tests remains difficult, especially since little is known about the components of rubber products.

"Lucky Luke" contact dermatitis from diapers: a new allergen?

"Lucky Luke" contact dermatitis is a particular pattern of diaper dermatitis, reminiscent of a cowboy's gunbelt holsters (1).

A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion.

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels ( 14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 1/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 1/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.

The UK epidemic of BSE: slow virus or chronic pesticide-initiated modification of the prion protein? Part 1: Mechanisms for a chemically induced pathogenesis/transmissibility.

It is proposed that exposure of the bovine embryo to specific high-dose lipophilic formulations of organophosphate insecticide (containing phthalimide) applied exclusively in the UK during the 1980s/early 1990s was the primary trigger that initiated the UK's bovine spongioform encephalopathy epidemic. Multi-site binding organophosphate toxic metabolites penetrate the fetus, covalently binding with, phosphorylating and ageing serine, tyrosine or histidine active sites on fetal central nervous system prion protein. An abnormal negative charge corrupts prion protein molecular surface, which blocks both proteases and chaperones from accessing their cleavage/bonding sites. This impairs normal degradation and folding of prion protein respectively. Once the abnormally phosphorylated abnormal prion protein isoform agent is initiated, any stress event ensuing in adult life induces a nerve growth factor-mediated synthesis of normal cellular prion protein isoform that aggregates to abnormally phosphorylated abnormal prion protein isoform, thereby becoming 'infected'/transformed into the same; due to the vicious circle of positive feedback invoked by the blocking of a prion protein-specific kinase. Prion protein could therefore serve as a hitherto unrecognized critical link in a chain of delayed neuroexcitotoxic proteins that are triggered off by chronic exposure to specific classes of chemical/metal that 'hit and run' during the vulnerable in utero period, producing spongioform encephalopathy disease years later.

The UK epidemic of BSE: slow virus or chronic pesticide-initiated modification of the prion protein? Part 2: An epidemiological perspective.

This paper elucidates the flaws in the official hypothesis that bovine spongioform encephalopathy originated from alterations in the way that scrapie-contaminated cattlefeeds were manufactured in the UK. An alternative hypothesis is proposed that cites exposure of the bovine embryo to various specific high-dose lipophilic formulations of organophosphates, such as the high-dose phthalimide containing organophosphate phosmet, (which were applied compulsorily and exclusively in the UK during the 1980s/early 1990s) as the primary trigger that initiated the deformation of prion protein and the onset of the bovine spongioform encephalopathy epidemic. The multi-site binding metabolites of these organophosphates penetrate the fetus, covalently phosphorylating various active sites on fetal prion protein. The extra charged phosphate groups left on aged prion protein blocks both proteases and chaperones from accessing their catalytic/bonding sites, creating the undergradable, misfolded isoform of prion protein, PrPsc. The resulting abnormally phosphorylated PrPsc aggregates to freshly synthesized PrPc, transforming it into same; due to a system of positive feedback invoked by the organophosphate-induced blockage of a prion protein-specific protein kinase. Both the timing, distribution and dynamics of usage of these specific organophosphates correlates with the epidemiology of bovine spongioform encephalopathy as well as accounting for the 23,000 cattle that have developed the disease, yet were born after the 1988 ban on scrapie-contaminated cattlefeed.

Allergic patch test reactions caused by the rubber chemical cyclohexyl thiophthalimide.

Rubber chemicals are among the most common occupational contact sensitizers. The most common rubber sensitizers are thiurams, thiazoles, carbamates and paraphenylenediamine derivatives. Here we present data on a less-well-known rubber chemical, N-(cyclohexylthio)phthalimide (CTP; CAS 17796-82-6). This chemical is currently the most widely used vulcanization retarder, but data on allergic contact dermatitis caused by CTP are lacking. We conducted a survey of 310 patients who had been patch tested with 30 rubber chemicals including CTP. 11 (3.5%) showed an allergic patch test reaction provoked by CTP, and 9.0% by thiurams. 4 of the patients reacted only to CTP and not to other rubber chemicals, whereas the other 7 concomitantly reacted to other rubber chemicals. After analyzing the patch test data of these 11 patients, it was concluded that CTP probably did not cross-react with the other rubber chemicals. Therefore the patch test results may indicate independent sensitization to CTP and other rubber chemicals. Because very little data on the components of rubber chemicals in rubber products are available, the source of the putative sensitization to the rubber vulcanization retarder CTP is unknown.

A controlled study with taltrimide and sodium valproate: valproate effective in partial epilepsy.

Taltrimide was compared with valproate and placebo in 17 patients with intractable epilepsy being on carbamazepine monotherapy. Taltrimide (400 mg/day), valproate (1000 mg/day) or placebo were added to the treatment for periods of 3 months using a randomized cross-over design. Serum carbamazepine concentrations remained within the therapeutic range throughout the trial. Thirteen patients completed the study. In partial epilepsy of 7 the seizure frequency was reduced by 27% during valproate (p less than 0.05), compared with placebo, while no improvement was found during taltrimide. In 6 with primary generalized epilepsy, the number of seizures was reduced by 49% during taltrimide and by 38% during valproate, but neither effect was significant, compared with placebo. Headache was reported by 3 patients while on taltrimide. One with hypersensitivity history developed petecchiae and nasal bleeding during taltrimide and, therefore, the treatment was stopped. The three other interruptions were independent of taltrimide. Thus, the only statistically significant effect in this study was that of valproate in partial epilepsy.

Effects of falipamil (AQ-A 39) on heart rate and blood pressure in resting and exercising healthy volunteers.

Falipamil (AQ-A 39) is a new verapamil derivative which exerts antitachycardic effects by a direct action on the sinus node. Its effects on heart rate (HR), blood pressure (BP) and ECG intervals were studied in 12 healthy volunteers, at rest and during bicycle exercise tests. In a double-blind, cross-over, single-dose study, the effects of falipamil (100 and 200 mg) during 8-h post-dosing were compared with those of placebo. Falipamil did not modify resting HR, BP, and electrocardiogram (ECG) intervals significantly. Maximal exercise HR significantly decreased by 5.3 +/- 2.9 (SD)% and 11.2 +/- 3.6% 2 h after the 100- and 200-mg dose respectively, whereas placebo had no effect. Exercise BP was not significantly modified by falipamil. The slopes of HR-workload relationships significantly decreased with falipamil. Peak plasma concentrations of falipamil occurred 1-1.5 h after absorption, and the falipamil-induced decrease in exercise HR over 8 h postdosing was proportional to falipamil plasma concentrations. These results suggest that falipamil decreases HR at exercise in normal subjects and may exert antianginal effects in patients with myocardial ischemia.