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The Cochrane Database of Systematic... Oct 2018Infantile colic is typically defined as full-force crying for at least three hours per day, on at least three days per week, for at least three weeks. This condition... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Infantile colic is typically defined as full-force crying for at least three hours per day, on at least three days per week, for at least three weeks. This condition appears to be more frequent in the first six weeks of life (prevalence range of 17% to 25%), depending on the specific location reported and definitions used, and it usually resolves by three months of age. The aetiopathogenesis of infantile colic is unclear but most likely multifactorial. A number of psychological, behavioural and biological components (food hypersensitivity, allergy or both; gut microflora and dysmotility) are thought to contribute to its manifestation. The role of diet as a component in infantile colic remains controversial.
OBJECTIVES
To assess the effects of dietary modifications for reducing colic in infants less than four months of age.
SEARCH METHODS
In July 2018 we searched CENTRAL, MEDLINE, Embase , 17 other databases and 2 trials registers. We also searched Google, checked and handsearched references and contacted study authors.
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of dietary modifications, alone or in combination, for colicky infants younger than four months of age versus another intervention or placebo. We used specific definitions for colic, age of onset and the methods for performing the intervention. We defined 'modified diet' as any diet altered to include or exclude certain components.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Our primary outcome was duration of crying, and secondary outcomes were response to intervention, frequency of crying episodes, parental/family quality of life, infant sleep duration, parental satisfaction and adverse effects.
MAIN RESULTS
We included 15 RCTs involving 1121 infants (balanced numbers of boys and girls) aged 2 to 16 weeks. All studies were small and at high risk of bias across multiple design factors (e.g. selection, attrition). The studies covered a wide range of dietary interventions, and there was limited scope for meta-analysis. Using the GRADE approach, we assessed the quality of the evidence as very low.Low-allergen maternal diet versus a diet containing known potential allergens: one study (90 infants) found that 35/47 (74%) of infants responded to a low-allergen maternal diet, compared with 16/43 (37%) of infants on a diet containing known potential allergens.Low-allergen diet or soy milk formula versus dicyclomine hydrochloride: one study (120 infants) found that 10/15 (66.6%) breastfed babies responded to dicyclomine hydrochloride, compared with 24/45 (53.3%) formula-fed babies. There was little difference in response between breastfed babies whose mother changed their diet (10/16; 62.5%) and babies who received soy milk formula (29/44; 65.9%).Hydrolysed formula versus standard formula: two studies (64 infants) found no difference in duration of crying, reported as a dichotomous outcome: risk ratio 2.03, 95% confidence interval (CI) 0.81 to 5.10; very low-quality evidence. The author of one study confirmed there were no adverse effects. One study (43 infants) reported a greater reduction in crying time postintervention with hydrolysed formula (104 min/d, 95% CI 55 to 155) than with standard formula (3 min/d, 95% CI -63 to 67).Hydrolysed formula versus another hydrolysed formula: one study (22 infants) found that two types of hydrolysed formula were equally effective in resolving symptoms for babies who commenced with standard formula (Alimentum reduced crying to 2.21 h/d (standard deviation (SD) 0.40) and Nutramigen to 2.93 h/d (SD 0.70)).Hydrolysed formula or dairy- and soy-free maternal diet versus addition of parental education or counselling: one study (21 infants) found that crying time decreased to 2.03 h/d (SD 1.03) in the hydrolysed or dairy- and soy-free group compared with 1.08 h/d (SD 0.7) in the parent education or counselling group, nine days into the intervention.Partially hydrolysed, lower lactose, whey-based formulae containing oligosaccharide versus standard formula with simethicone: one study (267 infants) found that both groups experienced a decrease in colic episodes (secondary outcome) after seven days (partially hydrolysed formula: from 5.99 episodes (SD 1.84) to 2.47 episodes (SD 1.94); standard formula: from 5.41 episodes (SD 1.88) to 3.72 episodes (SD 1.98)). After two weeks the difference between the two groups was significant (partially hydrolysed: 1.76 episodes (SD 1.60); standard formula: 3.32 episodes (SD 2.06)). The study author confirmed there were no adverse effects.Lactase enzyme supplementation versus placebo: three studies (138 infants) assessed this comparison, but none reported data amenable to analysis for any outcome. There were no adverse effects in any of the studies.Extract of Foeniculum vulgare, Matricariae recutita, and Melissa officinalis versus placebo: one study (93 infants) found that average daily crying time was lower for infants given the extract (76.9 min/d (SD 23.5), than infants given placebo (169.9 min/d (SD 23.1), at the end of the one-week study. There were no adverse effects.Soy protein-based formula versus standard cows' milk protein-based formula: one study (19 infants) reported a mean crying time of 12.7 h/week (SD 16.4) in the soy formula group versus 17.3 h/week (SD 6.9) in the standard cows' milk group, and that 5/10 (50%) responded in the soy formula group versus 0/9 (0%) in the standard cows' milk group.Soy protein formula with polysaccharide versus standard soy protein formula: one study (27 infants) assessed this comparison but did not provide disaggregated data for the number of responders in each group after treatment.No study reported on our secondary outcomes of parental or family quality of life, infant sleep duration per 24 h, or parental satisfaction.
AUTHORS' CONCLUSIONS
Currently, evidence of the effectiveness of dietary modifications for the treatment of infantile colic is sparse and at significant risk of bias. The few available studies had small sample sizes, and most had serious limitations. There were insufficient studies, thus limiting the use of meta-analysis. Benefits reported for hydrolysed formulas were inconsistent.Based on available evidence, we are unable to recommend any intervention. Future studies of single interventions, using clinically significant outcome measures, and appropriate design and power are needed.
Topics: Allergens; Colic; Crying; Diet Therapy; Female; Humans; Infant; Infant Formula; Lactase; Male; Randomized Controlled Trials as Topic; Soybean Proteins; Time Factors
PubMed: 30306546
DOI: 10.1002/14651858.CD011029.pub2 -
European Journal of Pharmaceutical... Oct 2018Spray-dried chitosan microparticles have been widely exploited as vehicles for mucosal drug delivery. Despite their advantages as pharmaceutical formulations, one of the...
Spray-dried chitosan microparticles have been widely exploited as vehicles for mucosal drug delivery. Despite their advantages as pharmaceutical formulations, one of the major challenges is achieving sustained drug release, which would diminish toxicity and dosage frequency. The aim of this study was to formulate mucoadhesive glutaraldehyde cross-linked chitosan microparticles loaded with doxylamine succinate and pyridoxine hydrochloride as potential nasal drug delivery systems with sustained release. Microparticle models were formulated via spray-drying technique, using glutaraldehyde in different concentrations (0.1-1.0 mg/mL) as a cross-linking agent for chitosan. The obtained particles were with spherical shape, smooth surface and median diameter of 4 μm. The drug entrapment efficiency was high (80.47%-94.25%), indicating a tendency to decrease at higher glutaraldehyde concentrations. FTIR data demonstrated that there were no chemical interactions between glutaraldehyde and the drugs. The in vitro studies showed that the cross-linking process substantially limited particles swelling. The cross-linked particles exhibited sustained drug release characteristics at pH 6.8 over a period of 5 h with an initial burst-effect in the first 30 min. Drug release followed Korsmeyer-Peppas kinetics. Although a decrease of the particles mucoadhesive properties was observed after modification, all cross-linked formulations demonstrated high in vitro adsorption of mucin. The proposed models of mucoadhesive microsphere with sustained drug release are a perspective ground for further development of a novel delivery system for nasal administration of doxylamine and pyridoxine.
Topics: Adhesiveness; Administration, Intranasal; Antiemetics; Chemistry, Pharmaceutical; Chitosan; Cross-Linking Reagents; Delayed-Action Preparations; Dicyclomine; Doxylamine; Drug Carriers; Drug Combinations; Drug Compounding; Drug Liberation; Feasibility Studies; Gastric Mucins; Glutaral; Kinetics; Microspheres; Pyridoxine; Solubility
PubMed: 30077710
DOI: 10.1016/j.ejps.2018.07.059 -
Indian Pediatrics Nov 2018Infantile colic is self-limiting condition but it can be a cause of anxiety for parents and challenge for doctors. The challenge for the doctors lies in correct... (Review)
Review
CONTEXT
Infantile colic is self-limiting condition but it can be a cause of anxiety for parents and challenge for doctors. The challenge for the doctors lies in correct identification of the condition and appropriate management. The objective of this review article is to summarize the pathophysiology, treatment options and outcome in infantile colic so that clinicians can have a fair idea about the condition, recent updates and future prospects.
EVIDENCE
A search of the Cochrane Library, PubMed, and Google Scholar was made using the key words "Infant colic", Infantile colic", "excessive crying in infants". All the materials were analyzed and summarized.
RESULTS
At present, infantile colic is an area of clinical research both in terms of etiology and treatment. Various etiological theories have been proposed but none of them are strong enough to completely describe the condition. Various treatment agents are being tried for colic like counseling and behavioral modification, dietary modification, lactase and probiotic supplementation, pain relieving agents, and chiropathy. Proper counseling of the parents is the first line of management at present. Simethicone has no role in decreasing the symptoms of colic and Dicyclomine is not recommended in children younger than six months. No specific recommendations have been made on the use of pain relieving agents and manipulative therapies in colic. At present strong evidence is lacking regarding the use of probiotics, lactase supplementation and dietary modification.
CONCLUSIONS
Counseling of parents about the benign nature of the condition is considered first line for now until an effective treatment is established. Other treatment options are prescribed on a case-based manner, and based on the parental perception of the condition.
Topics: Behavior Therapy; Colic; Counseling; Crying; Diet Therapy; Humans; Infant; Infant, Newborn; Parasympatholytics
PubMed: 29941700
DOI: No ID Found -
Investigative Ophthalmology & Visual... Jun 2018Myopia is a refractive disorder that degrades vision. It can be treated with atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, but the mechanism is...
PURPOSE
Myopia is a refractive disorder that degrades vision. It can be treated with atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, but the mechanism is unknown. Atropine may block α-adrenoceptors at concentrations ≥0.1 mM, and another potent myopia-inhibiting ligand, mamba toxin-3 (MT3), binds equally well to human mAChR M4 and α1A- and α2A-adrenoceptors. We hypothesized that mAChR antagonists could inhibit myopia via α2A-adrenoceptors, rather than mAChR M4.
METHODS
Human mAChR M4 (M4), chicken mAChR M4 (cM4), or human α2A-adrenergic receptor (hADRA2A) clones were cotransfected with CRE/promoter-luciferase (CRE-Luc; agonist-induced luminescence) and Renilla luciferase (RLuc; normalizing control) into human cells. Inhibition of normalized agonist-induced luminescence by antagonists (ATR: atropine; MT3; HIM: himbacine; PRZ: pirenzepine; TRP: tropicamide; OXY: oxyphenonium; QNB: 3-quinuclidinyl benzilate; DIC: dicyclomine; MEP: mepenzolate) was measured using the Dual-Glo Luciferase Assay System.
RESULTS
Relative inhibitory potencies of mAChR antagonists at mAChR M4/cM4, from most to least potent, were QNB > OXY ≥ ATR > MEP > HIM > DIC > PRZ > TRP. MT3 was 56× less potent at cM4 than at M4. Relative potencies of mAChR antagonists at hADRA2A, from most to least potent, were MT3 > HIM > ATR > OXY > PRZ > TRP > QNB > MEP; DIC did not antagonize.
CONCLUSIONS
Muscarinic antagonists block hADRA2A signaling at concentrations comparable to those used to inhibit chick myopia (≥0.1 mM) in vivo. Relative potencies at hADRA2A, but not M4/cM4, correlate with reported abilities to inhibit chick form-deprivation myopia. mAChR antagonists might inhibit myopia via α2-adrenoceptors, instead of through the mAChR M4/cM4 receptor subtype.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Atropine; CRISPR-Associated Protein 9; Carbachol; Chickens; Cholinergic Agonists; Clonidine; Gene Knockdown Techniques; HEK293 Cells; Humans; Ligands; Muscarinic Antagonists; Myopia; Receptor, Muscarinic M3; Receptor, Muscarinic M4; Receptors, Adrenergic, alpha-2; Receptors, Muscarinic; Transfection
PubMed: 29860464
DOI: 10.1167/iovs.17-22562 -
Neurochemistry International Jun 2018We demonstrated that activation of protein kinase Cδ (PKCδ) and inactivation of the glutathione peroxidase-1 (GPx-1)-dependent systems are critical for methamphetamine...
We demonstrated that activation of protein kinase Cδ (PKCδ) and inactivation of the glutathione peroxidase-1 (GPx-1)-dependent systems are critical for methamphetamine (MA)-induced recognition memory impairment. We also demonstrated that exposure to far-infrared rays (FIR) causes induction of the glutathione (GSH)-dependent system, including induction of the GPx-1 gene. Here, we investigated whether exposure to FIR rays affects MA-induced recognition memory impairment and whether it modulates PKC, cholinergic receptors, and the GSH-dependent system. Because the PKC activator bryostatin-1 mainly induces PKCα, PKCε, and PKCδ, we assessed expression of these proteins after MA treatment. MA treatment selectively increased PKCδ expression and its phosphorylation. Exposure to FIR rays significantly attenuated MA-induced increases in PKCδ phosphorylation. Importantly, bryostatin-1 potentiated MA-induced phosphorylation of PKCδ. MA treatment significantly decreased M1, M3, and M4 muscarinic acetylcholine receptors (mAChRs) and β2 nicotinic acetylcholine receptor expression. Of these, the decrease was most pronounced in M1 mAChR. Exposure to FIR significantly attenuated MA-induced decreases in the M1 mAChR and phospho-ERK, while it facilitated Nrf2-dependent GSH induction. Dicyclomine, an M1 mAChR antagonist, and l-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH synthesis, counteracted against the protective potentials mediated by FIR. More importantly, the memory-enhancing potential of FIR rays was significantly counteracted by bryostatin-1, dicyclomine, and BSO. Our results suggest that exposure to FIR rays attenuates MA-induced impairment in recognition memory via up-regulation of M1 mAChR, Nrf2-dependent GSH induction, and ERK phosphorylation by inhibiting PKCδ phosphorylation by bryostatin-1.
Topics: Animals; Glutathione Peroxidase; Memory Disorders; Methamphetamine; Mice, Knockout; NF-E2-Related Factor 2; Protein Kinase C-delta; Receptor, Muscarinic M1; Up-Regulation; Glutathione Peroxidase GPX1
PubMed: 29572053
DOI: 10.1016/j.neuint.2018.03.009 -
Journal of the Neurological Sciences Feb 2018
Topics: Aged; Cerebral Amyloid Angiopathy; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Social Behavior; White Matter
PubMed: 29406906
DOI: 10.1016/j.jns.2018.01.001 -
The Journal of Antibiotics Mar 2018Dicyclomine is a human muscarinic acetylcholine receptor antagonist used for the treatment of abdominal cramps. We are reporting here that dicyclomine can inhibit the in...
The human muscarinic acetylcholine receptor antagonist, Dicyclomine targets signal transduction genes and inhibits the virulence factors in the human pathogen, Candida albicans.
Dicyclomine is a human muscarinic acetylcholine receptor antagonist used for the treatment of abdominal cramps. We are reporting here that dicyclomine can inhibit the in vitro growth and virulence factors of the human pathogen Candida albicans very effectively. Dicyclomine inhibited adhesion, early biofilm, mature biofilm, and planktonic growth. Yeast to hyphal form transition of C. albicans in various inducer media such as serum, proline, glucose, and N-acetylglucosamine was inhibited. Dicyclomine also could kill C. albicans cells within 15 min of exposure. Dicyclomine appears to inhibit the yeast to hyphal conversion by affecting signal transduction pathway. The expression of selected genes associated with yeast to hyphal form transition in serum in presence of dicyclomine was studied using real-time polymerase chain reaction (RtPCR). The RtPCR analysis showed that dicyclomine targets both cAMP pathway as well as MAPK cascade. Eight genes were upregulated. Out of these, three major upregulated genes were Bcy1, Tup1, and Mig1. Dicyclomine downregulated Ume6, Ece1, and Pde2 genes which are involved in cAMP signaling pathway and also downregulated the DNA binding protein gene, Rfg1. Dicyclomine significantly upregulated the master negative regulator of hyphal formation, Tup1. Based on this study we suggest that the muscarinic acetylcholine receptor antagonist, dicyclomine could be repositioned as a potential anti-Candida albicans as well as anti-virulence agent.
Topics: Biofilms; Candida albicans; Candidiasis; Cyclic AMP; Dicyclomine; Gene Expression Regulation, Fungal; Humans; Hyphae; Mitogen-Activated Protein Kinases; Muscarinic Antagonists; Real-Time Polymerase Chain Reaction; Signal Transduction; Virulence Factors
PubMed: 29348527
DOI: 10.1038/s41429-017-0013-z -
Journal of Ethnopharmacology Mar 2018Cyperus species are famous for their traditional uses and very commonly used for their anti-spasmodic and anti-diarrheal activities. Cyperus niveus Retz. is used in...
ETHNOPHARMACOLOGICAL RELEVANCE
Cyperus species are famous for their traditional uses and very commonly used for their anti-spasmodic and anti-diarrheal activities. Cyperus niveus Retz. is used in local traditional system of medicine in Pakistan to treat diarrhea and emesis.
AIM OF THE STUDY
The aim of the study was to validate the traditional uses and to provide the possible mechanisms for the medicinal use of Cyperus niveus Retz. as anti-spasmodic, anti-diarrheal and anti emetic.
MATERIALS AND METHODS
The in-vivo studies of anti-diarrheal, charcoal meal GI transit test and anti-emetic activities were conducted in rats, mice and chicks respectively, while isolated tissues of rabbit's jejunum and rat's ileum were used for in-vitro experiments. Phytochemical analysis was also undertaken.
RESULTS
The phytochemical study of hydro-ethanolic extract of Cyperus niveus Retz. showed the presence of flavonoids, phenols, alkaloids, tannins, saponins and glycosides. Cn. Cr caused significant inhibition of castor oil-induced diarrhea in rats (300,500 & 700mg/kg) using loperamide (10mg/kg, p.o) as standard. Cn. Cr also significantly decreased the motility in charcoal meal GI transit test at 100-200mg/kg in mice, using atropine (3.0mg/kg) as positive control. In jejunum tissue, Cn. Cr relaxed carbachol(1µM) and K(80mM)-induced contractions, similar to the effect of dicyclomine. Pre-incubation of isolated rat ileum tissues with Cn. Cr (0.1mg/mL) caused the corresponding shift of CCh concentration response curve (CRC) to right without decrease in max. response whereas at the concentration of 0.3mg/mL caused the rightward nonparallel shift with max. response suppression, similar to dicyclomine. Antimuscarinic effect was further confirmed when prior administration of Cn. Cr (0.1, 0.3 and 1mg/mL) caused concentration dependent inhibition of induced contractions of carbachol, comparable to atropine (1µM). To confirm the Ca channel blocking (CCB), the rabbit jejunum was pre-incubated with Cn. Cr (0.3 & 1.0mg/mL), produced a shift in CRCs of calcium toward right with decrease in the maximum response at next concentration, similar to that of dicyclomine. The organic fraction of Cyperus niveus Retz. (Cn. Dcm) showed Ca antagonist and anticholinergic activities with higher potency against K(80mM) induced contractions, like verapamil, while aqueous fraction (Cn. Aq) relaxed only carbachol(1µM) induced contractions with no prominent effect on K (80mM)-contractions even at the higher concentration of 10mg/mL, similar to atropine. Cn. Cr also showed significant anti-emetic effect in Chick emesis model using chlorpromazine as standard.
CONCLUSION
This study shows the presence of antidiarrheal and spasmolytic activities in Cyperus niveus Retz. extract, mediated by dual blocking mechanisms of muscarinic receptors and Ca channels. The results further indicate the presence of anti-emetic activity in Cn. Cr, which may be because of its anti-muscarinic potential. This study provides the scientific bases to the traditional use of Cn. Cr in diarrhea and emesis.
Topics: Animals; Antidiarrheals; Antiemetics; Calcium Channel Blockers; Castor Oil; Chickens; Copper Sulfate; Cyperus; Diarrhea; Female; Flavonoids; Folklore; Gastrointestinal Transit; Ileum; Jejunum; Male; Medicine, Traditional; Mice, Inbred BALB C; Muscarinic Antagonists; Pakistan; Parasympatholytics; Phenols; Phytotherapy; Plant Extracts; Rabbits; Rats, Sprague-Dawley; Vomiting
PubMed: 29122673
DOI: 10.1016/j.jep.2017.11.006 -
International Journal of Biological... Feb 2018Lipase is one of the most important groups of enzymes for industry and medicine. It breaks down triacylglycerol to glycerol and fatty acids. Some bacteria use lipase to...
Lipase is one of the most important groups of enzymes for industry and medicine. It breaks down triacylglycerol to glycerol and fatty acids. Some bacteria use lipase to degrade the extracellular matrix of the host cells to penetrate into the tissues. Dicyclomine is a muscarinic antagonist receptor that relieves the smooth muscle spasm of the gastrointestinal tract and affects the cardiovascular system. In this research, the effect of a dicyclomine on the lipase activity of Pseudomonas aeruginosa was studied. Hanes-Woolf plot showed that the drug inhibited the enzyme by competitive inhibition. The IC value (60uM) and Ki (30uM) of the drug revealed that the drug bound to enzyme with high affinity. Determination of enzyme activity in various temperature showed that the maximum activity of lipase was at 60°C both in the presence and absence of the drug. Arrhenius plot determined that the activation energy of the enzyme reaction was increased in the presence of the drug. The model of binding demonstrated that the drug entered a pocket containing 10 amino acids and interacted by hydrogen bond and hydrophobic interaction and the conformational change of the enzyme after binding of the drug was confirmed by fluorescence measurement.
Topics: Cardiovascular System; Dicyclomine; Gastrointestinal Tract; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lipase; Muscle, Smooth; Pseudomonas aeruginosa; Spasm; Temperature
PubMed: 29055706
DOI: 10.1016/j.ijbiomac.2017.10.123 -
Phytotherapy Research : PTR Nov 2017Achyranthes aspera L. is traditionally used to relieve constipation, diarrhea, and asthma. Its crude extract (Aa.Cr) was evaluated through in vivo and ex vivo...
Achyranthes aspera L. is traditionally used to relieve constipation, diarrhea, and asthma. Its crude extract (Aa.Cr) was evaluated through in vivo and ex vivo experiments to rationalize these medicinal uses of A. aspera and to provide their scientific basis. Aa.Cr, at 3 and 10 mg/kg, increased fecal output, similar to castor oil, whereas at 30, 100, 300, and 700 mg/kg, it protected against castor oil-induced diarrhea in mice when administered orally. Aa.Cr caused spasmogenic effect on rabbit jejunum and guinea pig ileum preparations, which was partially inhibited by atropine while completely blocked by cyproheptadine preincubation. Aa.Cr also relaxed high K (80 mM)-induced contraction in rabbit jejunum. Aa.Cr inhibited CCh (100 μg/kg)-induced bronchospasm in rats, similar to aminophylline. Like dicyclomine, Aa.Cr relaxed high K and CCh (1 μM)-induced contractions in guinea pig trachea and caused rightwards parallel shift of CCh concentration-response curves at the lower concentrations followed by non-parallel shift at the higher concentrations. On activity-directed fractionation, spasmogenic and spasmolytic activities of Aa.Cr were concentrated in aqueous and organic fraction, respectively. This study suggests the presence of dose-specific laxative and antidiarrheal effects in A. aspera, possibly mediated through cyproheptadine-sensitive receptors and dual cholinergic and calcium channel blockade, respectively. The latter combination is also a suggested mechanism underlying its bronchodilator effect. Copyright © 2017 John Wiley & Sons, Ltd.
Topics: Achyranthes; Animals; Antidiarrheals; Bronchodilator Agents; Calcium Channel Blockers; Castor Oil; Constipation; Diarrhea; Female; Guinea Pigs; Ileum; Jejunum; Laxatives; Male; Mice; Mice, Inbred BALB C; Parasympatholytics; Plant Extracts; Rabbits; Rats; Rats, Sprague-Dawley; Trachea
PubMed: 28840614
DOI: 10.1002/ptr.5907