Infectious complications of CAR T-cell therapy across novel antigen targets in the first 30 days.

Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated among 5 phase 1 CAR T-cell clinical trials.

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution.

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis.

Pneumocystis jirovecii Pneumonia in a Treatment-Naive Patient With Chronic Lymphocytic Leukemia.

pneumonia is a known complication in patients with chronic lymphocytic leukemia who are treated with fludarabine-based chemotherapy; however, it is extremely uncommon in treatment naïve patients. Here we report a case of pneumonia in a patient with untreated chronic lymphocytic leukemia.

Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib.

Ibrutinib is not known to confer risk for Pneumocystis jirovecii pneumonia (PCP). We observed 5 cases of PCP in 96 patients receiving single-agent ibrutinib, including 4 previously untreated. Clinical presentations included asymptomatic pulmonary infiltrates, chronic cough, and shortness of breath.

In vitro and in vivo evaluation of O-alkyl derivatives of tramadol.

Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. O-Alkyl, N-desmethyl, and non-phenol containing derivatives of tramadol were synthesized to probe their effect on metabolic stability and both in vitro and in vivo potency.

Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys.

Rationale: The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABA(A) receptor complex; however, it is not clear how enantiomers or metabolites of zopiclone contribute to the benzodiazepine-like behavioral effects of racemic zopiclone.

Objectives: Racemic zopiclone, its ( R)- and ( S)- enantiomers, and the ( S)-N-desmethyl metabolite, were evaluated for discriminative stimulus effects in untreated and diazepam treated rhesus monkeys.

Methods: One group of monkeys discriminated the benzodiazepine midazolam and another group, treated daily with the benzodiazepine diazepam (5.

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite.

We evaluated racemic zopiclone, its (S)- and (R)-enantiomers and a metabolite, (S)-desmethylzopiclone, for their actions on locomotor activity, rotarod performance, the elevated plus maze and the Vogel conflict test of anxiety, and electroconvulsive shock-induced seizures duration. Zopiclone and its (R)- and (S)-enantiomers reduced locomotor activity, and zopiclone and its (S)-enantiomer disrupted rotarod performance at 10 mg/kg. (S)-desmethylzopiclone did not alter these measures at doses of less than 200 mg/kg.

A population analysis of nebulized (R)-albuterol in dogs using a novel mixed gut-lung absorption PK-PD model.

Purpose: The objectives of this study were to 1) construct a pharmacokinetic-pharmacodynamic (PK-PD) model, and 2) determine the PKs and PDs of (R)-albuterol when given by nebulization to 8 dogs for 7 consecutive days.

Methods: Four doses were evaluated (0.002, 0.

Differential effects of spinal (R)-ketoprofen and (S)-ketoprofen against signs of neuropathic pain and tonic nociception: evidence for a novel mechanism of action of (R)-ketoprofen against tactile allodynia.

The spinal activity of racemic ketoprofen and its enantiomers in models of neuropathic and tonic pain was explored in rats. Tactile allodynia and thermal hyperalgesia were induced by tight ligation of the L(5)/L(6) spinal nerves. Tonic pain was modeled by the formalin-induced flinch response.

Enantioselective behavioral effects of sibutramine metabolites.

The anti-obesity agent, racemic (RS)-sibutramine, has two active metabolites, desmethylsibutramine and didesmethylsibutramine. To the extent that sibutramine itself mediates some of its side effects, desmethylsibutramine and/or didesmethylsibutramine might be safer and just as therapeutically effective. Because both desmethylsibutramine and didesmethylsibutramine are also optically active, the present study assessed the anorexic effects (2.

Influence of (S)-ketoprofen and fluoride on caries in rats.

Objective: Non-steroidal anti-inflammatory agents (e.g., ketoprofen) used topically appear to be effective in reducing bone loss in the ligature model of periodontitis.

Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)- ketoprofen, (R)- flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial.

Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, causes gastroduodenal hemorrhages and erosions in 10-15% of patients. The (S)- enantiomer exhibits most of the anti-inflammatory properties, with concomitant gastrointestinal toxicity. The (R)- enantiomer, however, was recently found to have analgesic properties independent of prostaglandin inhibition.

Bilateral changes in striatal dopamine metabolism after unilateral intracarotid and intrastriatal administration of apomorphine.

Following cannulation of the common carotid artery of female Sprague-Dawley rats, 3 microCi (10 micrograms) of [3H]apomorphine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following intracarotid infusion of apomorphine, approximately a 65-fold right/left difference in apomorphine concentrations was attained in all forebrain structures, and this difference steadily diminished with time as a result of declining drug levels in the infused hemisphere.

Single versus multiple infusions of fentanyl analogues in a rat EEG model.

Administration of anesthetic agents to rats produces a loss of righting (LOR) which is predictive of clinical anesthesia. Following bolus i.v.

Bilateral neurochemical changes induced by unilateral cerebral haloperidol administration: evidence for cerebral asymmetry in the rat.

Bilateral alterations in dopamine metabolism were determined in the striatum, olfactory tubercle, and frontal cortex of rats pretested for circling behavior. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine, and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography 15 min after right or left intracarotid infusion of haloperidol. Concentrations of DOPAC and HVA were significantly increased in the striatum and frontal cortex ipsilateral to the side of haloperidol infusion, regardless of whether it was right or left.

An in vivo alpha-2 assay reversal of opioid-induced muscular rigidity and neuroleptic-induced ptosis.

A method is described to detect selective alpha-2 adrenergic agonists in vivo. Palpebral ptosis is induced in rats by the neuroleptic agent haloperidol (Hal), or by tetrabenazine (TBZ) methanesulfonate. Twenty minutes later, test compounds are injected, and ptosis is scored.

New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics.

A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics.

Reversal of opioid-induced muscular rigidity in rats: evidence for alpha-2 adrenergic involvement.

Compounds from several different pharmacological classes were tested for their ability to reverse the muscular rigidity induced by an intravenous dose of fentanyl that also caused loss of the righting reflex (LOR). Opioid antagonists reversed the entire syndrome--LOR and rigidity but, generally, rigidity could be reversed nonspecifically by doses of compounds that caused LOR by themselves (e.g.

Unilateral cerebral drug administration: pharmacokinetics of haloperidol and amphetamine.

Following cannulation of the right common carotid artery of female Sprague-Dawley rats, 3 microCi (10 micrograms) of either [3H]haloperidol or [3H]amphetamine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following unilateral intracarotid infusion of haloperidol, approximately a 90-100-fold right/left (ipsilateral/contralateral) difference in drug concentrations was attained in the striatum and the posterior forebrain, while more than a 75-fold difference was evident in the anterior forebrain.

Circling behavior in mice and rats: possible relationship to isolation-induced aggression.

The relationship between circling behavior (rotation), isolation, and aggression was investigated in normal male mice and rats. Initially the animals were tested for spontaneous nocturnal rotation, then conspecific aggression and muricidal behavior was observed for mice and rats respectively. Subsequently, animals were paired on the basis of net nocturnal rotations and either group-housed or individually housed.

Intersex difference in striatal amphetamine concentration is independent of age.

Amphetamine sulfate (1.0 mg/kg) was administered intraperitoneally to two groups of male and female rats, 5 and 15 weeks of age. After 30 minutes, striata were removed and analyzed for amphetamine concentrations using gas-liquid chromatography.

Sexual dimorphism in rats with respect to locomotor activity and circling behavior.

Male and female rats were tested for locomotor activity and spontaneous circling (rotation) at 4, 6, 8, 11, 13 and 15 weeks of age. Locomotor activity of females increased with age, and significant intersex differences which became apparent by 8 weeks of age were attributed to the greater persevering tendency of the females. Spontaneous rotation, on the other hand, did not change with age and significant intersex differences were not evident.