Hiding in Plain Sight: A Case of Perinephric Abscess Diagnosed by POCUS.

An 87 year old male with obstructive uropathy was initially diagnosed with acute kidney injury (AKI), a new renal mass and hydronephrosis. When transferred to a facility with a hospital medicine POCUS program, the renal mass was correctly identified as a perinephric abscess, which was percutaneously drained leading to resolution of AKI and the underlying infection. Renal POCUS is readily taught via brief educational interventions and empowers providers to identify common (hydronephrosis) and uncommon (perinephric abscess) renal pathology at the bedside.

Relative bioavailability of salicylic acid following dermal application of a 30% salicylic acid skin peel preparation.

A single-center, single-sequence, two-period crossover study was performed to compare the systemic exposure to salicylic acid (SA) following facial application of a 30% SA cosmetic skin peel formulation applied for 5 min and an oral dose of 650 mg aspirin in nine healthy male and female subjects. The mean (SD) maximum SA concentration (Cmax) was 0.81 (0.32) microg/mL and 56.4 (14.2) microg/mL. The AUC-based safety margin ratio was 50:1. A depot effect was observed during topical application of the skin peel solution as the absorption of SA continued beyond the 5-min application period. Plasma SA Cmax values were achieved from 1.4 to 3.5 h after topical application and from 0.5 to 1.5 h after oral aspirin. The plasma concentrations in the present study (30%; 5 min) were similar to that of a low concentration (2%) applied in a leave-on product to the same body surface area. In conclusion, our results suggest that the use of this SA facial peel should not pose any significant systemic health risks.

Posterior reversible encephalopathy syndrome after renal transplant: a simple solution for a complicated patient.

BACKGROUND: Posterior reversible leukoencephalopathy syndrome (PRES) is characterized by an acute neurologic dysfunction coupled with characteristic findings on brain imaging. PRES occurs in the setting of hypertensive emergencies, eclampsia and as a neurotoxic effect of immunosuppressive agents. While overwhelmingly reversible without residual deficits when promptly recognized, vague symptomatology may delay the diagnosis of PRES. RESULTS/SUMMARY: A 50-year-old man who had undergone a recent kidney transplant was admitted to our clinic due to multiple episodes of seizure. He had no prior history of seizures or alcoholism. His transplantation had been without complication; he was discharged and given prednisone, tacrolimus, mycophenolate, acyclovir, trimethoprim-sulfamethoxazole, atenolol and enalapril. On the day of presentation, he experienced a severe headache, blurred vision and tonic-clonic seizure-like activity. His neurologic examination was limited by sedation, although no focal deficits were evident. Laboratory studies were unremarkable. A lumbar puncture revealed normal opening pressure, negative Gram stain, benign CSF analysis and India ink preparation. An MRI of the brain revealed bilateral enhancing parietal-occipital lesions, seen prominently on FLAIR sequence. Tacrolimus and all other medications were continued. The patient remained afebrile and normotensive and was extubated on the second hospital day. The patient reported no neurologic symptoms and was discharged on the third hospital day after a full recovery. CONCLUSIONS: While the outcome of PRES is typically benign, a delay in diagnosis may lead to permanent neurologic deficits, and misdiagnosis can be lethal. The cornerstone of treatment is removal of the offending agent or treatment of the underlying etiology. A clinical picture of headache, visual abnormalities, altered mentation and seizures is sufficient to prompt an empiric discontinuation of agents known to cause PRES. Calcineurin inhibitors such as tacrolimus are known to cause PRES, and in our patient, discontinuation led to a complete clinical resolution.

Studies of the safety, pharmacokinetics and immunogenicity of repeated doses of intravenous staphylococcal protein A in cynomolgus monkeys.

Three Good Laboratory Practice safety studies were performed with intravenous injections of highly purified staphylococcal protein A (SPA) in cynomolgus monkeys, in support of a clinical development programme utilizing this protein as an immunomodulator. These studies established a no-observable-adverse-effect level (NOAEL) for up to 12 weekly doses of SPA, as well as toxicokinetic profiles for SPA, evaluation of antiproduct antibodies and biomarkers to better characterize the pharmacodynamic response to SPA. Biomarkers included neopterin, C-reactive protein (CRP), troponin I and the change in the blood absolute lymphocyte count (ALC) 24 hr after SPA dosing. The transient decrease in ALC noted at 24 hr after dosing was similar to that seen in human Phase 1 trials. The majority of active-treated monkeys developed antibodies against SPA. Cmax was not affected by development of antidrug antibodies (ADAs), and after the first dose was 87 (SD 19) ng/mL, 330 (SD 84) ng/mL and 1191 (SD 208) ng/mL for 5, 25 and 100 µg/kg doses, respectively. The development of ADAs increased plasma clearance of SPA. By the sixth weekly dose, the AUC was decreased by 76%, 54% and 66% for the 5, 25 and 100 µg/kg dose groups, respectively. These results indicate that SPA can be administered intravenously to non-human primates without observable toxicity at weekly doses of up to 100 µg/kg.

Tolerability and pharmacokinetic properties of ondansetron administered subcutaneously with recombinant human hyaluronidase in minipigs and healthy volunteers.

BACKGROUND: Subcutaneous ondansetron facilitated by recombinant human hyaluronidase PH20 (rHuPH20) is an alternative for treating nausea/vomiting in patients who cannot receive ondansetron by other routes of administration. OBJECTIVE: Based on preclinical results in minipigs, a Phase I study was designed to assess the tolerability and pharmacokinetic properties of subcutaneous ondansetron + rHuPH20 compared with intramuscular, intravenous, or oral ondansetron monotherapy in healthy volunteers. METHODS: In a crossover design, 3 minipigs were dosed with subcutaneous ondansetron 0.08 mg/kg + rHuPH20, or as intramuscular or intravenous monotherapy, for the evaluation of plasma ondansetron concentrations and local tolerability. In a randomized, open-label, 4-way crossover study, subjects received a randomized sequence of SC ondansetron 4 mg + rHuPH20, or ondansetron monotherapy IM (4 mg), IV (4 mg), or PO (8 mg), over 4 daily visits. Study participants included healthy volunteers aged 19 to 65 years with adequate venous access in both upper extremities and no history of QT-interval prolongation. Primary tolerability end points (administration-site observations, systemic adverse events [AEs], and subject-assessed pain) were assessed, and pharmacokinetic parameters (AUC, Cmax, Tmax, t½) were computed to compare relative rate and extent of systemic exposure. Results were described using summary statistics, and bioequivalence was determined with a linear mixed-effects model. RESULTS: In the preclinical study, no adverse events or significant local reactions were observed. The Cmax (45.8 ng/mL at 0.08 hour) with subcutaneous administration + rHuPH20 was 83% greater and was achieved 68% faster than with intramuscular administration (Cmax = 25 ng/mL at 0.25 hour). In the clinical study, a total of 12 subjects (7 women, 5 men; white majority; mean age, 44.8) were randomized. The majority of AEs were at the injection site, mild in severity, and transient. After subcutaneous administration of ondansetron + rHuPH20, geometric mean Cmax was 35% higher than with intramuscular ondansetron, 43% lower than with intravenous ondansetron, and 126% higher than with oral ondansetron (corrected for dose). Bioequivalence tests demonstrated that systemic exposure after subcutaneous administration was similar to that after intramuscular or intravenous administration and significantly greater than that after oral administration. CONCLUSIONS: Subcutaneous ondansetron + rHuPH20 was generally well-tolerated. Subcutaneous dosing resulted in an extent of systemic exposure similar to that with intramuscular or intravenous dosing and greater than that with oral administration, and may be an option for clinical administration of ondansetron. ClinicalTrials.gov identifier: NCT01572012.

Safety, pharmacokinetic, immunogenicity, and pharmacodynamic responses in healthy volunteers following a single intravenous injection of purified staphylococcal protein A.

A single-dose study was conducted to characterize the safety, pharmacokinetic, immunogenicity, and pharmacodynamic activity of highly purified Staphylococcal protein A (SPA), a native bacterial protein with immune-modulatory activity. Twenty healthy adults received a single intravenous dose of either 0.3 µg/kg (n = 8) or 0.45 µg/kg (n = 8) of SPA or placebo (n = 4). Changes in C-reactive protein and neopterin were used as markers of immune activation. All treatment-related AEs were of mild severity. Twelve of 16 active-dosed subjects developed detectable anti-protein A antibodies after dosing. These subjects had notably more rapid plasma clearance of SPA even prior to development of detectable titers. A transient post-dose decrease in circulating lymphocytes was observed as a notable pharmacodynamic effect, but was not correlated with plasma clearance or AUC. In peripheral blood mononuclear cells, SPA dosing increased transcription of multiple genes regulated by type-1 interferons, and up-regulation of several of these genes correlated with the degree of lymphopenia seen 24 hours after dosing. This study demonstrates the safety and tolerability of small intravenous doses of SPA and delineates acute and transient pharmacodynamic effects not previously reported.

Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults.

PURPOSE: To investigate the safety, tolerability, and pharmacokinetics (PKs) of topical SAR 1118 Ophthalmic Solution in healthy adults. SAR 1118 is an investigational small molecule lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLß2) antagonist that inhibits LFA-1 binding to intercellular adhesion molecule-1 (ICAM-1; CD54) targeting T-cell-mediated inflammation. METHODS: A randomized, double-masked, placebo-controlled, dose-escalation study of SAR 1118 was performed in 4 cohorts with 7 randomized subjects per cohort (2 placebo: 5 active drug subjects; 0.1%, 0.3%, 1.0%, 5.0%) in 28 healthy adults. Dosing was divided into 3 periods each separated by a 72-h treatment-free observation: once-daily (QD) × 1, twice-daily (BID) × 10, and thrice-daily (TID) × 10 days. Data obtained at the beginning and end of each period included: slit-lamp, best-corrected visual acuity (BCVA), Schirmer tear test (STT) without anesthesia, tear film break-up time (TBUT), intraocular pressure (IOP), and tear/plasma samples for PK analysis. RESULTS: All subjects completed the study; there were no tolerability issues or missed treatments (total, 1,428 administered doses). No serious ocular or nonocular adverse events (AEs) occurred over 1,148 subject study days (41 days/subject) and no significant abnormalities were identified on ocular exam. There were 38 ocular AEs (N = 11 subjects) and 21 nonocular AEs (N = 11 subjects). Most AEs were mild in severity and occurred in the 0.3% and placebo groups. No changes were observed in CD3, CD4, and CD8 blood lymphocyte counts. Tear PK profiles support a QD/BID dosing schedule. Plasma levels of SAR 1118 in the 0.1% and 0.3% groups were below level of quantitation (BLQ; <0.50 ng/mL) at all time points and transiently detected within the first 5 min to ∼1 h following administration in the 1.0% and 5.0% groups. CONCLUSION: SAR 1118 Ophthalmic Solution appears safe and well-tolerated up to 5.0% TID in healthy adult subjects. PK analysis shows adequate ocular exposure with minimal systemic exposure.

Confirmatory reanalysis of incurred bioanalytical samples.

Bioanalytical methods used to support the drug development process are validated to ensure that they function in the manner in which they are intended. "Incurred" or study samples can vary in their composition when compared with the standards and quality control samples used to validate the method and analyze these samples. During the 3rd American Association of Pharmaceutical Scientists(AAPS)/Food and Drug Administration(FDA) Bioanalytical Workshop, it was suggested that the reproducibility in the analysis of incurred samples be evaluated in addition to the usual prestudy validation activities performed. This manuscript provides recommendations concerning the number and types of samples that should be analyzed in such an evaluation, as well as the manner in which the resultant data should be analyzed. Suggestions as to follow-up activities and data reporting are also discussed. This approach is at best a beginning and is offered as a platform for future discussion, comments, and revision.