Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure

Pulmonary administration provides a useful alternative to oral and invasive routes of administration while enhancing and prolonging the accumulation of drugs into the lungs and reducing systemic drug exposure. In this study, chloroquine, as a model drug, was loaded into niosomes for potential pulmonary administration either via dry powder inhalation or intratracheally. Chloroquine-loaded niosomes have been prepared and extensively characterized. Furthermore, drug-loaded niosomes were lyophilized and their flowing properties were evaluated by measuring the angle of repose, Carr’s index, and Hausner ratio. The developed niosomes demonstrated a nanosized (100–150 nm) spherical morphology and chloroquine entrapment efficiency of ca. 24.5%. The FT-IR results indicated the incorporation of chloroquine into the niosomes, whereas in vitro release studies demonstrated an extended-release profile of the drug-loaded niosomes compared to the free drug. Lyophilized niosomes exhibited poor flowability that was not sufficiently improved after the addition of lactose or when cryoprotectants were exploited throughout the lyophilization process. In vivo, intratracheal administration of chloroquine-loaded niosomes in rats resulted in a drug concentration in the blood that was 10-fold lower than the oral administration of the free drug. Biomarkers of kidney and liver functions (i.e., creatinine, urea, AST, and ALT) following pulmonary administration of the drug-loaded nanoparticles were of similar levels to those of the control untreated animals. Hence, the use of a dry powder inhaler for administration of lyophilized niosomes is not recommended, whereas intratracheal administration might provide a promising strategy for pulmonary administration of niosomal dispersions while minimizing systemic drug exposure and adverse reactions.

Oral Lichenoid Reaction: An Uncommon Side Effect of Rituximab

Oral lichenoid reactions (OLR) can be caused by systemic drug exposure. To the best of our knowledge, this is the second report describing a case of OLR induced by rituximab administration in a patient with a diagnosis of non-Hodgkin B-cell lymphoma. After 5 doses of rituximab, a typical pattern of OLP was identified with bilateral and symmetrical lesions on the buccal mucosa and on the right lingual margin. This temporal relationship suggested a probable association between oral lesions and drug therapy. The clinical diagnosis of a rituximab-induced OLR was confirmed by an incisional biopsy reporting a histopathological result of lichenoid mucositis consistent with oral lichen planus. Because of the increasing use of rituximab, it is necessary to know and recognize this uncommon side effect.

Intrathecal Riluzole for the Treatment of Patients With Amyotrophic Lateral Sclerosis

INTRODUCTION Oral riluzole is the only approved treatment known to improve survival in patients with amyotrophic lateral sclerosis (ALS), with modest efficacy and dosing limited by hepatic toxicity and asthenia. We postulated that a continuous intrathecal (IT) delivery of low daily doses of riluzole could elevate spinal cord (SC) concentrations well above those achievable with oral treatment alone, without increasing side-effects. METHODS A 6-wk and a 24-wk GLP study were conducted to evaluate the safety of IT riluzole in purpose-bred hound dogs. Oral riluzole, equivalent to 50 mg BID in humans, was administered in combination with one of 3 IT doses given through continuous infusion. Plasma, SC, and brain concentrations of riluzole were measured, along with assessments of safety and tolerability. RESULTS In the 6-wk study, when combining the oral and IT routes, IT infusion significantly increased SC concentrations well above those achieved with oral drug administration alone, without increasing brain concentrations. All IT doses in combination with oral administration were well tolerated by the animals. In the 6-mo study, the lowest dose used in the 6-wk study was dropped and a higher dose was added. This highest dose of IT riluzole was not tolerated by the dogs and yielded SC and brain concentrations significantly higher than achieved in any of our previous studies. CONCLUSION Continuous IT administration of riluzole when combined with oral administration can increase the SC concentration of riluzole above those achievable with oral therapy, without increasing the risk for adverse events associated with systemic drug exposure or off-target side-effects in the brain. Therefore, IT riluzole infusion when used in conjunction with oral therapy may safely enhance lower motor neuron neuroprotection and improve the survival benefit of the drug through enhanced SC delivery, and, with a careful selection of IT doses, it could be implemented in patients with ALS.

Symmetrical drug-related intertriginous and flexural exanthema due to clindamycin

Systemic drug exposure can produce a skin reaction consisting of symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) occurs after systemic exposure to a drug in which the patient was not previously sensitised, either in the first dose or after several doses. The mechanism of SDRIFE is unknown but is hypothesised to be the result of a delayed hypersensitivity response resulting in a cutaneous eruption some days after the exposure to the drug. The diagnosis should be clinical, based on the history and examination, but skin tests can also be performed to confirm sensitisation. But, as always, the gold-standard test is oral provocation. It is important to know this clinical entity to prevent re-exposure to the responsible allergen in the future.

Feasibility of a Fixed-Dose Regimen of Pyrazinamide and Its Impact on Systemic Drug Exposure and Liver Safety in Patients with Tuberculosis

ABSTRACTHistorically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [Cmax]), the time above the MIC (t> MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.