dihydroergotoxine

Summary

Summary: A mixture of three different hydrogenated derivatives of ERGOTAMINE: DIHYDROERGOCORNINE; DIHYDROERGOCRISTINE; and DIHYDROERGOCRYPTINE. Dihydroergotoxine has been proposed to be a neuroprotective agent and a nootropic agent. The mechanism of its therapeutic actions is not clear, but it can act as an alpha-adrenergic antagonist and a dopamine agonist. The methanesulfonate salts of this mixture of alkaloids are called ERGOLOID MESYLATES.

Top Publications

  1. Kohler J, Riepe M, Jendroska K, Pilartz H, Adler G, Berger F, et al. [Early diagnosis and treatment of Alzheimer's disease. Implementation in the doctor's office]. Fortschr Med Orig. 2002;120:135-41 pubmed
    ..They therefore provide the basis for a modern diagnostic work-up and treatment strategy, which will also meet economical demands. ..
  2. Bronzetti E, Felici L, Polidori C, Amenta F. Interactions between calcium channel blockers and alpha-adrenoceptors in the human coronary and mammary arteries: a radioligand binding study. J Auton Pharmacol. 1994;14:79-85 pubmed
    ..This property may account for the lower sympathetic stimulatory activity elicited by nicardipine, in comparison with other Ca2+ channel blockers used in cardiovascular therapy. ..
  3. Pons Rocher F. [The effect of pharmacological treatment in the compensation of vertigo]. An Otorrinolaringol Ibero Am. 1999;26:271-91 pubmed
    ..8 g Piracetam each hours compared with the other two groups. It can be concluded that the association D-P is an effective treatment for vertigo, getting also a higher normalization of the vestibular tests than Placebo. ..
  4. Bonuccelli U, D ANTONIO P, D Avino C, Piccini P, Muratorio A. Dihydroergocryptine in the treatment of Parkinson's disease. J Neural Transm Suppl. 1995;45:239-45 pubmed
    ..1992; Yoshikawa et al., 1994). In this minireview we resume the data reported about neuroprotective activity and therapeutic efficacy of a new ergot derivative, alpha-dihydroergocryptine (DHEC). ..
  5. Aranda B, Dumoulin P, Groothold G. [Controlled study of the effect of dihydroergocristine on organic brain psychosyndrome]. Arzneimittelforschung. 1992;42:1406-9 pubmed
    ..Safety was good (placebo: one case of diarrhea; DHEC: one case of gastralgia and dizziness). Nine patients dropped out for reasons unrelated to treatment.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  6. Bergamasco B, Frattola L, Muratorio A, Piccoli F, Mailland F, Parnetti L. Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study. Acta Neurol Scand. 2000;101:372-80 pubmed
    ..The results indicate that alpha-dihydroergocryptine is safe and effective in improving symptoms of de novo parkinsonian patients. ..
  7. Dubini F, Bignami P, Zanotti A, Coppi G. Mutagenicity studies on dihydroergocristine. Drugs Exp Clin Res. 1990;16:255-61 pubmed
    ..Dihydroergocristine is a drug free of mutagenic activity on the basis of all the results obtained from the above in vitro and in vivo tests. ..
  8. Stowell L, McIntosh C, Cooke R, Ellis P. Adrenoceptor and imipramine receptor binding during the menstrual cycle. Acta Psychiatr Scand. 1988;78:366-8 pubmed
    ..A significant cyclic variation in the number of beta 2-adrenoceptor sites on intact lymphocytes was found during the menstrual cycle, while binding to alpha 2-adrenoceptors and imipramine receptors remained unchanged...
  9. Melena J, Santafe J, Segarra J. The effect of topical dihydroergocristine on the intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits. Methods Find Exp Clin Pharmacol. 1998;20:861-7 pubmed
    ..Our findings suggest that topical dihydroergocristine may be useful in the treatment of ocular hypertension. ..

More Information

Publications62

  1. Neusch C, Böhme V, Riesland N, Althaus M, Moser A. The dopamine D2 receptor agonist alpha-dihydroergocryptine modulates voltage-gated sodium channels in the rat caudate-putamen. J Neural Transm (Vienna). 2000;107:531-41 pubmed
    ..The results give one rationale for the proposed neuroprotective effect of alpha-DHEC. ..
  2. Dominiak P, Weidinger G. [Therapy comparison between the combination hydergine/nifedipine and nifedipine alone in patients with isolated systolic hypertension]. Med Klin (Munich). 1991;86:15-9 pubmed
    ..As drug specific adverse events flush symptoms were more frequent in the Nifedipine group, whereas in the Hydergine/Nifedipine group gastrointestinal symptoms occurred more often. ..
  3. Ezan E, Ardouin T, Delhotal Landes B, Flouvat B, Hanslik T, Legeai J, et al. Bioequivalence study of alpha-dihydroergocryptine: utility of metabolite evaluation. Int J Clin Pharmacol Ther. 1996;34:32-7 pubmed
    ..25 (AUC0-infinity) and 0.7-1.43 (Cmax) for DHECT with metabolites but not for unchanged DHECT. This study describes a particular case where only measurements on the basis of the metabolites can justify the assumption of bioequivalence. ..
  4. Abdul M, Mccray S, HOOSEIN N. Expression of gamma-aminobutyric acid receptor (subtype A) in prostate cancer. Acta Oncol. 2008;47:1546-50 pubmed publisher
    ..However, dihydroergotoxine, which binds the GABAar chloride ion-channel, inhibited cellular proliferation (IC(50) 18-38 microM)...
  5. Ogawa N, Nomura M, Haba K, Asanuma M, Tanaka K, Hori K, et al. Effects of dihydroergotoxine on central cholinergic neuronal systems and discrimination learning test in aged rats. Brain Res. 1992;586:229-34 pubmed
    ..However, intraperitoneal injection of 1 mg/kg of dihydroergotoxine (DHET) for 14 days normalized both ChAT and MCR in the cerebral cortex and hippocampus...
  6. Gorini A, Arnaboldi R, Vercesi L, Dossena M. Influence of some ergot alkaloids on the cerebral reduced glutathione. Farmaco Sci. 1988;43:887-90 pubmed
    ..The results indicate that, within a specific dose-range, the concentration of the cerebral reduced glutathione may be modified by exogenous intervention. ..
  7. Amenta D, Ferrante F, Franch F, Amenta F. Effects of long-term Hydergine administration on lipofuscin accumulation in senescent rat brain. Gerontology. 1988;34:250-6 pubmed
    ..In 22-month-old rats, Hydergine administration (0.6 and 1 mg/kg p.o.) started at 16 months caused a significant dose-related decrease in lipofuscin accumulation within the cytoplasm of the various kinds of nerve cells examined. ..
  8. Nappi C, Colace G, Di Carlo C, Affinito P, Ruotolo C, Montemagno R, et al. Effect of dihydroergocryptine on serum prolactin levels and milk secretion in puerperal women. Gynecol Endocrinol. 1993;7:129-33 pubmed
    ..No side-effects occurred during the treatment. These results suggest that dihydroergocryptine might be considered an effective drug in the suppression of puerperal lactation. ..
  9. Adams K, Allen J, Brooker P, Jones E, Proudlock R, Mailland F, et al. Evaluation of the mutagenicity of a-dihydroergocryptine in vitro and in vivo. Arzneimittelforschung. 1993;43:1253-7 pubmed
    ..All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays. ..
  10. Petersen K, Ortgiese R, Schuler G, Khalaf N, Schliebs B, Kerp L. [Glucose tolerance and electrolyte metabolism in nifedipine and nifedipine dihydroergotoxin treated healthy subjects]. Arzneimittelforschung. 1989;39:612-4 pubmed
    ..Basal plasma norepinephrine concentrations were lower following nifedipine/dihydroergotoxine than after nifedipine alone (2 p less than 0.05)...
  11. Kalishevskaya T, Golubeva M, Bashkov G. Use of alpha-adrenoceptor antagonist dihydroergotoxin in experimental anticoagulant and fibrinolytic therapy. Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115:157-61 pubmed
    ..Administration of this complex in the combination with DET resulted in a steady hypocoagulation and hyperfibrinolysis in blood stream. ..
  12. Martinkova J, Tilser I, Krejci V, Parizek J, Volenec K. Effect of palmitoyl-DL-carnitine on the 3H-dihydroergotoxine intestinal absorption in rat. Arzneimittelforschung. 1990;40:145-9 pubmed
    Using the methods of rat intestine perfusion in situ and kinetics examination in vivo, absorption of 3H-dihydroergotoxine (3HDHE) from the gastrointestinal tract into systemic blood was investigated...
  13. Grognet J, Istin M, Zanotti A, Mailland F, Coppi G. Pharmacokinetics of alpha-dihydroergocryptine in rats after intravenous and oral administration. Arzneimittelforschung. 1991;41:689-91 pubmed
    ..78 h). The alpha-DHEK was largely metabolized as results from the complex metabolite profile in body fluids and from very low urinary elimination of unchanged drug. ..
  14. Weiss M, Shaeffer Z, Eisenstein Z. Postural hypotension: pressor effect of octreotide not mediated by norepinephrine. South Med J. 1990;83:1315-7 pubmed
    ..Hence, the pressor effect of octreotide is not mediated by stimulation of the sympathetic nervous system, but probably through splanchnic vasoconstriction...
  15. Müller Schweinitzer E. Venoconstrictor responses to dihydroergocristine and dihydroergotamine: evidence for the involvement of 5-HT1 like receptors. Cardiovasc Drugs Ther. 1990;4:1455-60 pubmed
    ..It is suggested that the venoconstrictor responses to both DHEC and DHE are mediated through 5-HT1-like receptors. ..
  16. Schmidt A, Vetter W, Dennler H, Groll S, Orengo P. [Combined uni- and multicenter double-blind studies in hypertensive patients. Comparison of blood pressure measurements]. Schweiz Rundsch Med Prax. 1991;80:849-55 pubmed
    ..g. method or time of measurement) as well as a greatest possible standardization of investigation (e.g. identical measuring apparatus and investigator.) ..
  17. Ogawa N, Mizukawa K, Sora I. Chronic dihydroergotoxine administration increases muscarinic cholinergic receptor binding in aged-rat brain. Res Commun Chem Pathol Pharmacol. 1987;57:149-59 pubmed
    Changes in the distribution and densities of muscarinic cholinergic receptors (mCh-R) and the effects of dihydroergotoxine (DHET) administration on these changes were studied in the aged-rat brain by in vitro autoradiography...
  18. Anami K, Setoguchi M, Senoh H. [Pharmacological studies on Y-8894. (VIII). Effects on learning and memory in the radial maze task in mice]. Nihon Yakurigaku Zasshi. 1988;92:113-8 pubmed
    ..b>Dihydroergotoxine (5 mg/kg, i.p...
  19. Althaus M, Retzow A, Castell J, Gomez Lechon M, Amalou Z, Rose T, et al. In vitro identification of the cytochrome P450 isoform responsible for the metabolism of alpha-dihydroergocryptine. Xenobiotica. 2000;30:1033-45 pubmed
    ..3. The data suggest that DHEC metabolism in humans is primarily mediated by the CYP3A4 isoform. The results are in accordance with findings derived from other ergot alkaloids. ..
  20. Dominiak P, Grevel J, Abisch E, Grobecker H, Dennler H, Welzel D. The absolute systemic availability of a new oral formulation of co-dergocrine in healthy subjects. Eur J Clin Pharmacol. 1988;35:53-7 pubmed
    ..The intravenous and oral doses produced similar pharmacological effects (reduction of plasma prolactin concentrations) despite the small value of f. ..
  21. Sachs G, Gelenberg A, Bellinghausen B, Wojcik J, Falk W, Farhadi A, et al. Ergoloid mesylates and ECT. J Clin Psychiatry. 1989;50:87-90 pubmed
    ..Unexpectedly, patients treated with ergoloid mesylates had a significantly better antidepressant response. ..
  22. Gurevich K, Varfolomeev S. Probability description of ligand-receptor interactions. Evaluation of reliability of events with small and supersmall doses. I. Kinetics of ligand-receptor interactions. Biochemistry (Mosc). 1999;64:1038-48 pubmed
    ..Using data from the literature, we show that LRI description using the mass-action law under these conditions can cause significant errors in interpretation of experimental data. ..
  23. Agliati G, Lazzaroni M, Mariani G, Marras F, Massetto N, Menozzi C, et al. [One-year therapy with dihydroergocristine for treatment of impaired alertness and memory in elderly patients. Placebo-controlled multicenter study]. Arzneimittelforschung. 1992;42:1414-6 pubmed
    ..Based on results of this 1-year investigation, it is concluded that DHEC treatment should not be abruptly interrupted, but continued for as long as possible. ..
  24. Battino M, Littarru G, Gorini A, Villa R. Coenzyme Q, peroxidation and cytochrome oxidase features after parkinson's-like disease by MPTP toxicity in intra-synaptic and non-synaptic mitochondria from Macaca fascicularis cerebral cortex and hippocampus: action of dihydroergocriptine. Neurochem Res. 1996;21:1505-14 pubmed
    ..Dihydroergocriptine treatment appeared to be effective in MPTP-treated animals in improving those mitochondrial features that probably suffered free radical insults. ..
  25. Grognet J, Riviere R, Istin M, Zanotti A, Coppi G. [The pharmacokinetics of dihydroergocristine after intravenous and oral administration in rats]. Arzneimittelforschung. 1992;42:1394-6 pubmed
    ..An extensive biotransformation of DHEC was indicated by an almost complete absence of unchanged drug in the urine and a high systemic clearance (2.65 l.h-1 x kg-1). A large volume of distribution (52 l.kg-1) was calculated. ..
  26. Janka H, Mehnert H. [Antihypertensive therapy with co-dergocrine mesilate/nifedipine in comparison with nifedipine in type II diabetes]. Arzneimittelforschung. 1990;40:980-3 pubmed
    ..Both drugs--nifedipine and co-dergocrine/nifedipine--did not change the concentrations of glucose in the blood or urine or of HbA1. ..
  27. Culp D, McBride R, Graham L, Marin M. Alpha-adrenergic regulation of secretion by tracheal glands. Am J Physiol. 1990;259:L198-205 pubmed
    ..Collectively, these results demonstrate alpha 1-adrenergic regulation of glandular glycoconjugate secretion and suggest alpha 2-adrenergic receptors may modulate beta-adrenergic-stimulated secretion. ..
  28. Setoguchi M, Takehara S, Sakamori M, Anami K, Maruyama Y. [Pharmacological studies on Y-8894 (VI). The effect on monoamine uptake and turnover in mouse brain]. Nihon Yakurigaku Zasshi. 1987;90:41-9 pubmed
    ..These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by ..
  29. Rexroad C, Guthrie H. Alpha-adrenergic receptors in myometrium of pregnant and nonpregnant pigs until day 19 postestrus. Biol Reprod. 1983;29:615-9 pubmed
    ..Embryo migration to the site of implantation may be associated with reduced concentration of DHE binding sites on Days 10 to 12 of pregnancy in pigs. ..
  30. Beck T, Vogg P, Krieglstein J. Uncoupling of cerebral blood flow and glucose utilization by dihydroergocristine in the conscious rat. Naunyn Schmiedebergs Arch Pharmacol. 1988;338:82-7 pubmed
    ..The divergent effects on LCBF and LCGU at a dose of 2.5 mg/kg suggest a potential capacity of dihydroergocristine to uncouple the close interrelation of cerebral blood flow and cerebral energy metabolism. ..
  31. Nobuhara K. [A quantitative pharmaco-EEG study on psychotropic properties of cerebral metabolic enhancers: comparison between young and elderly healthy volunteers]. Seishin Shinkeigaku Zasshi. 1993;95:392-416 pubmed
    ..The drugs tested were five CMEs, dihydroergotoxine mesylate (DHE), propentofylline (PPF), nicergoline (NCG), lisuride maleate (LIS) and ibudilast (IDL)...
  32. Retzow A, Althaus M, de Mey C, Mazur D, Vens Cappell B. Study on the interaction of the dopamine agonist alpha-dihydroergocryptine with the pharmacokinetics of digoxin. Arzneimittelforschung. 2000;50:591-6 pubmed
    ..On the basis of these observations there is no indication for an a priori adjustment of the dose of digoxin when concomitant treatment with DHEC is initiated. ..
  33. Mas Chamberlin C, Bromet N, Olgiati V, Girardello R, Lowenthal D. Metabolism study of dihydro-alpha-ergocryptine,9,10-[9,10-3H(N)] in rat and human hepatocyte cultures and rat, monkey, and human microsomes. Am J Ther. 1997;4:291-9 pubmed
    ..The conclusion is that all the observed metabolites in human are produced either in rats (for a major part) or in monkeys, so that these two species cover the human metabolic pattern for toxicological studies. ..
  34. Anger C, Van Aken H, Hoch D, Lawin P. The influence of ketanserin, droperidol and hydergine on postoperative hypertension during early recovery following major abdominal surgery. Acta Anaesthesiol Belg. 1987;38:153-9 pubmed
    ..Neither hydergine nor placebo had a significant effect on blood pressure. It is concluded, that both ketanserin and droperidol have a moderate and short acting antihypertensive effect. ..
  35. Martignoni E, Pacchetti C, Sibilla L, Bruggi P, Pedevilla M, Nappi G. Dihydroergocryptine in the treatment of Parkinson's disease: a six months' double-blind clinical trial. Clin Neuropharmacol. 1991;14:78-83 pubmed
    ..The authors demonstrate the efficacy and the good tolerability of DEK as a new DA agonist drug that can be added to LD in the treatment of parkinsonian patients. ..
  36. Pagliano F, Galbiati G. Comparison of the efficacy and safety of daily dosages of 6 mg and 20 mg dihydroergocristine in the treatment of chronic cerebro-vascular disease. J Int Med Res. 1995;23:219-27 pubmed
    ..01) in the 20 mg group. The only adverse event reported was a case of mild gastric pain at the end of treatment with 20 mg dihydroergocristine. ..
  37. Radosavljevic M, Pajovic B, Radunovic M, Radojevic N, Bjelogrlic B. Influence of dihydroergotoxine, bromocriptine, and ergotamine on penile erection in Wistar rats. J Androl. 2012;33:866-71 pubmed
    ..The influence of dihydroergotoxine, bromocriptine, and ergotamine was studied on the erection ability in intact, two-grade outbred male ..
  38. Berezina T, Ovsyannikov V. Mechanism for the inhibition of contractile activity of the gastric antrum and pylorus in rabbits during psychogenic stress. Bull Exp Biol Med. 2009;147:296-300 pubmed
    ..It resulted from the influence of a hormonal stress factor on the stomach, which was probably realized through nonadrenergic inhibitory neurons of the enteric nervous system...
  39. Kuskowski M, Morley G, Malone S, Dysken M, Okaya A. Hydergine treatment and psychophysiological measures in primary degenerative dementia. J Geriatr Psychiatry Neurol. 1990;3:41-7 pubmed
    ..However, the results of several other measures of the quality of pursuit eye movements failed to corroborate this finding. ..
  40. Kucukhuseyin C, Silan C, Akbas N, Payat M, Oncel H, Barlas A. On the mechanisms of adenosine induced pulmonary vasoconstriction in rats. J Basic Clin Physiol Pharmacol. 1997;8:287-99 pubmed
  41. Lombardi C, Missale C, de Cotiis R, Spedini C, Pizzoccolo G, Memo M, et al. Inhibition of the aldosterone response to sodium depletion in man by stimulation of dopamine DA2 receptors. Eur J Clin Pharmacol. 1988;35:323-6 pubmed
    ..These results suggest that the dopaminergic inhibition of aldosterone secretion in man is mediated by DA2 receptors in the adrenal cortex. ..
  42. Jensen R, Berndt W. Characterization of adrenergic receptors on proximal tubular basolateral membranes. Life Sci. 1988;43:1473-8 pubmed
    ..These results support previous demonstrations of alpha adrenergic receptors in rat renal cortex and concur with studies which suggest a limited presence of beta receptors on rat proximal tubules. ..
  43. Ricci A, Amenta D, Cavallotti C, Rossodivita I, Amenta F. Autoradiographic localization of peripheral [3H]-hydergine binding sites. Arch Int Pharmacodyn Ther. 1990;304:75-92 pubmed
    ..The above findings suggest that [3H]-hydergine is bound by various structures involved in the regulation of cardiovascular homeostasis. Interaction with these sites probably accounts for the antihypertensive action of hydergine. ..
  44. Berezina T, Ovsiannikov V. [Mechanisms of inhibition of the contractile activity in the ileo-caecal zone in rabbits under psychogenic stress]. Ross Fiziol Zh Im I M Sechenova. 2005;91:893-902 pubmed
  45. Rossi G, Manunta P, Hamlyn J, Pavan E, De Toni R, Semplicini A, et al. Immunoreactive endogenous ouabain in primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels. J Hypertens. 1995;13:1181-91 pubmed
    ..The latter do not appear to be secondary to hypertension, are unrelated to plasma renin activity, and may not involve adrenal type-2 dopaminergic receptors. ..
  46. Bernocchi G, Gerzeli G, Scherini E, Vignola C. Neuroprotective effects of alpha-dihydroergocryptine against damages in the substantia nigra caused by severe treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Acta Neuropathol. 1993;85:404-13 pubmed
    ..The findings suggest that DEK preserves neuronal morphology and brain architecture. ..
  47. Izumiyama K, Kogure K. Effect of dihydroergotoxine mesylate (Hydergine) on delayed neuronal death in the gerbil hippocampus. Acta Neurol Scand. 1988;78:214-20 pubmed
    ..necrosis with delayed onset following 5 min ischemia were reduced markedly by the systemic administration of dihydroergotoxine mesylate (Hydergine; HYG)...
  48. Florio J, Palermo Neto J. Effects of dihydroergotoxine on some dopamine-related behaviors in rats. Gen Pharmacol. 1990;21:411-5 pubmed
    1. The effects of dihydroergotoxine on open-field behavior, apomorphine-induced stereotype and haloperidol-induced catalepsy were studied quantitatively in rats. 2...
  49. Kirsten R, Nelson K, Weidinger G, Welzel D. Co-dergocrine mesylate inhibits the increase in plasma catecholamines caused by nifedipine in essential hypertension. Eur J Clin Pharmacol. 1990;39:435-9 pubmed
    ..Nif caused an increase in renin activity but no increase in aldosterone. Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  50. Wade J. Multi-infarct dementia: prevention and treatment. Alzheimer Dis Assoc Disord. 1991;5:144-8 pubmed
    ..Progression is generally considered the consequence of recurrent stroke (Hachinski, 1983): the mainstay of treatment, therefore, is the prevention of further ischemic events. ..
  51. Drago F, Valerio C, D Agata V, Lauria N, Scapagnini U. Dihydroergocryptine improves behavioral deficits of aged male rats. Neurobiol Aging. 1988;9:285-90 pubmed
    ..It is possible that the improvement of behavioral deficits of aged rats after the treatment with DHECP depends on the facilitating effect of this drug on central dopamine transmission that may be impaired in these animals. ..
  52. Tvrdeić A, Pericic D. Dihydrogenated ergot compounds bind with high affinity to GABAA receptor-associated Cl- ionophore. Eur J Pharmacol. 1991;202:109-11 pubmed
    ..3H]TBOB) to crude synaptosomal membranes of the mouse brain (cerebrum minus cortex) in the presence of dihydroergotoxine, dihydroergosine, dihydroergotamine and gamma-aminobutyric acid (GABA) was studied in vitro...
  53. Woodcock B, Herrmann W, Habedank W. Co-dergocrine plasma concentrations and blood pressure changes in hypertensive patients during therapy with slow-release co-dergocrine mesylate. Int J Clin Pharmacol Ther Toxicol. 1992;30:63-5 pubmed
    ..Blood glucose fell progressively and was 10% lower (p less than 0.02) after 6 weeks medication. Clinical and laboratory parameters showed that slow-release co-dergocrine mesylate was well tolerated with negligible adverse reactions. ..