Anticholinergic syndrome after atropine overdose in a supposedly homeopathic solution: a case report.

BACKGROUND: A 53-year-old male with no pre-existing conditions and no permanent medication presented to our emergency department with an anticholinergic syndrome including confusion, anxiety, ataxia and dysarthria after ingestion of a homeopathic solution containing Atropa belladonna extract supposedly in a D4 dilution. METHODS: Atropine sulphate was quantitatively analysed in serum and the homeopathic preparation via liquid chromatography/mass spectrometry. RESULTS: Analysis revealed concentrations of approximately 3 mg/mL atropine sulphate in the homeopathic solution and a serum level of 5.7 ng/mL (±1.4) in the patient's blood proving a 600-fold overdose of atropine due to a production error of the homeopathic dilution. The patient was observed and recovered without further intervention. CONCLUSION: Rare but possibly dangerous manufacturing errors should be considered when faced with symptoms occurring after ingestion of homeopathic or holistic remedies.

Screening of drugs and homeopathic products from Atropa belladonna seed extracts: Tropane alkaloids determination and untargeted analysis.

Homeopathic products are still a controversial issue in modern medicine, understood as complementary or alternative medicine (CAM). In this particular case, homeopathic products prepared from Atropa belladonna extracts may present specific problems due to the effects derived from its components. This article applies a simple, rapid, reliable method to the analysis of different homeopathic products obtained from Atropa belladonna; drugs containing high concentration of plant extracts; and Atropa belladonna seeds. The method was based on a simple solid-phase preconcentration method followed by ultra-high pressure liquid chromatography (UHPLC) coupled to high resolution mass spectrometry using Exactive-Orbitrap as an analyser. An in-house database was set and atropine and scopolamine were the compounds detected at highest concentrations in homeopathic products from Atropa belladonna extracts (4.57 and 2.56 µg/kg, respectively), in Belladonna ointment (4007 and 1139 µg/kg, respectively) and Belladonna seeds (338 and 32.1 mg/kg, respectively). Other tropane alkaloids such as tropine, apoatropine, aposcopolamine, tropinone, homatropine, and anisodamine were detected at lower concentrations (0.04-1.36 µg/kg). When untargeted analysis was performed, other tropane alkaloids were identified in the tested samples, such as ecgonine (0.003 µg/kg), benzoylecgonine (0.56 µg/kg), calystegines A (19.6 µg/kg), B (33.1 µg/kg), and C (1.01 µg/kg). Finally other compounds present in the homeopathic products, such as sugars (fructose, glucose, and lactose) or amino acids (valine, ornithine, leucine, and phenylalanine), were identified.

Atropa belladonna neurotoxicity: Implications to neurological disorders.

Atropa belladonna, commonly known as belladonna or deadly nightshade, ranks among one of the most poisonous plants in Europe and other parts of the world. The plant contains tropane alkaloids including atropine, scopolamine, and hyoscyamine, which are used as anticholinergics in Food and Drug Administration (FDA) approved drugs and homeopathic remedies. These alkaloids can be very toxic at high dose. The FDA has recently reported that Hyland's baby teething tablets contain inconsistent amounts of Atropa belladonna that may have adverse effects on the nervous system and cause death in children, thus recalled the product in 2017. A greater understanding of the neurotoxicity of Atropa belladonna and its modification of genetic polymorphisms in the nervous system is critical in order to develop better treatment strategies, therapies, regulations, education of at-risk populations, and a more cohesive paradigm for future research. This review offers an integrated view of the homeopathy and neurotoxicity of Atropa belladonna in children, adults, and animal models as well as its implications to neurological disorders. Particular attention is dedicated to the pharmaco/toxicodynamics, pharmaco/toxicokinetics, pathophysiology, epidemiological cases, and animal studies associated with the effects of Atropa belladonna on the nervous system. Additionally, we discuss the influence of active tropane alkaloids in Atropa belladonna and other similar plants on FDA-approved therapeutic drugs for treatment of neurological disorders.

Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant human muscarinic M2 receptors.

Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects.

Preoperative Belladonna and Opium Suppository for Ureteral Stent Pain: A Randomized, Double-blinded, Placebo-controlled Study.

OBJECTIVE: To investigate whether the use of a belladonna and opium (B&O) rectal suppository administered immediately before ureteroscopy (URS) and stent placement could reduce stent-related discomfort. METHODS: A randomized, double-blinded, placebo-controlled study was performed from August 2013 to December 2014. Seventy-one subjects were enrolled and randomized to receive a B&O (15 mg/30 mg) or a placebo suppository after induction of general anesthesia immediately before URS and stent placement. Baseline urinary symptoms were assessed using the American Urological Association Symptom Score (AUASS). The Ureteral Stent Symptom Questionnaire and AUASS were completed on postoperative days (POD) 1, 3, and after stent removal. Analgesic use intraoperatively, in the recovery unit, and at home was recorded. RESULTS: Of the 71 subjects, 65 had treatment for ureteral (41%) and renal (61%) calculi, 4 for renal urothelial carcinoma, and 2 were excluded for no stent placed. By POD3, the B&O group reported a higher mean global quality of life (QOL) score (P = .04), a better mean quality of work score (P = .05), and less pain with urination (P = .03). The B&O group reported an improved AUASS QOL when comparing POD1 with post-stent removal (P = .04). There was no difference in analgesic use among groups (P = .67). There were no episodes of urinary retention. Age was associated with unplanned emergency visits (P <.00) and "high-pain" measure (P = .02) CONCLUSION: B&O suppository administered preoperatively improved QOL measures and reduced urinary-related pain after URS with stent. Younger age was associated with severe stent pain and unplanned hospital visits.

[Italian guidelines and recommendations for prevention and treatment of pain in the newborn]. / Linee-guida e raccomandazioni per la prevenzione ed il trattamento del dolore nel neonato.

OBJECTIVE: Despite accumulating evidence that procedural pain experienced by preterm infants may have acute detrimental and even long-term effects on an infant's subsequent behavior and neurological outcome, neonates admitted to Neonatal Intensive Care Units still frequently experience acute and prolonged uncontrolled pain. Many invasive and surgical procedures are routinely performed at the bedside in the NICU without adequate pain management. AIM: To develop evidence-based guidelines and recommendations for pain control and prevention in Italian i.e. heel lancing, venipuncture and percutaneous venous line positioning, tracheal intubation, mechanical ventilation, lumbar puncture, chest tube positioning, for certain surgical procedures performed at the NICU, e.g. central venous cutdown, surgical PDA ligation, and cryotherapy, laser therapy for ROP, and for postoperative pain management. CONCLUSION: Adequate pain prevention and management should be an essential part of standard health care at the NICU, and recognizing and assessing sources of pain should be routine in the day-to-day practice of physicians and nurses taking care of the newborn. We hope these guidelines will contribute towards increasing the NICU caregiver's awareness and understanding of the importance of adequate pain control and prevention.

Receptor mediated presynaptic modulation of the release of noradrenaline in human papillary muscle.

OBJECTIVE: The aim was to determine the presynaptic modulation of noradrenaline (NA) release from the sympathetic nerve terminals in human isolated papillary muscle. METHODS: Papillary muscle and the right atrial appendage were obtained from operations on 22 patients (10 men and 12 women). The papillary muscle preparations were preincubated with [3H]NA and the release of [3H] at rest and in response to field stimulation was measured. RESULTS: Using an immunohistochemical method dopamine-beta-hydroxylase-positive neurones were found in the papillary muscle and right atrial appendage sample. The release of noradrenaline from the papillary muscle, associated with axonal activity, was enhanced by 7,8(methylenedioxy)-14-alpha-hydroxyalloberbane HCl (CH-38083), a selective alpha 2 adrenoceptor antagonist, and inhibited by xylazine, an alpha 2 adrenoceptor agonist, indicating that negative feedback modulation was functioning. In addition, the release of [3H]NA was enhanced by atropine, pancuronium, and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), a selective M3 muscarinic receptor antagonist, and reduced by oxotremorine, a selective muscarinic receptor agonist, indicating that acetylcholine released from the parasympathetic nerve ending was able to reach the varicose noradrenergic axon terminals that are equipped with inhibitory M3 muscarinic receptors. CONCLUSIONS: These findings, obtained for the first time in human papillary muscle, indicate that the release of noradrenaline is modulated by alpha 2 autoreceptors activated by noradrenaline and M3 muscarinic heteroreceptors. Thus during parasympathetic stimulation the release of noradrenaline from the sympathetic axon terminals is presynaptically controlled through muscarinic receptors.

Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms.

Exposure to high doses of organophosphorus nerve agents such as soman, even with carbamate pretreatment, produces a variety of toxic cholinergic signs, including secretions, convulsions and death. Evidence suggests that soman-induced convulsions may be associated with postexposure brain neuropathology. The purpose of this study was to investigate the pharmacologic mechanism of action of soman-induced convulsions and of anticonvulsant drugs. Various classes of compounds were evaluated for their efficacy in preventing soman-induced convulsions in rats pretreated with the oxime HI-6 to increase survival time, along with various doses of the test compounds (IM) either in the absence or presence of atropine sulfate (16 mg/kg, IM) 30 minutes prior to a soman challenge dose (180 micrograms/kg, SC; equivalent to 1.6 x LD50) that produced 100% convulsions. Without atropine sulfate, only tertiary anticholinergics (scopolamine, trihexyphenidyl, biperiden, benactyzine, benztropine, azaprophen and aprophen), caramiphen, carbetapentane and MK-801 were effective anticonvulsants. In the presence of atropine sulfate, the benzodiazepines (diazepam, midazolam, clonazepam, loprazolam and alprazolam), mecamylamine, flunarizine, diphenylhydantoin, clonidine, CGS 19755 and Organon 6370 studied were effective. We have examined the possibility that diazepam may exert some of its anticonvulsant effects through cholinergic mechanisms and found that a reduced release of ACh into synapses after diazepam and atropine treatment may account for diazepam's anticonvulsant activity against soman. We also found that at anticonvulsant doses biperiden and trihexyphenidyl each significantly reversed the effects of soman on striatal levels of DOPAC and HVA, the metabolites of dopamine, and have concluded that in addition to actions on muscarinic receptors, the anticonvulsant effects of these anticholinergics in soman poisoning may be partially related to their actions on the striatal dopaminergic system. These findings allow us to postulate that central muscarinic cholinergic mechanisms are primarily involved in eliciting the convulsions following exposure to soman and that subsequent recruitment of other excitatory neurotransmitter systems and loss of inhibitory control may be responsible for sustaining the convulsions and for producing the subsequent brain damage. Future studies to confirm these neuropharmacological mechanisms are proposed.

Determination of the muscarinic receptor subtype mediating vasodilatation.

The muscarinic receptor mediating vasodilatation of the rabbit aorta and dog femoral artery has been assessed using muscarinic antagonists. With the exception of pirenzepine, the antagonist affinities were similar to those reported for the ileal receptors and dissimilar to those reported for the atrial receptors. Pirenzepine exhibited an affinity (7.54) intermediate between that reported for the CNS receptors (8.4) and that reported for the ileal receptors (6.77). This value for pirenzepine was confirmed using acetylcholine as the agonist and using the dog femoral artery as the vascular tissue. It is concluded that the muscarinic receptor profile mediating vasodilatation is not easily accommodated into the current receptor classification.

Paediatric anaesthesia: pharmacological considerations.

The young infant differs from the adult in his quantitative responses to many anaesthetic drugs and adjuncts. In the neonate, the larger extracellular fluid volume and blood volume, the smaller muscle mass and fat stores, and presumable greater blood flow to the central organs, not only influence the distribution of drugs to their active site but also secondary redistribution. The neonatal hepatic anzyme systems responsible for the metabolism of drugs are incompletely developed or absent. Glomerular filtration, important for drug excretion, is inefficient by adult standards. The neonate has increased toxicity and sensitivity to a variety of sedative-hypnotics, narcotics, and local anaesthetics. On the other hand, the infant requires more suxamethonium (succinylcholine) and ketamine on a weight basis that does the adult. The response of some infants to non-depolarising muscle relaxants resembles that of the myasthenic patients. The rate of uptake of alveolar levels of inhalation anesthetics is more rapid in infants and children than in adults. In addition, the neonate requires more anaesthetic than the adult for a given surgical stimulus. Biotransformation of inhalation anaesthetics is limited in neonates. Awareness of these pharmacological differences and their probable explanations allows one to provide rational, safer anaesthesia to infants.

Investigation of pleural effusion: an evaluation of the new Olympus LTF semiflexible thoracofiberscope and comparison with Abram's needle biopsy.

STUDY OBJECTIVES: Recently, pulmonologists have performed thoracoscopy under local anesthesia using rigid thoracoscopes or flexible bronchoscopes. The latter allow greater access within the pleural cavity but are difficult to manipulate. The Olympus LTF semiflexible fiberoptic thoracoscope combines features of both instruments, having a solid body and a flexible terminal section. In the first study with this instrument, we evaluated ease of use and compared diagnostic yield with closed needle biopsy. PATIENTS: Twenty-four patients with pleural effusion were investigated. SETTING: Scottish University Hospital. DESIGN: Thoracoscopy was performed in the bronchoscopy suite after premedication with atropine and papaveretum. Following a standard Abram's needle biopsy, the LTF thoracoscope was inserted through a flexible introducer (Olympus Optical Co Ltd; Tokyo, Japan). The pleura was inspected and biopsy specimens were taken of suspicious areas. RESULTS: The final diagnosis was malignant pleural effusion in 16 of 24 patients. Ten of 16 were positive by Abram's biopsy, giving a sensitivity of 62%. Thirteen of 16 were positive by fiberoptic thoracoscopy, giving an improved sensitivity of 81%. The LTF thoracoscope was easy to use for pulmonologists experienced in rigid thoracoscopy and flexible bronchoscopy. Excellent views of the pleura were obtained from a single entry point. The procedure was well tolerated and no complications were encountered. CONCLUSION: The LTF thoracoscope allows excellent pleural access but a larger biopsy channel (currently 2 mm) might increase the accuracy of diagnosis.

Antagonists discriminate muscarinic excitation and inhibition in sympathetic ganglion.

The effect of muscarinic antagonists was studied on the muscarinic slow IPSP (inhibitory postsynaptic potential) and slow EPSP (excitatory postsynaptic potential) in bullfrog sympathetic ganglia using the sucrose-gap recording method. Pirenzepine, alcuronium and atropine reduced slow IPSP amplitude more than slow EPSP amplitude. The most selective antagonists studied were pancuronium and gallamine which blocked or substantially reduced the slow IPSP without significantly affecting slow EPSP amplitude. The results suggest that the muscarinic inhibitory response may involve a different muscarinic receptor subtype, and/or receptor-ion-channel complex, than the muscarinic excitatory response.

Nerve-induced tachykinin-mediated vasodilation in skeletal muscle is dependent on nitric oxide formation.

Nerve-induced vasodilatation was studied by intravital microscopy of the rabbit tenuissimus muscle, pretreated with pancuronium, phentolamine, and guanethidine. Nerve stimulation of the tenuissimus nerve induced a vasodilatation which was frequency and pulse duration-dependent and insensitive to atropine and propanolol but abolished by tetrodotoxin. The nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM), but not its enantiomer, D-NAME, markedly inhibited the vasodilation induced by nerve stimulation or by exogenous substance P or neurokinin A. Vasodilatation due to calcitonin gene-related peptide, prostaglandin E2 or nitroprusside was unaffected. The substance P antagonist, spantide (30 microM), significantly attenuated nerve-induced vasodilatation, in parallel with L-NAME. Our results indicate that nerve-induced vasodilatation in skeletal muscle can be attributed to the release of substance P and/or other tachykinins and that nitric oxide subsequently mediates the response to endogenous tachykinins released from nerves.

Human isolated small intestine: motor responses of the longitudinal muscle to field stimulation and exogenous neuropeptides.

(1) Longitudinal muscle strips from the human small intestine (jejunum/ileum) responded to electrical field stimulation (1-50 Hz) with frequency-related primary contractions which were largely atropine- (3 microM) sensitive. When the tone was raised by addition of galanin (0.3-1 microM), prostaglandin (PG) E2 (1-10 microM) or neurokinin A (NKA, 0.1 microM), a frequency-related relaxation was evident which was potentiated by atropine. All the responses to field stimulation were abolished by tetrodotoxin (1 microM), thus indicating their neural origin. (2) The atropine-sensitive primary contraction to field stimulation was virtually abolished by omega conotoxin fraction GVIA (CTX, 0.1-0.3 microM) while the relaxations were CTX-resistant. The field stimulation-induced relaxations, which were observed in the presence of atropine and guanethidine (3 microM), were also unaffected by apamin (0.1 microM). (3) NKA and substance P (SP) produced a concentration- (1 nM-1 microM for both peptides) related contraction, NKA being about 53 times more potent than SP. [Pro9]SP sulphone and [MePhe7]-NKB, selective agonists of the NK-1 and NK-3 receptor, respectively, were barely effective. On the other hand, [beta Ala8]NKA(4-10), a selective NK-2 receptor agonist, had a potent contractile activity, similar to that of NKA. (4) Galanin (1 nM-1 microM) produced an atropine- and tetrodotoxin-resistant concentration-related contraction of longitudinal muscle of human isolated small intestine. The response to galanin did not show any sign of fading and was particularly suitable to study the evoked relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)

The interaction of McN-A-343 with pirenzepine and other selective muscarine receptor antagonists at a prejunctional muscarine receptor.

The effect of several muscarine receptor antagonists on responses to carbachol (CCh) and McN-A-343 (McN) were compared in the perfused rabbit ear artery preparation stimulated via noradrenergic nerves at 3 Hz in the presence of cocaine (10 microM) and yohimbine (1 microM). The slope of the dose-response curve to McN was significantly less (P less than 0.05) than that for CCh although both agonists produced up to 100% inhibition of responses to nervous stimulation. All the antagonists investigated produced parallel shifts of the dose-response curve to the agonists and atropine, fenipramide or stercuronium gave a similar pA2 value with either agonist. Pirenzepine was a competitive antagonist when CCh was used, as judged by a slope of 0.96 +/- 0.10 for the Arunlakshana-Schild (A-S) plot (pKB 6.2). Displacement of 3H-(-)QNB binding by pirenzepine gave a pKI value of 6.0 which was not significantly different to the pKB value. When McN was used as the agonist, the dose-ratios obtained with pirenzepine (0.5 microM) were significantly different (P less than 0.01) to those with CCh as agonist and the slope of the A-S plot over the concentration range of 0.1 to 3 microM was significantly less than 1.0 (P less than 0.01), indicating that the inhibition was not a simple competitive interaction. It is suggested that the interaction of McN and pirenzepine may involve an allosteric mechanism.

Pancuronium and gallamine are antagonists for pre- and post-junctional muscarinic receptors in the guinea-pig lung.

The effects of atropine, pancuronium and gallamine were tested on pre- and post-junctional muscarinic receptors in the lung. Inhibition of bronchoconstriction induced by intravenous injection of acetylcholine (ACh) was used as a measure of post-junctional receptor blockade. All three antagonists reduced ACh-induced bronchoconstriction. The effects were dose-related for atropine and pancuronium and complete inhibition was obtained with 0.01 mg/kg and 10 mg/kg respectively. Gallamine was much less potent than the other two drugs; the inhibitory effect was not dose-related and never exceeded 50% even at a dose of 10 mg/kg. In contrast, blockade of pre-junctional inhibitory muscarinic receptors in pulmonary parasympathetic nerves by these three antagonists, produced potentiation of bronchoconstriction induced by vagal-nerve stimulation. Consequently, the effect of the three antagonists on vagally-induced bronchoconstriction is dependent on the balance between their pre- and post-junctional blocking activity. Gallamine was the most effective and atropine the least effective antagonist for potentiating nerve-induced bronchoconstriction. At doses which produce 100% neuromuscular blockade, both pancuronium (0.04 mg/kg) and gallamine (4 mg/kg) potentiated vagally-induced bronchoconstriction. At these doses, pancuronium doubled and gallamine caused a four-fold increase in vagally-induced bronchoconstriction, despite partial concurrent blockade of muscarinic receptors in the smooth muscle of the airways.

Monitoring of liver oxygenation during neuroleptanalgesia in the dog.

In an animal study (7 mongrel dogs) the effects of neuroleptanalgesia (NLA) and combinations of NLA with nitrous oxide (N2O) and isoflurane on the macro- and microcirculation of the liver were investigated. Measurements were made in three steps. After NLA alone the dogs were supplementarily ventilated with nitrous oxide/oxygen at a ratio of 2:1. During the last step, 1 MAC isoflurane was added to the inspired gas. From the portal vein, arterial and mixed-venous systems' hemodynamic parameters, blood gases, and acid-base balance were recorded. As a parameter of oxygenation the tissue PO2 of the liver was measured with a multiwire surface electrode. During NLA stable hemodynamic conditions and a balanced acid-base status were observed. The nitrous oxide combination resulted in an increase of the mean pulmonary artery pressure of 16%. The addition of isoflurane had a negative inotropic effect: The heart index decreased to 74% of the starting value and the total peripheral resistance (TPR) increased by 27%. The summarized PO2 histograms under NLA and NLA/N2O showed arithmetic mean values of 34.1 and 35.2 mm Hg, respectively. The addition of isoflurane resulted in a left shift and a decrease of the mean value to 28.6 mm Hg. This histogram corresponds exactly to the oxygen pressure distribution in the dog liver during piritramide basic anesthesia. It seems that NLA and the combination of NLA/N2O increase the liver perfusion with a higher portal-venous and tissue PO2. This effect can be explained only by a massive change of visceral circulation. It is canceled by the addition of isoflurane.

Neuromuscular blocking action of vecuronium in the dog and its reversal by neostigmine.

Vecuronium bromide is one of a new series of competitive or nondepolarising muscle relaxants which is closely related chemically to pancuronium. Doses of 0.06, 0.1 and 0.2 mg kg-1 produced neuromuscular block in the anaesthetised dog. There were no observable effects on arterial blood pressure. The neuromuscular block was readily reversible with neostigmine preceded by atropine.

Ventilation and cardiovascular studies during mechanical control of ventilation in horses.

Eleven out of 12 horses were underventilating while breathing spontaneously during halothane anaesthesia with high arterial carbon dioxide tensions. In addition, large alveolar to arterial oxygen tension gradients were found to be present. Mechanically, controlled ventilation with an intermittent positive pressure of 20-30 cm H2O reduced arterial carbon dioxide levels to normal. The alveolar to arterial oxygen gradients did not increase and in some cases decreased. These (A - a) Po2 gradients were due mainly to true shunt of the order of 30 per cent and not to ventilation perfusion inequality.

The effect of some anti-diarrhoeal drugs on intestinal transit and faecal excretion of water and electrolytes in the horse.

The effect of morphine, Tinct. opii, loperamide, pethidine and atropine on intestinal transit and the faecal and urinary excretion of water and electrolytes was studied in ponies. The rate of passage of a particulate marker was slowed by morphine, hastened then slowed by loperamide and Tinct. opii, and hastened by atropine. The liquid marker was slowed by Tinct. opii and hastened then slowed by the other drugs. Only loperamide decreased the faecal sodium excretion. This drug also decreased faecal water and weight; it appeared worthy of clinical trial in diarrhoea. Tinct. opii decreased by morphine, pethidine and atropine increased faecal water.