Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP-positive populations using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP-positive small peptidergic sensory neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP-positive free nerve endings in the skin. These changes were not present in nerve-injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine-treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.

Objective Unexplained chronic cough (UCC) is a perplexing condition treated with neuromodulators. Although previous literature describes the effectiveness of neuromodulators, there is little on the development of tachyphylaxis or dependence to neuromodulators over time. Our objective is to capture the experience of a large cohort of patients with UCC over an extended period, looking for these 2 phenomena. Study Design Case series with chart review. Setting Tertiary care hospital. Subjects and Methods We performed a retrospective review of patients diagnosed with UCC from 2010 to 2014. Patient outcomes were measured through percentage improvement scores. Treatment failures were attributed to no benefit, intolerable side effects, or tachyphylaxis. Tachyphylaxis was defined as the need for higher doses of medication following diminishing therapeutic benefit, while dependence was defined as a failure to stop therapy following attempted de-escalation or resurgence following drug cessation. Results Sixty-eight patients were included in the study. Tachyphylaxis was observed among 35% of patients while dependence was observed among 27% of successfully treated patients, together effecting >50% of the cohort. Sixty-eight percent of patients ultimately experienced successful treatment with neuromodulators, demonstrating strikingly distinct responses to different neuromodulator drug classes. Conclusion Tachyphylaxis and dependence occur frequently during UCC treatment and have a major impact on treatment outcomes. Patients sometimes demonstrate distinct responses to different neuromodulator classes. The majority of patients will experience successful treatment for their cough, although several trials may be required.

Because of the low levels of nortriptyline in breastmilk, amounts ingested by the infant are small and usually not been detected in the serum of the infant, although the less active metabolites are often detectable in low levels in infant serum. Immediate side effects have not been reported and a limited amount of follow-up has found no adverse effects on infant growth and development. Most authoritative reviewers consider nortriptyline one of the preferred antidepressants during breastfeeding.[1][2][3]

Candida albicans is a commensal yeast of the human body, able to form biofilms on solid surfaces such as implanted medical devices, and contributes to nosocomial infections. Biofilms have the capacity to resist to higher levels of antifungals compared to planktonic cells and can develop tolerance to commonly used treatments. The necessity to overcome acquired drug resistance, and identify new active molecules with low toxicity is a significant problem. It has been reported that some antidepressants have antibacterial properties, but little is known on the effect that these drugs have on fungi. In this paper, it is demonstrated the capacity to inhibit Candida growth and biofilm formation by the three tricyclic antidepressants doxepin, imipramine, and nortriptyline. The antimicrobial potential of the drugs was assessed by studying gene expression, hyphae formation, biofilm growth, and maturation. Their negative impact on the growth of Candida albicans, and other Candida species is shown in vitro, and with the hepatic S9 system, which is preliminary to any in vivo test. It is here demonstrated that the molecules considered can inhibit not only hyphae, and biofilm formation, but also killed cells in a mature biofilm. Moreover, cell lysis by the tricyclic antidepressant nortriptyline is shown, along with its synergistic activity with amphotericin B. These findings suggest that tricyclic antidepressants, and particularly nortriptyline, might be further studied in drug repositioning programs to fully assess their antimycotic capacity.

The physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite-nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology. The cardiac effect with regard to QT and RR interval lengths was assessed. The Emax model to describe the relationship between amitriptyline concentration and heart rate (RR) length was proposed. The developed PBPK model was used to mimic 29 clinical trials and 19 cases of amitriptyline intoxication. Three clinical trials and 18 cases were simulated with the use of PBPK-QSTS approach, confirming lack of cardiotoxic effect of amitriptyline in therapeutic doses and the increase in heart rate along with potential for arrhythmia development in case of amitriptyline overdose. The results of our study support the validity and feasibility of the PBPK-QSTS modeling development for personalized medicine.

Background and purpose Postherpetic neuralgia (PHN) is a complication of acute herpes zoster (HZ). The evidence base for management of PHN has increased by recent publications. Therefore, we reviewed incidence of HZ, prevalence, risk factors, and mechanism of PHN pain, prevention and treatment of PHN with special interest in studies on adult vaccination and topical application of lidocaine and concentrated capsaicin patch. Methods We searched databases with an English language restriction: MEDLINE 1944-2011, EMBASE 1988-2011, PubMed, and the Cochrane Controlled Trial Register and Cochrane Library (2011). From retrieved publications, we selected studies focusing on our main goals, prevention and treatment of PHN in particular. The review was therefore systematic, but with a pragmatic approach to which studies to select for closer review. Results From the large number of abstracts retrieved we selected 65 papers for closer review and as evidence base for our conclusions and recommendations for prevention and treatment of HZ and PHN. The incidence of HZ and risks of having PHN after HZ increases markedly with age above 60-70. Severity of symptoms and their impact on quality of life is a major health problem of persons above 70 years of age. Adult vaccination with the reinforced varicella virus vaccine reduces the incidence of HZ and PHN by about 50%. This is an important health and quality of life gain for the elderly. Antiviral drugs given early in an episode of HZ reduce pain and duration of HZ and decrease the risk of PHN. Pharmacological management of PHN are with nortriptyline (or amitriptyline in the younger patients), and or a gabapentinoid as first line drugs. Early treatment also is with topical lidocaine for immediate but short-lasting relief of burning hyperalgesia, and topical capsaicin relieving hypersensitivity for up to 12 weeks. A number of second and third line drugs have less evidence-base for effect, and often more adverse effects than the first line drugs: serotonin and noradrenaline uptake inhibitors (venlafaxin, duloxetin), antiepileptics (valproate), and opioid analgesics. Opioids are indicated for bridging in patients with severe PHN-symptoms while waiting for the more specific first line drugs to take effect. In these elderly patients, systemic pharmacological treatments are always a difficult balance between effects and adverse effects. It is important with close supervision of the patients, especially during start-up of systemically administered drugs, in order to prevent tragic complications from falls in sedated, dizzy, and confused elderly patients. Topical treatment with lidocaine and capsaicin patches does not have these problems. Conclusions Prevention of this significant health problem of the increasing elderly population is now possible through adult vaccination against varicella zoster virus (VZV) reactivation, as well as vigorous and early antiviral treatment during acute HZ. The evidence -base supports the oral use of tricyclic antidepressants, gabapentinoids, and opioids for bridging till the first line drugs take effect. Topical therapy with lidocaine and capsaicin patches is effective and well supported by evidence. A number of second and third line drugs and treatments are available, but have less evidence-base. All drug treatments, except topical lidocaine and capsaicin, have adverse effects that are often problematic and can be dangerous in the elderly patients. Close supervision of the patients is mandatory. Implications Recent advances in prevention and management of this serious health problem should be better known and implicated: Adult vaccination for prevention of varicella zoster virus reactivation, antiviral drugs and combinations of drugs can reduce the suffering from acute HZ and chronic PHN. Topical lidocaine and capsaicin are now evidence-based therapies that reduce suffering from hypersensitivity and hyperalgesia in patients with PHN. When properly applied, they have few complications.

Seven commonly utilized antidepressants (amitriptyline, fluoxetine, sertraline, citalopram, paroxetine, venlafaxine, and bupropion) and three of their metabolites were detected in four wastewater treatment plants (WWTPs) and corresponding receiving waters including the mainstream and three of the tributaries of Huangpu River, Shanghai. The concentration levels of selected antidepressants in wastewater and receiving water were both at ng L-1 level, but those antidepressants that were found in wastewater were typically in a range of one and even two orders of magnitude higher than those that were present in the receiving water except for the concentration levels of paroxetine, norfluoxetine, and nortriptyline. Venlafaxine and its metabolite O-desmethylvenlafaxine were the primary compounds (reaching up to 132.04 and 173.68 ng L-1 as well as 3.03 and 4.53 ng L-1 in wastewater and receiving water, respectively). Based on the mass loadings of selected antidepressants in four WWTPs, the mass loading of sertraline in effluent for this study was at the highest level when compared to other countries. The important finding was that the sampling sites H11 and H13 were much more likely to be polluted by side-pollution sources (the accumulation areas of Grade A of Class-three hospitals and pharmaceutical factories) than point pollution sources (WWTP 1 and WWTP2) through analysis of Spearman correlation. The results have shown that the RQs for these antidepressants were less than 0.1 except for the RQ of venlafaxine in an effluent for mollusks, which was less than 1. This indicated that the concentration levels of antidepressants would not pose a high risk for aquatic organisms, but sustained attention should still be paid.

The inward rectifier potassium (Kir) channel Kir4.1 (KCNJ10) carries out important physiologic roles in epithelial cells of the kidney, astrocytes in the central nervous system, and stria vascularis of the inner ear. Loss-of-function mutations in KCNJ10 lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, and sensorineural deafness. Although genetic approaches have been indispensable for establishing the importance of Kir4.1 in the normal function of these tissues, the availability of pharmacological tools for acutely manipulating the activity of Kir4.1 in genetically normal animals has been lacking. We therefore carried out a high-throughput screen of 76,575 compounds from the Vanderbilt Institute of Chemical Biology library for small-molecule modulators of Kir4.1. The most potent inhibitor identified was 2-(2-bromo-4-isopropylphenoxy)-N-(2,2,6,6-tetramethylpiperidin-4-yl)acetamide (VU0134992). In whole-cell patch-clamp electrophysiology experiments, VU0134992 inhibits Kir4.1 with an IC50 value of 0.97 µM and is 9-fold selective for homomeric Kir4.1 over Kir4.1/5.1 concatemeric channels (IC50 = 9 µM) at -120 mV. In thallium (Tl+) flux assays, VU0134992 is greater than 30-fold selective for Kir4.1 over Kir1.1, Kir2.1, and Kir2.2; is weakly active toward Kir2.3, Kir6.2/SUR1, and Kir7.1; and is equally active toward Kir3.1/3.2, Kir3.1/3.4, and Kir4.2. This potency and selectivity profile is superior to Kir4.1 inhibitors amitriptyline, nortriptyline, and fluoxetine. Medicinal chemistry identified components of VU0134992 that are critical for inhibiting Kir4.1. Patch-clamp electrophysiology, molecular modeling, and site-directed mutagenesis identified pore-lining glutamate 158 and isoleucine 159 as critical residues for block of the channel. VU0134992 displayed a large free unbound fraction (fu) in rat plasma (fu = 0.213). Consistent with the known role of Kir4.1 in renal function, oral dosing of VU0134992 led to a dose-dependent diuresis, natriuresis, and kaliuresis in rats. Thus, VU0134992 represents the first in vivo active tool compound for probing the therapeutic potential of Kir4.1 as a novel diuretic target for the treatment of hypertension.