Intra- and inter-session reliability of electrical detection and pain thresholds of cutaneous and muscle primary afferents in the lower back of healthy individuals.

To advance evidence-based practice and targeted treatments of low back pain (LBP), a better pathophysiological understanding and reliable outcome measures are required. The processing of nociceptive information from deeper somatic structures (e.g., muscle, fascia) might play an essential role in the pathophysiology of LBP. In this study, we measured the intra- and inter-session reliability of electrical detection and pain thresholds of cutaneous and muscle primary afferents of the lower back. Twenty healthy participants attended two study visits separated by 27.7 ± 1.7 days. To determine the location-specific electrical detection threshold (EDT) and pain threshold (EPT), needle electrodes were inserted in the epidermal layer over, and in the lumbar erector spinae muscle. Additionally, established quantitative sensory testing (QST) parameters were assessed. Reliability was determined by differences between measurements, intraclass correlation coefficients (ICC2,1), Bland-Altman plots, and standard error of measurement (SEM). Correspondence between QST parameters and electrical thresholds was assessed using Pearson's correlation. Except for cutaneous EPT, no significant (p ≤ 0.05) intra- and inter-session differences were observed. Excellent intra-session reliability was shown for cutaneous and intramuscular electrical stimulations and all QST parameters (ICC: 0.76-0.93). Inter-session reliabilities were good (ICC: 0.74-0.75) except for electrical stimulations (ICC: 0.08-0.36). Limits of agreement and SEM were higher for inter-session than intra-session. A medium to strong relationship was found between electrical and mechanical/pressure pain thresholds. In conclusion, cutaneous and intramuscular electrical stimulation will potentially close an important diagnostic gap regarding the selective examination of deep tissue afferents and provide location-specific information for the excitability of non-nociceptive and nociceptive afferents.

Increased levels of urinary phenylacetylglycine associated with mitochondrial toxicity in a model of drug-induced phospholipidosis.

BACKGROUND: Phospholipidosis (PLD) is a lysosomal storage disorder induced by a class of cationic amphiphilic drugs. However, drug-induced PLD is reversible. Evidence of PLD from animal studies with some compounds has led to discontinuation of development. Regulatory authorities are likely to request additional studies when PLD is linked to toxicity. OBJECTIVE: We conducted a trial to investigate urinary phenylacetylglycine (uPAG) as a biomarker for PLD. MATERIALS AND METHODS: Five groups of 12 male Wistar rats were dosed once with vehicle, 300 mg/kg or 1500 mg/kg of compound A (known to induce PLD), or 300 mg/kg or 1000 mg/kg of compound B (similar structure, but does not induce PLD) to achieve similar plasma exposures. Following dosing, urine and blood samples underwent nuclear magnetic resonance (NMR), proteomic, and biochemical analyses. Necropsies were performed at 48 and 168 h, organ histopathology evaluated, and gene expression in liver analyzed by microarray. Electron microscopic examination of peripheral lymphocytes was performed. RESULTS: For compound A, uPAG increased with dose, correlating with lamellar inclusion bodies formation in peripheral lymphocytes. NMR analysis showed decreased tricarboxylic acid cycle intermediates, inferring mitochondrial toxicity. Mitochondrial dysfunction was suggested by uPAG increase, resulting from a switch to anaerobic metabolism or disruption of the urea cycle. DISCUSSION AND CONCLUSION: uPAG shows utility as a noninvasive biomarker for mitochondrial toxicity associated with drug-induced PLD, providing a mechanistic hypothesis for toxicity associated with PLD likely resulting from combined direct and indirect mitochondrial toxicity via impairment of the proton motor force and alteration of fatty acid catabolism.

In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.

Phospholipidosis (PLD) is a lysosomal storage disorder induced by compounds, notably cationic amphiphilic drugs, which although reversible interferes with cellular phospholipids.The in silico method described utilizes the amphiphilic moment ΔΔG(AM) (kJ/mol) together with basic pK(a) values to assign PLD inducing potential to a compound. The new model was accurate and sensitive (85% and 82%, respectively) when compared to other data sets. Therefore, the parallel in vitro assay for PLD was discontinued. The data reinforce our view that the amphiphilic moment is far more informative for determining a compound's potential to induce PLD than the combined use of basic pK(a) and ClogP values.

An aminomethylpyrimidine DPP-IV inhibitor with improved properties.

A recently identified DPP-IV inhibitor (1) was found to induce phospholipidosis and to inhibit CYP3A4. A small series of less lipophilic and less amphiphilic analogues was synthesized in an effort to overcome these issues. One compound from this series was equipotent to 1, did not induce phospholipidosis and showed a reduced CYP3A4 inhibition.