In this issue of JEM, Chu and An et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20221316) describe the role of the tricyclic antidepressant nortriptyline in inhibition of fatty acid uptake. Nortriptyline promotes cell acidification and suppresses macropinocytosis, providing a link between fatty acid uptake and tumor progression.

This study aimed to compare the efficacy and safety of Vernonia cinerea (VC) and nortriptyline for smoking cessation. A randomized, active-comparator, open-label trial was conducted in 2019. A total of 84 patients participated in the study, and equally randomized with 42 participants in each group. Overall, there was no statistically significant difference of continuous abstinence rate (CAR) between VC and nortriptyline group (Odd ratio 0.68, 95%CI 0.25-1.85, P=0.451). After week 12, the end of treatment, CAR between both groups was not different (44.44% vs 45.95%, Odd ratio 0.77, 95%CI 0.23-2.54, P>0.999). After follow up by the end of research at week 24, the CAR in both groups was not different (41.67% vs 43.24%, Odd ratio 0.76, 95%CI 0.23-2.55, P>0.999). After week 24, relapse rate between VC and nortriptyline group was not different (13.89% vs 10.81%, P=0.923). In addition, both groups were effective in reducing the number of cigarettes per day compared to baseline. However, there was no difference between the groups. Overall, the VC group had an 8% smoking rate less than nortriptyline group, but not statistically significant (IRR 0.92, 95%CI 0.59-1.43, P=0.702). They also resulted in reducing the exhaled CO level at treatment period and wash out period (at week 12; 7(-17-20) vs 7(-12-16), mean difference 0.78, 95%CI -3.07-4.63, P>0.999, at week 24; 8(-5-22) vs 8.5(-5-17), mean difference 0.39, 95%CI -3.46-4.24, P>0.999). Overall, there was no difference between either group (mean difference -0.31, 95%CI -3.10-2.47). For safety data, adverse events including tongue bitter taste or numbness were found in VC group to be greater than in nortriptyline group (61.9% vs 30.95%, P=0.004), whereas dry mouth and drowsiness were greater found in nortriptyline group (35.71% vs 90.48%, P<0.001 and 16.67% vs 90.48%, P<0.001, respectively). Serious adverse events were not found. In smoking cessation, efficacy and safety of either VC or nortriptyline showed no difference.

In the present study, on-chip electromembrane surrounded solid phase microextraction (EM-SPME) was employed in the determination of tricyclic antidepressants (TCAs), including amitriptyline, nortriptyline, imipramine, desipramine, maprotiline, and sertraline, from various biological fluids. In this regard, poly(3,4-ethylenedioxythiophene)-graphene oxide (PEDOT-GO) was electrodeposited on an SPME fiber as a conductive coating, then the fiber played the acceptor-electrode role during the extraction. Thus, the immigration of the analytes under the influence of an electric field and their absorption onto the fiber coating were accomplished simultaneously. Under the optimized conditions, the limits of detection for the target analytes were acquired in the range of 0.005-0.025 µg L-1 using gas chromatography-mass spectrometry. The linearity of the method was 0.010-500 µg L-1 for the imipramine and sertraline, 0.025-500 µg L-1 for the amitriptyline, nortriptyline, and desipramine, and 1.000-250 µg L-1 for the maprotiline (R2 ≥ 0.9984). Moreover, this method provided suitable precision and fiber-to-fiber reproducibility, with RSDs ≤ 8.4%. The applicability of the proposed setup was eventually investigated for extraction of the drugs from human bone marrow aspirate, urine, plasma, and well water samples, in which satisfactory relative recoveries, from 93-105%, were obtained.

Purpose: Treatment of chemotherapy-induced peripheral neuropathy (CIPN) is challenging for clinicians, and many clinical trials and meta-analyses on CIPN are controversial. There are also few comparisons of the efficacy among drugs used to treat CIPN. Therefore, this systematic review aimed to study the efficacy of drugs in treating CIPN using existing randomized controlled trials. Methods: Electronic databases were searched for randomized controlled trials (RCTs) involving any pharmaceutical intervention and/or combination therapy of treating CIPN. Results: Seventeen RCTs investigating 16 drug categories, duloxetine, pregabalin, crocin, tetrodotoxin, venlafaxine, monosialotetrahexosyl ganglioside (GM1), lamotrigine, KA (ketamine and amitriptyline) cream, nortriptyline, amitriptyline, topical Citrullus colocynthis (bitter apple) oil, BAK (baclofen, amitriptyline hydrochloride, and ketamine) pluronic lecithin organogel, gabapentin, and acetyl l-carnitine (ALC), in the treatment of CIPN were retrieved. Many of the included RCTs consisted of small sample sizes and short follow-up periods. It was difficult to quantify due to the highly variable nature of outcome indicators. Conclusion: Duloxetine, venlafaxine, pregabalin, crocin, tetrodotoxin, and monosialotetrahexosyl ganglioside exhibited some beneficial effects in treating CIPN. Duloxetine, GM1, and crocin showed moderate benefits based on the evidence review, while lamotrigine, KA cream, nortriptyline, amitriptyline, and topical Citrullus colocynthis (bitter apple) oil were not beneficial. Further studies were necessary to confirm the efficacy of gabapentin in the treatment of CIPN because of the controversy of efficacy of gabapentin. Furthermore, BAK topicalcompound analgesic gel only had a tendency to improve the CIPN symptoms, but the difference was not statistically significant. ALC might result in worsening CIPN. Most studies were not of good quality because of small sample sizes. Therefore, standardized randomized controlled trials with large samples were needed to critically assess the effectiveness of these drugs in treating CIPN in the future.

Some of the most commonly used analgesic drugs in animals are of questionable efficacy or present adverse side effects among the various species of reptiles. Tricyclic antidepressants have been demonstrated to have antinociceptive effects in several animal models of pain and could be a good alternative for use in reptiles. The aim of the study was to investigate the antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise. A total of 24 animals weighing 600-1000 g were used for nociceptive tests, i.e., formalin, capsaicin, and hot plate tests. Drugs were administered intracoelomically 30 min before starting the tests. The time spent in nocifensive behavior and the associated observable effects during the tests were recorded. Only the highest dose of 40 mg/kg of nortriptyline hydrochloride caused statistically significant decrease in nocifensive behavior in both the formalin and the capsaicin test. Desipramine hydrochloride at doses of 20 and 40 mg/kg caused statistically significant decrease in nocifensive behavior in the formalin test. Also, desipramine hydrochloride at doses of 15, 20, and 60 mg/kg caused statistically significant decrease in nocifensive behavior in the capsaicin test. None of the doses used for both drugs had any statistically significant effect on nocifensive behavior in the hot plate test. The results show that nortriptyline and desipramine hydrochloride have significant antinociceptive effects in the chemical but not thermal inflammatory pain-related behavior in the Speke's hinge-back tortoise. The most common associated side effect following administration of the higher doses of either of the drugs is excessive salivation.

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.

A solid phase extraction-based (SPE) procedure for simultaneous preconcentration of five tricyclic antidepressants (TCAs), amitriptyline hydrochloride (AMT), nortriptyline hydrochloride (NOR), doxepin hydrochloride (DOX), imipramine hydrochloride (IMI), and clomipramine hydrochloride (CLO) from water samples with determination by HPLC-DAD is proposed. Polymers were characterized by FT-IR, SEM, and thermogravimetric analysis. SPE-based methods were carried out by the preconcentration of 320.0 mL of TCAs at pH 7.0 (buffered with 0.01 mol L-1 phosphate buffer) through 70.0 mg of adsorbent packed into a SPE cartridge, followed by elution with 1.0 mL of ACN : MeOH : acetic acid solution (45 : 45 : 10% v/v). Higher preconcentration factors were obtained ranging from 117.9 to 372.2 and 207.1 to 396.1 by using poly(MAA-co-EGDMA) and poly(AA-co-EGDMA), respectively, yielding lower limits of detection (0.03 to 0.12 μg L-1) and (0.03 to 0.15 μg L-1). These outcomes show satisfactory detectability of SPE-based methods, with slightly better performance using poly(MAA-co-EGDMA). On the other hand, poly(AA-co-EGDMA) was able to preconcentrate TCAs in the presence of humic acid (7.0 mg L-1) without interference. The precision of methods assessed as RSD (%) was very similar, ranging from 1.7% to 16.3% for poly(MAA-co-EGDMA) and 1.7% to 13.4% for poly(AA-co-EGDMA). SPE cartridges packed with the polymers showed high reusability (52 cycles of preconcentration and elution) without losing adsorption efficiency. The methods were applied to determine TCAs in tap, lake, and stream water samples and the accuracy was attested by addition and recovery tests (86.7-116.0%), with determined nortriptyline ranging from 0.48 to 0.52 μg L-1 in lake water samples.

Medication overuse headache (MOH), new daily persistent headache (NDPH), and persistent refractory headache attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection represent a significant burden in terms of disability and quality of life, and a challenge in terms of definition, pathophysiology, and treatment. Regarding MOH, prevention without withdrawal is not inferior to prevention with withdrawal. Preventive medications like topiramate, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies improve chronic migraine with MOH regardless of withdrawal. The differential diagnosis of NDPH is broad and should be carefully examined. There are no guidelines for the treatment of NDPH, but options include a short course of steroids, nerve blocks, topiramate, nortriptyline, gabapentin, CGRP monoclonal antibodies, and onabotulinumtoxinA. The persistence of headache 3 months after SARS-CoV2 infection is a predictor of poor prognosis.

There is a critical requirement for alternative strategies to provide the better treatment in colorectal cancer (CRC). Hence, our goal was to propose novel biomarkers as well as drug candidates for its treatment through differential interactome based drug repositioning. Differentially interacting proteins and their modules were identified, and their prognostic power were estimated through survival analyses. Drug repositioning was carried out for significant target proteins, and candidate drugs were analyzed via in silico molecular docking prior to in vitro cell viability assays in CRC cell lines. Six modules (mAPEX1, mCCT7, mHSD17B10, mMYC, mPSMB5, mRAN) were highlighted considering their prognostic performance. Drug repositioning resulted in eight drugs (abacavir, ribociclib, exemestane, voriconazole, nortriptyline hydrochloride, theophylline, bromocriptine mesylate, and tolcapone). Moreover, significant in vitro inhibition profiles were obtained in abacavir, nortriptyline hydrochloride, exemestane, tolcapone, and theophylline (positive control). Our findings may provide new and complementary strategies for the treatment of CRC.

Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.

Graphene is a two-dimensional material with unique physical and chemical properties, whose excellent biocompatibility has also attracted widespread attention in the field of biosensing and medical detection. Graphene provides a novel solution for dramatically improving the sensitivity of terahertz metasurface sensors, since the electrical conductivity can be modified by contact with biomolecules. In this paper, a metal-graphene hybrid metasurface is proposed and demonstrated for high-sensitive nortriptyline sensing based on the plasmon-induced transparency (PIT) resonances. The π-π stacks between nortriptyline and graphene lead to an increase in the Fermi level of graphene and a decrease in the conductivity, thus enhancing the PIT resonance. Experimental results show that the peak-to-peak amplitude magnitude of the PIT window is enhanced up to 3.4-fold with 1 ng nortriptyline analyte, and the minimum detection limit is extended down to 0.1 ng. But no significant change is observed from the samples without graphene as a comparative experiment, which demonstrates that the presence of graphene greatly enhances the bonding to the drug molecules and improves the sensing sensitivity. This metasurface sensor has the advantages of high sensitivity, fast detection speed, label-free and steady properties, which has potential applications in the fields of trace molecular sensing and disease diagnosis.

The cognitive adverse effects (AEs) of electroconvulsive therapy (ECT) limit the wider use of the treatment. These AEs can be attenuated by changing the way ECT is administered; however, such changes may reduce the response rate, the speed of response, or both. A recent systematic review and meta-analysis identified more than a dozen pharmacologic interventions in 26 randomized controlled trials (RCTs) that sought to reduce ECT-induced cognitive AEs. Because of large differences across RCTs, only a few outcomes for a few interventions could be pooled in meta-analysis, and most pooled analyses included only 2-3 RCTs. Important findings were that acetylcholinesterase inhibitors, ketamine, memantine, and liothyronine were associated with improved global cognitive functioning at 1-14 days post-ECT. Anti-inflammatory treatments and opioid receptor antagonists were not associated with improvement in general cognitive outcome at 1-14 days post-ECT. Meta-analysis was not possible for the remaining interventions, including piracetam, melatonin, pemoline, nortriptyline, herbal agents, drugs acting on the cortisol pathway, opioid receptor antagonists, l-tryptophan, vasopressin analogs, calcium channel blockers, and others; in individual RCTs, some of these interventions attenuated some cognitive measures as some time points after ECT. Regrettably, none of the RCTs examined clinically meaningful outcomes such as subjective cognitive impairment, impairments in daily life, and persistent autobiographical memory deficits. Future research should study such clinically meaningful outcomes (rather than laboratory tests), using pharmacologic interventions, perhaps in combination, for ECT procedures that are associated with higher cognitive AE burden. A risk is that whatever attenuates ECT-induced cognitive AEs may also attenuate ECT-related therapeutic benefits.

The connection between smoking and Obstructive sleep apnea (OSA) is not yet clear. There are studies that have confirmed the effect of smoking on sleep disordered breathing, whereas others did not. Nicotine affects sleep, as smokers have prolonged total sleep and REM latency, reduced sleep efficiency, total sleep time, and slow wave sleep. Smoking cessation has been related with impaired sleep. The health consequences of cigarette smoking are well documented, but the effect of smoking cessation on OSA has not been extensively studied. Smoking cessation should improve OSA as upper airway oedema may reduce, but there is limited data to support this hypothesis. The impact of smoking cessation pharmacotherapy on OSA has been studied, especially for nicotine replacement therapy (NRT). However, there are limited data on other smoking cessation medications as bupropion, varenicline, nortriptyline, clonidine, and cytisine. The aim of this review was to explore the current evidence on the association between smoking and OSA, to evaluate if smoking cessation affects OSA, and to investigate the possible effects of different pharmacologic strategies offered for smoking cessation on OSA.

Recent advance of medications and devices brings more effective treatment intervention to the patients with asthma. As far as obeying guidelines, approximately 90% of patients with asthma acquire good control. However, there are still small number of patients with asthma who resist conventional treatment. Most of them are corticosteroid-insensitive. It would be thought that there are two ways to deal with this problem. The first one is biologics. However, these are very expensive. The second way is a treatment intervention focusing on cancellation of corticosteroid-resistance. In early 2010s, a new-intracellular signaling pathway (phosphatydilinositol-3-kinese: PI3K pathway) is proven to be closely associated with corticosteroid-resistance. PI3K-inhibitor should be one of the promising candidates to attenuate corticosteroid-resistance. But PI3K-inhibitor also has a toxicity when given systemically. Drug-repositioning (DR) is a good option to deal with it. To find out PI3K-inhibitor from numerous medicines gives an answer how to inhibit PI3K pathway. The presenter has found both low-dose theophylline and long-acting beta-2 agonist have a potential to antagonize PI3K. These medicines have been prescribed for decades and their safety has already been proved. It is possible for clinicians to inhibit PI3K activation in patients with asthma associated with corticosteroid-resistance using these medicines without waiting for development of bran-new PI3K inhibitors. DR revealed that nortriptyline acts as a steroid-enhancer via its anti-PI3K activity. Calcium-channel blocker saves lung function in patients with asthma in long-term observation. DR promises us to find cheap and safe options to treat difficult asthma by inhibiting specific intracellular signaling pathways.

The effect of LC mobile phase composition and flow rate (2-50 µL/min) on mobility behavior in vacuum differential mobility spectrometry (vDMS) was investigated for electrosprayed isobaric antidepressant drugs (AD); amitriptyline, maprotiline, venlafaxine; and structurally related antidepressants nortriptyline, imipramine, and desipramine. While at 2 µL/min, no difference in compensation voltage was observed with methanol and acetonitrile, at 50 µL/min, acetonitrile used for LC elution of analytes enabled the selectivity of the mobility separation to be improved. An accurate and sensitive method could be developed for the quantification of six AD drugs in human plasma using trap/elute micro-LC setup hyphenated to vDMS with mass spectrometric detection in the selected ion monitoring mode. The assay was found to be linear over three orders of magnitude, and the limit of quantification was of 25 ng/mL for all analytes. The LC-vDMS-SIM/MS method was compared to a LC-MRM/MS method, and in both cases, inter-assay precisions were lower than 12.5 and accuracies were in the range 91.5-110%, but with a four times reduced analysis time (2 min) for the LC-vDMS-SIM/MS method. This work illustrates that with vDMS, the LC mobile phase composition can be used to tune the ion mobility separation and to improve assay selectivity without additional hardware.

Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.

Fluphenazine HCl (FLU) is an anxiolytic, while Nortriptyline HCl (NOR) is an anti-depressant. They are co-formulated together to treat depression and schizophrenia. Perphenazine (PER) and dibenzosuberone (DBZ) are the pharmacopeial impurities of FLU and NOR, respectively. Four spectrophotometric and multivariate chemometric methods were developed to determine the two drugs together or in presence of their two impurities in their bulk and pharmaceutical formulation. Method (A) is the triple divisor-ratio derivative (TDR) method, where the zero order spectrum of each component was divided by a mixture of the other 3 components, then the peak amplitudes of the first derivative spectra of FLU, NOR and DBZ were measured at 265, 245.4 and 283.2 nm, respectively. Method (B) is the double divisor-ratio difference-dual wavelength (DD-RD-DW) method, in which each component spectrum mixture was divided by a binary mixture of 2 of the interfering components. In the resulting ratio spectra, the amplitude difference is calculated between 2 wavelengths at which the third interfering component has zero difference. Methods (C and D) are the principle component analysis (PCA) and partial least squares (PLS) models. Methods (A and B) failed to quantify PER (FLU impurity), while (C and D) succeeded to quantify all components. The four methods have been applied for the prediction of the FLU and NOR in their pharmaceutical formulation with good accuracy and precision. The proposed methods have been validated according to the ICH guidelines and the results were within the acceptable limits.

Disturbed pitch perception is a rare but well-known side effect of the antiepileptic drug carbamazepine and its derivates. A patient is presented who used three antidepressants because of depression. After recovering, the medication was continued, but as a violinist, the patient was told that his intonation was too low with the consequence that he was not allowed to participate in the orchestra where he had been for years. After phasing out the medications, his pitch perception returned to normal. This observation is unique as no other examples of this side effect are found in the literature in relation to antidepressants.

Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival.[1] Countless studies have been published supporting Dr. Gideon Koren's 1993 landmark article "Medications Which Can Kill a Toddler with One Tablet or Teaspoonful" in the Journal of Toxicology.[2][3][4][5] while each has its own merits, most focus solely on pediatric overdoses, and relatively few of them provide an exhaustive list or act as a "quick-reference" when dealing with real-time ingestions.  Despite widespread public education, childproof containers, and other safety measures, accidental overdoses continue to occur.  In the United States, poison control centers receive over 2.2 million calls each year, 47% of which concern children less than six years of age.  Most pediatric accidental ingestions involve cosmetics and personal care products, followed by cleaning products, and then analgesics and prescription medications.  Adult overdoses usually are due to the intentional ingestion of analgesics and sedative-hypnotics.  Following are the list of toxic drugs (in decreasing severity/difficulty of treatment) included in this summary:  1. Alpha-2 adrenergic agonists - clonidine, naphazoline, oxymetazoline, tetrahydrozoline. 2. Sulfonylureas - chlorpropamide, glyburide, glipizide, glimepiride. 3. Calcium channel blockers - nifedipine, verapamil, diltiazem, amlodipine, nicardipine. 4. Beta-blockers - metoprolol, labetalol. 5. Tricyclic antidepressants - imipramine, desipramine, amitriptyline, nortriptyline. 6. Opioids - codeine, hydrocodone, methadone, morphine, heroin. 7. Anti-diarrheals - diphenoxylate + atropine, loperamide. 8. Salicylates/Methyl salicylates - wintergreen oil, bismuth subsalicylate, mentholated balms. 9. Antipsychotics - loxapine, thioridazine, chlorpromazine. 10. Antimalarials - chloroquine, hydroxychloroquine, quinine. 11. Antiarrhythmics - quinidine, disopyramide, procainamide, flecainide. 12. Terpenoid (camphor) - analgesic, anti-itch, and cooling gels, ointments, and balms. 13. Non-alkaloid toxic lignan - podophyllin, podofilox. 14. Plant toxin/secondary metabolite - colchicine. 15. Oral acetylcholinesterase inhibitors - rivastigmine, donepezil, galantamine. 16. Methylxanthine - theophylline: 1,3-dimethylxanthine. 17. Partial opioid agonist/synthetics - buprenorphine/fentanyl. 18. Toxic alcohols - methanol, ethylene glycol. 19. Caustics /household products - acidic or alkaline household products, hydrofluoric acid, selenious acid, ammonia fluoride, methacrylic acid (cosmetic glue), naphthalene (mothballs).

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus. Tight glycaemic management focused on lowering haemoglobin A1C and increasing time in the target glucose range along with metabolic risk factor management form the cornerstone of DPN prevention. However, there is limited evidence supporting the efficacy of glycaemic and metabolic control in reducing the symptoms and complications of DPN, including pain once painful DPN develops. DPN treatments include pharmacological agents and non-pharmacological interventions such as foot care and lifestyle modifications. Pharmacological agents primarily address pain symptoms, which affect 25-35% of people with DPN. First-line agents include the anticonvulsants pregabalin and gabapentin, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine, and secondary amine tricyclic antidepressants, including nortriptyline and desipramine. All agents have unique pharmacological, safety and clinical profiles, and agent selection should be guided by the presence of comorbidities, potential for adverse effects, drug interactions and costs. Even with the current treatment options, people are commonly prescribed less than the recommended dose of medications, leading to poor management of DPN symptoms and treatment discontinuation. By keeping up with the latest therapy algorithms and treatment options, healthcare professionals can improve the care for people with DPN.