Efficacy and Safety of Drugs for Gastroparesis: Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs). METHODS: We searched the literature to September 7, 2022. We judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to P-score. RESULTS: We identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR, 0.30; 95% CI, 0.16-0.57; P-score = .99) followed by domperidone (RR, 0.68; 95% CI, 0.48-0.98; P-score = .76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR, 0.58; 95% CI, 0.44-0.77; P-score = .96) and tachykinin-1 antagonists (RR, 0.69; 95% CI, 0.52-0.93; P-score = .83). For individual symptoms, oral metoclopramide ranked first for nausea (RR 0.46; 95% CI, 0.21-1.00; P-score = .95), fullness (RR 0.67; 95% CI, 0.35-1.28; P-score = .86), and bloating (RR 0.53; 95% CI, 0.30-0.93; P-score = .97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo. CONCLUSIONS: In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.

The structural conformation of the tachykinin domain drives the anti-tumoural activity of an octopus peptide in melanoma BRAFV600E.

BACKGROUND AND PURPOSE: Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma. EXPERIMENTAL APPROACH: We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish). KEY RESULTS: Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAFV600E -mutated cells with minimal effects on fibroblasts. In melanoma-treated cells, Octpep-1 increased ROS with unaltered mitochondrial membrane potential and promoted non-mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep-1 depends upon the α-helix and polyproline conformation in the C-terminal region of the peptide. A truncated form of the C-terminal end of Octpep-1 displayed enhanced potency and efficacy against melanoma. Octpep-1 reduced the progression of tumours in xenograft melanoma mice and zebrafish. CONCLUSION AND IMPLICATIONS: We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.

Subcutaneous injection of endokinin C/D attenuates carrageenan-induced inflammation.

Endokinins, encoded by the human preprotachykinin C (PPT-C)/TAC4 gene, are peptides that consist of endokinin A (EKA), B (EKB), C (EKC) and D (EKD) and belong to the tachykinin family. Intrathecal injection of EKC/D (using the common carboxyl-terminal duodecapeptide in EKC and EKD) markedly attenuated the induction of thermal hyperalgesia and scratching behavior by intrathecal administration of substance P (SP), indicating that EKC/D has an antagonistic effect on the neurokinin 1 receptor (NK1R), SP-preferring receptor, at the spinal level; however, the pharmacological function of EKC/D at the periphery is not yet understood. Therefore, to clarify the effect of EKC/D on the peripheral tissue, the effect of subcutaneous injection of EKC/D on carrageenan-induced inflammation was examined. Subcutaneous injection of EKC/D attenuated an increase in paw volume following carrageenan-induced inflammation in a dose-dependent manner. Indeed, the increased paw volume was significantly decreased 40 min after treatment with 10(-4) M (10 nmol) and 10(-3) M (100 nmol) EKC/D (100 microl/rat). Similarly, injection of NK1R antagonists such as L-703,606 and Spantide I (10(-3) M) attenuated the increased paw volume following inflammation. Furthermore, the reduced withdrawal latency evoked by inflammation following subcutaneous injection of carrageenan was also dose-dependently attenuated by EKC/D administration. These results indicate that subcutaneous injection of EKC/D elicits an anti-inflammatory effect on carrageenan-induced inflammation.

Effects of Endokinin A/B and Endokinin C/D on the modulation of pain in mice.

Endokinins are novel tachykinins encoded on the human TAC4 and consist of Endokinin A (EKA), B (EKB), C (EKC) and D (EKD). To date, the function of Endokinins in pain processing was not fully understood. Therefore the aim of this study was to investigate the effects of Endokinin A/B (EKA/B, the common C-terminal decapeptide in EKA and EKB) and Endokinin C/D (EKC/D, the common C-terminal duodecapeptide in EKC and EKD) on pain modulation at supraspinal level in mice. Intracerebroventricular (i.c.v.) administration of EKA/B (1, 3, 12, 20nmol/mouse) dose dependently induced potent analgesic effect. This effect could be fully antagonized by SR140333B but not SR48968C or SR142801. Naloxone could also block the analgesic effect, suggesting that this analgesic effect is related to opioid receptors. However, i.c.v. administration of EKA/B (10, 30, 100pmol/mouse) caused hyperalgesic effect significantly, with a "U" shape curve. Interestingly, the hyperalgesic effect induced by EKA/B could be attenuated by SR140333B, SR142801 but not SR48968C. I.c.v. administration of EKC/D (1, 3, 12, 20nmol/mouse) also dose dependently induced analgesic effect, which could not be blocked by SR48968C or SR142801 or naloxone. But to our astonishment, it could be significantly enhanced by SR140333B. More interestingly, the hyperalgesic effect induced by EKA/B could be significantly attenuated by EKC/D. In addition, the analgesic effect induced by co-administration of EKA/B and EKC/D was much less stronger than the effect of either EKA/B or EKC/D.

Leucine at the carboxyl-terminal of endokinins C and D contributes to elicitation of the antagonistic effect on substance P in rat pain processing.

Endokinins are tachykinin peptides designated from a human preprotachykinin C (PPT-C, TAC4) gene and consist of endokinin A (EKA), endokinin B (EKB), endokinin C (EKC) and endokinin D (EKD). A representative of mammalian tachykinins is substance P (SP), which functions as a neurotransmitter or modulator in the pain system; however, little is known about the role of these endokinins, especially EKC and EKD, in pain processing. Therefore, we evaluated the effects of EKC/D (using the common carboxyl-terminal duodecapeptide in EKC and EKD) on pain processing in rats. Pretreatment with EKC/D prevented induction of scratching behavior and thermal hyperalgesia by intrathecal administration of EKA/B (using the common C-terminal decapeptide in EKA and EKB) and SP and c-Fos expression in laminae I/II and V/VI of the spinal cord by noxious thermal stimulation. A prominent difference between EKC/D and SP is the presence of leucine instead of methionine at the carboxyl-terminal of EKC/D. Thus, to clarify whether leucine at the carboxyl-terminal of EKC/D plays an important role in determining the inhibitory effect of this peptide, we intrathecally administered [Met(12)]-EKC/D in which only leucine of EKC/D is replaced by methionine. This peptide did not exhibit the inhibitory effect on SP-induced scratching behavior or thermal hyperalgesia but conversely caused thermal hyperalgesia. Taken together, these findings indicate that EKC/D has an inhibitory effect on pain processing in the rat spinal cord, and the effect is due to leucine at the carboxyl-terminal of EKC/D.

Developments in the pharmacotherapy of the overactive bladder.

PURPOSE OF REVIEW: The overactive bladder is a common and distressing condition that has a significant impact on the quality of life of many people worldwide. Anticholinergics remain the first line in pharmacotherapy, however the use of these agents is hindered by adverse effects and limited efficacy. Thus there is a need for more effective treatments. Recently, there has been a move towards targeting novel pathways thought to play a role in overactivity. This review aims to provide an insight into the recent developments in pharmacotherapy of the overactive bladder. RECENT FINDINGS: With recent advances in our understanding of the basic science of the overactive bladder it is becoming clear that the control of bladder functioning is far more complex than previously believed. Peripherally, a prominent role has emerged for the urothelium and the underlying suburothelium in mechanosensory control, and the role of afferent pathways in pathophysiology is increasingly recognized. SUMMARY: Recent research has highlighted several potential targets for treatment of the overactive bladder, particularly within the mechanosensory pathways. With the exception of botulinum toxin, however, few new therapies have emerged showing clinical benefits. A clearer understanding of the pathophysiology of the bladder will hopefully lead to more effective and tolerated treatments.

Tachykinins and their receptors in human malignancies.

The possibility of links between psychosocial factors and cancer incidence and progression has generated considerable scientific and public interest. Tachykinins, including substance P, neurokinin A and B, hemokinin-1 and endokinins, are a family of neuropeptides, acting through three types of transmembrane G-protein coupled receptors denoted NK1, NK2 and NK3. Besides their role as neurotransmitters in peripheral and central nervous system, tachykinins and their receptors are also expressed in several non neuronal cells contributing to the fine connections between nervous systems and peripheral organ system such as respiratory, cardiovascular, immune, endocrine, gastrointestinal and genitourinary. Being so much involved in regulating physiological functions, they, of course, can concur to pathological conditions including cancer. Tachykinins can act on different steps of carcinogenesis. Tumors expressing NK receptors, such as astrocytoma, glioma, neuroblastoma, pancreatic cancer and melanoma, can misuse tachykinin-induced signaling, operating in normal cells, to promote proliferation and survival of cancer cells and to release cytokines and soluble mediators favoring tumor growth. In neuroblastoma, breast and prostate carcinomas tachykinins facilitate tumor metastatic infiltration in the bone marrow. In neuroendocrine carcinoma, tachykinins are responsible of symptoms associated with these pathologies including flushing, diarrhea, wheezing and right heart disease. In addition, regardless tumor histology, tachykinins may favor cancer incidence and metastatic progression by influencing blood flux and neovascularization in tumor formation as well as inducing immunosuppression mediated by neurogenic inflammation due to stress or surgery. However, the precise involvement of tachykinins in cancer pathologies and the potentiality to become effective pharmacological drug targets remain to be fully defined.

Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea.

BACKGROUND AND AIMS: The mechanisms underlying intestinal secretion in rotavirus diarrhoea remain to be established. We previously reported that rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5-HT(3)) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for 5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus induced diarrhoea. METHODS: Neurotransmitter antagonists were administered to wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM) or heterologous (RRV) rotavirus. RESULTS: While RRV infected mice had diarrhoea for 3.3 (0.2) days (95% confidence interval (CI) 3.04-3.56), the 5-HT(3) receptor antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe(6),Leu(17))-VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3) (95% CI 1.31-2.9) (p<0.01). EDIM infected mice treated with granisetron had a significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with untreated mice (8.0 (0.4) days; p<0.01). Experiments with neurokinin 1 receptor antagonists suggest that this receptor may possibly be involved in the secretory response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated in the neurokinin 1 receptor knockout mice. CONCLUSIONS: Our results suggest that the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea; observations that could imply new principles for treatment of this disease with significant global impact.

Involvement of substance P in scratching behaviour in an atopic dermatitis model.

Substance P is speculated to be a key mediator of itching in atopic dermatitis, possibly acting via the tachykinin NK1 receptor. Thus, we examined the effect of a tachykinin NK1 antagonist, BIIF 1149 CL, on scratching behaviour in a picrylchloride-induced dermatitis model in NC/Nga mice. BIIF 1149 CL ((S)-N-[2-[3,5-bis(trifluoromethyl) phenyl]ethyl]-4-(cyclopropylmethyl)-N-methyl-alpha-phenyl-1-piperazineacetamide, monohydrochloride, monohydrate) at a dose of 100 mg/kg, p.o., significantly inhibited scratching behaviour immediately after administration, and the effect continued up to 6 h. The results suggest that clinical trials of tachykinin NK1 antagonists for the treatment of itching in atopic dermatitis patients would be warranted.

Abnormal magnesium metabolism in etiology of salt-sensitive hypertension and type 2 diabetes mellitus.

A previously unknown genetic defect in magnesium metabolism (i.e., the magnesium-binding defect [MgBD]) was found to be associated with the cause of "salt-sensitive" essential hypertension in humans and rats. It inhibits the entrance of Mg2+ into the cell so that the intracellular concentrations of Mg2+ and MgATP2- are decreased. Consequently, the 300 enzyme reactions in the cell, especially the 100 that either use or produce MgATP2-, are inhibited. Thus, because the extrusion of intracellular Na+ requires MgATP2-, hypertension results when the involved MgATP2- requiring enzyme is inhibited. The MgBD is corrected by the tachykinin substance P, which occurs in normal blood plasma, and by the pentapeptide and its contained tetrapeptide, which are released from the C-terminal region of substance P by plasma aminopeptidases. In vivo, the intravenous administration of the tetrapeptide corrects the hypertension and the MgBD as well. The MgBD also occurs in type 2 diabetes mellitus and, thus, the decreased intracellular concentrations of Mg2+ and MgATP2- ions appear to be involved also in the cause of this disease, which is reputed to be the fifth most deadly disease in the world.

Recent developments in the management of detrusor overactivity.

PURPOSE OF REVIEW: Detrusor overactivity is a relatively common yet embarrassing symptom complex with significant impact on quality of life. The mainstay of current pharmacological treatment involves use of muscarinic receptor antagonists, but their therapeutic efficacy is limited by their troublesome side effects resulting in the non-continuance of treatment in a significant number of patients. Therefore, the development of new drugs can proceed by targeting alternative pathways affecting detrusor overactivity. In this article, the pharmacological basis for the current therapeutic alternatives for managing detrusor overactivity and possible future developments are discussed. RECENT FINDINGS: It is clear that far from being a passive container for urine, the urothelium is a crucial part of the bladder. Its functions are complex, dynamic and important, and only now becoming understood. The release of ATP from urothelium in response to distension and its action on P2X receptors resulting in activating both motor and sensory neurons is being increasingly recognised. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction. However, in functionally abnormal bladders, a non-cholinergic activation via the purinergic receptors may occur. The central nervous mechanisms controlling the micturition reflex have also recently attracted attention. SUMMARY: Recent research has suggested that several transmitters may modulate voiding. However, few drugs with clinical benefits have been developed so far. Present treatments for overactive bladders have significant non-compliance rates. Hopefully, future research will lead to drugs with greater therapeutic benefits and better tolerance.

Pharmacologic perspective on the physiology of the lower urinary tract.

Myogenic activity, distention of the detrusor, and signals from the urothelium may initiate voiding. In the bladder, afferent nerves have been identified not only in the detrusor, but also suburothelially, where they form a plexus that lies immediately beneath the epithelial lining. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been shown that bladder distention causes release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably, not only ATP but also a cascade of inhibitory and stimulatory transmitters and mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. These mechanisms may be targets for future drugs. The central nervous control of micturition involves many transmitter systems, which may be suitable targets for pharmacologic intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and noradrenaline receptors and mechanisms are known to influence micturition, and potentially, drugs that affect these systems could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain. Most drugs currently used for treatment of detrusor overactivity have a peripheral site of action, mainly the efferent (cholinergic) neurotransmission and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis, as well as in the aging bladder, a noncholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions.

Potential therapeutic targets for treatment of the overactive bladder.

Muscarinic receptor antagonists remain the main therapy for the treatment of the overactive bladder yet severe adverse effects make them unsuitable for a large number of patients. The development of new drugs with novel mechanisms of action for the treatment of this condition is therefore essential. This article considers some of the targets currently under investigation for the development of such compounds. Beta-adrenoceptor agonists and KATP channel openers inhibit detrusor muscle activity and remain targets for drug development. There is also evidence that alpha-adrenoceptor antagonists may be effective in the overactive bladder, but the mechanism involved in this action is unclear. Finally the role of tachykinins in regulating bladder function through both the sensory and the motor innervation make them a potential target for drug development, but as with the the others, a selective action on the bladder must remain the goal of drug development.

Neurokinin receptor antagonists.

Studies on tachykinin peptides and the corresponding neurokinin receptors (NKr) have increased dramatically recently due to the discovery of selective, orally-active, metabolically stable and sometimes CNS penetrating NKr antagonists. After demonstrating the potential use for NKr antagonists in animal models, some compounds have recently progressed into clinical trials and a few results have been published. NKr antagonists have demonstrated efficacy for the treatment of emesis and depression, while results in other areas have been disappointing. Nonetheless, this area is coming to the exciting time of proof of concept in humans. Demonstration of the involvement of tachykinin peptides in biological functions continues to grow, as do the potential indications for NKr antagonists. More drug candidates are undergoing clinical trials for various conditions and these results could widen the potential use for NKr antagonists.

Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?

This review provides an overview of preclinical and clinical evidence of a role for the neuroactive peptides cholecystokinin (CCK), corticotropin-releasing factor (CRF), neuropeptide Y (NPY), tachykinins (i.e., substance P, neurokinin [NK] A and B), and natriuretic peptides in anxiety and/or stress-related disorders. Results obtained with CCK receptor antagonists in animal studies have been highly variable, and clinical trials with several of these compounds in anxiety disorders have been unsuccessful so far. However, future investigations using CCK receptor antagonists with better pharmacokinetic characteristics and animal models other than those validated with the classical anxiolytics benzodiazepines may permit a more precise evaluation of the potential of these compounds as anti-anxiety agents. Results obtained with peptide CRF receptor antagonists in animal models of anxiety convincingly demonstrated that the blockade of central CRF receptors may yield anxiolytic-like activity. However, the discovery of nonpeptide and more lipophilic CRF receptor antagonists is essential for the development of these agents as anxiolytics. Similarly, there is clear preclinical evidence that the central infusion of NPY and NPY fragments selective for the Y1 receptor display anxiolytic-like effects in a variety of tests. However, synthetic nonpeptide NPY receptor agonists are still lacking, thereby hampering the development of NPY anxiolytics. Unlike selective NK1 receptor antagonists, which have variable effects in anxiety models, peripheral administration of selective NK2 receptor antagonists and central infusion of natriuretic peptides produce clear anxiolytic-like activity. Taken as a whole, these findings suggest that compounds targeting specific neuropeptide receptors may become an alternative to benzodiazepines for the treatment of anxiety disorders.

[Neuromediators in dermatology. Therapeutic prospectives]. / Les neuromédiateurs en dermatologie perspectives thérapeutiques.

Neuropeptides are neurotransmitters and neurohormones that play a role in various cutaneous functions. Keratinocytes and dermal endothelial cells are able to synthesize neuropeptides which are transported by nerve fibers or immune cells. Specific receptors for neuropeptides are also present on cutaneous cells. Neuropeptides intervene as neurogenic modulators of inflammatory reactions and therefore participate in the pathogenesis of skin diseases. An increasing body of evidence supports the setting up of clinical trials using topically neuropeptide agonists and/or antagonists in the treatment of chronic inflammatory skin disorders such as post-herpetic neuralgia, prurigo nodularis, localized pruritus, psoriasis, atopic dermatitis, contact dermatitis, cold urticaria, nostalgia paresthetica, diabetic neuropathy, Raynaud's phenomenon. In the near future, neuropeptides will represent a new approach to skin therapy.