Kegg Pathway: Anticonvulsants

J Psychopharmacol. 2008 Jun; 22(4): 452-6
Franks M, Macritchie K, Mahmood T, Young A

In bipolar disorder the discontinuation of lithium prophylaxis is associated with early episode precipitation. Is this ;rebound' phenomenon peculiar to lithium? This naturalistic retrospective case note review investigated the frequency of immediate recurrence after discontinuation of any prophylactic treatment. Bipolar patients who stopped at least one medication after at least 6 months of remission were studied. A total of 310 case notes were examined in a systematic search. A total of 53 cases of discontinuation in 48 subjects were found. Discontinued medications included lithium, valproate, carbamazepine, typical and atypical antipsychotics and antidepressants. Recurrence occurred within 3 months of medication withdrawal in 39 cases (74%). Over half of the discontinuation episodes involved lithium: recurrence occurred in 86% of these cases. In the groups stopping other prophylactic agents, a majority of subjects suffered recurrence: Anticonvulsants (89%), antipsychotics (64%) and antidepressants (58%). However, these groups were small and the clarity of the data was undermined by the simultaneous withdrawal of other agents. Manic and hypomanic episodes were the most common form of recurrences. Depressive episodes occurred proportionately most frequently following antidepressant withdrawal. More than half of recurrences required hospital admission. This study provides preliminary naturalistic evidence that early episode recurrence in bipolar disorder is not peculiar to lithium withdrawal but may occur following withdrawal of medication from all classes recommended in prophylaxis. These findings, if replicated, have important implications for clinical practice and for research.

Crit Care Med. 2008 Jul; 36(7 Suppl): S346-57
Malchow RJ, Black IH

BACKGROUND: The evolution of military medical care to manage polytrauma, critically ill-wounded warriors from the greater war on terrorism has been accompanied by significant changes in the diagnosis, management, and modulation of acute and chronic trauma-related pain. A paradigm shift in pain management includes early treatment of pain at the point of injury and throughout the continuum of care with a combination of standard and novel therapeutic interventions. These concepts are important for all critical care providers because they translate to most critically ill patients, including those resulting from natural disasters. Previous authors have reported a high incidence of moderate to severe pain and poor analgesia in intensive care units associated with sleep disturbances, tachycardia, pulmonary complications, increased stress response with thromboembolic incidents, and immunosuppression, increased intensive care unit and hospital stays, and needless suffering. Although opioids have traditionally been the cornerstone of acute pain management, they have potential negative effects ranging from sedation, confusion, respiratory depression, nausea, ileus, constipation, tolerance, opioid-induced hyperalgesia as well as potential for immunosuppression. Alternatively, multimodal therapy is increasingly recognized as a critical pain management approach, especially when combined with early nutrition and ambulation, designed to improve functional recovery and decrease chronic pain conditions. DISCUSSION: Multimodal therapy encompasses a wide range of procedures and medications, including regional analgesia with continuous epidural or peripheral nerve block infusions, judicious opioids, acetaminophen, anti-inflammatory agents, Anticonvulsants, ketamine, clonidine, mexiletine, antidepressants, and anxiolytics as options to treat or modulate pain at various sites of action. SUMMARY: With a more aggressive acute pain management strategy, the military has decreased acute and chronic pain conditions, which may have application in the civilian sector as well.

Epilepsia. 2008 Jul 8;
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other Anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other Anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other Anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.

Semin Arthritis Rheum. 2008 Jul 10;
Furst DE

OBJECTIVES: To determine the relationship between the levels of serum immunoglobulin (Ig) levels and risk of infection. The following 2 main questions are addressed: (1) At what level do reduced serum concentrations of the different Ig species (focusing on IgA, IgG, and IgM) significantly increase the risk of infection above background and (2) For how long can Ig depletion be tolerated before an increased risk of infection becomes apparent. METHODS: Information was gathered from a search of PubMed and relevant congress abstracts up to and including November 2007. RESULTS: Sustained, very low levels of IgA, IgG, or IgM, as occur in primary immunodeficiency syndromes, are associated with significantly increased risks of infections, primarily respiratory tract infections of bacterial origin. Patients with IgG levels <100 mg/dL or IgM levels <20 mg/dL for prolonged periods have an increased risk of recurrent and sometimes life-threatening infectious episodes. Generally, IgA deficiency appears better tolerated. Replenishment of IgG in patients with hypogammaglobulinemia reduces the infection risk to background if IgG levels are maintained at approximately 500 mg/dL, although higher levels may be necessary in the presence of certain comorbidities. Transient depletion of IgG and/or IgM (or, less commonly, IgA) can occur in some patients following the administration of certain drugs, including Anticonvulsants, corticosteroids, and rituximab. Available evidence suggests that such changes are not generally associated with an increased risk of infections. CONCLUSIONS: While prolonged, very low levels of IgG and/or IgM are associated with a heightened risk of infections, transient or less severe immunodeficiency appears to be tolerated in most subjects.

Rinsho Shinkeigaku. 2008 Jun; 48(6): 393-400
Naritomi H

Many elderly people complain dizziness which may continue occasionally for months or years. According to epidemiological studies, 25-29% of subjects with more than 60 years of age have the experience of dizziness. Dizziness occurs most commonly during head positional changes or walking. Clinical studies have indicated that causes of dizziness are nonspecific and multi-factorial; cerebrovascular diseases, cervical spondylosis, depressive state, poor vision, orthostatic hypotension, whiplash injury, or low cerebrospinal fluid syndrome may play a role in the development of dizziness. Patients with dizziness commonly have neck/shoulder pain, insomnia, left-right imbalance of visual acuity, scoliosis, white matter lesions on head MRI. Little, however, has yet been known as to how these symptoms and radiological findings are related to mechanisms of dizziness. During the last several years, we performed cerebral functional studies using auditory-evoked magneto-encephalography (MEG) in elderly people with chronic dizziness. Two types of functional abnormalities were found in dizziness patients. One is a rotational abnormality of MEG signals at the temporal cortex (Type A) which can be detected by current arrow mapping analysis. This abnormality is similar to that detected by non-evoked MEG in temporal lobe epilepsy patients. In patients with Type A abnormality, administration of Anticonvulsants brought about dramatic improvement of dizziness in association with disappearance of rotational abnormalities. The other is abnormal prolongation of interhemispheric neural conduction time (INCT) between the left and right temporal cortices (Type B) which can be estimated from the difference of left and right N100 m peak latencies. The INCT was found to be prolonged correlating with the grade of white matter lesions on MRI. The INCT also seems to be prolonged by lack of sleep. Patients with Type B abnormality commonly have the asymmetry of body, such as left-right imbalance of visual acuity, left-right neck pain, or remarkable scoliosis, in association with insomnia and/or depressive state. According to the study of Penfield, dizziness or vertigo is manifested by stimulation of upper temporal cortex and lower parietal cortex. Mechanisms of dizziness can be hypothecated on the basis of MEG findings as follows: Presumably, there are head-position recognizing (HPR) centers in the left and right cerebral hemispheres. The HPR centers may correspond to the vestibular cortex or the combined system of vestibular, visual and somatosensory cortices. The HPR centers in two hemispheres are receiving head-position signals from vestibular, visual and somatosensory corices and are readjusting the dissociation of information which may exist between each other through rapid interhemispheric neural conduction. In patients with Type A abnormality, dizziness may be caused by abnormal neuronal excitements in left or right HPR center. In patients with Type B abnormalities, dizziness may be caused by the combined factors, one the abnormal prolongation of INCT between left and right HPR centers and the other the large dissociation of head position signals between the left and right HPR centers due to the body asymmetry, such as scoliosis or left-right neck pain imbalance.

Curr Neuropharmacol. 2007 Jun; 5(2): 115-25
Detlev B

Despite recent advances in the development of antiepileptic drugs, refractory epilepsy remains a major clinical problem affecting up to 35% of patients with partial epilepsy. Currently, there are few therapies that affect the underlying disease process. Therefore, novel therapeutic concepts are urgently needed. The recent development of experimental cell and gene therapies may offer several advantages compared to conventional systemic pharmacotherapy: (i) Specificity to underlying pathogenetic mechanisms by rational design; (ii) specificity to epileptogenic networks by focal delivery; and (iii) avoidance of side effects. A number of naturally occurring brain substances, such as GABA, adenosine, and the neuropeptides galanin and neuropeptide Y, may function as endogenous Anticonvulsants and, in addition, may interact with the process of epileptogenesis. Unfortunately, the systemic application of these compounds is compromised by limited bioavailability, poor penetration of the blood-brain barrier, or the widespread systemic distribution of their respective receptors. Therefore, in recent years a new field of cell and gene-based neuropharmacology has emerged, aimed at either delivering endogenous anticonvulsant compounds by focal intracerebral transplantation of bioengineered cells (ex vivo gene therapy), or by inducing epileptogenic brain areas to produce these compounds in situ (in vivo gene therapy). In this review, recent efforts to develop GABA-, adenosine-, galanin-, and neuropeptide Y- based cell and gene therapies are discussed. The neurochemical rationales for using these compounds are discussed, the advantages of focal applications are highlighted and preclinical cell transplantation and gene therapy studies are critically evaluated. Although many promising data have been generated recently, potential problems, such as long-term therapeutic efficacy, long-term safety, and efficacy in clinically relevant animal models, need to be addressed before clinical applications can be contemplated.

N Engl J Med. 2008 Jul 10; 359(2): 166-76
French JA, Pedley TA

World J Biol Psychiatry. 2008 Jan 25; 1-10
Schule C, Baghai TC, Eser D, Nothdurfter C, Rupprecht R

Background. The purpose of the present open-label study was to investigate the antidepressant efficacy of lithium and carbamazepine as augmentation strategies in unipolar depressed inpatients. Method. Forty-six patients suffering from unipolar depression (major depressive episode according to DSM-IV criteria) were pre-treated with mirtazapine for 2 weeks initially (week -2 to week 0). Thereafter, the patients received either continuation of mirtazapine monotherapy (n=23), combination treatment with mirtazapine and lithium (n=13), or combination therapy with mirtazapine and carbamazepine (n=10) for further 3 weeks (week 0 to week 3). Severity of depression was estimated weekly using the 21-item version of the Hamilton Depression Rating Scale (21-HAMD). Response was defined by a reduction of at least 50% in the 21-HAMD sum score after 3 weeks of pharmacotherapy (week 0-3). Results. Additional administration of lithium, but not adjunctive carbamazepine significantly augmented the antidepressant efficacy of mirtazapine in the unipolar depressed patients. Moreover, carbamazepine but not lithium significantly lowered the serum concentrations of mirtazapine. Conclusion. Whereas the clinical importance of Anticonvulsants in the treatment of bipolar disorder is not in doubt, the therapeutic efficacy of antiepileptic drugs such as carbamazepine is obviously limited in the pharmacotherapy of unipolar depression.

J Enzyme Inhib Med Chem. 2008 Jun 12; 1
Karki SS, Bahaduria VS, Rana V, Kumar S, Subbaro PG, Das U, Balzarini J, De Clercq E, Dimmock JR

Various substituted 1-arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones 3a-h, 1-benzyl-2,3-dioxo-2,3-dihydroindole N(4)-aryl thiosemicarbazones 4a-i and 1-benzyl-2,3-dioxy-2,3-dihydroindole N(4)-cyclohexylthiocarbazone 5 were synthesized. All of these compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Nearly 40% of these compounds possess low micromolar IC(50) values and some are either more potent than, or equipotent with, melphalan. Various correlations between the structures of these compounds and cytotoxic potencies were obtained which included the use of QSAR and molecular modeling techniques. Representative compounds displayed anticonvulsant properties in rats and were well tolerated by these animals. The encouraging biodata noted affords adequate rationale for outlining guidelines for further development of these molecular scaffolds.

Eur J Med Chem. 2008 Jul 4;
Obniska J, Kaminski K, Skrzynska D, Pichor J

In the present study, on the development of new Anticonvulsants, the series of N-[(4-arylpiperazin-1-yl)-alkyl]-3-(2-methylphenyl)- (8a-e, 10a-h) and 3-(2-trifluoromethyl-phenyl)-pyrrolidine-2,5-diones (9a-e, 11a-i) were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens. Their neurotoxicity were determined applying the rotorod test. In this series, the most active were N-[(4-phenylpiperazin-1-yl)-methyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione (9a) with the ED(50)=20.78mg/kg, when given orally to rats and N-[3-{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione (11i) with the ED(50)=132.13mg/kg after intraperitoneally injection to mice.

Biol Psychiatry. 2008 Jul 2;
Ongür D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, Renshaw PF

BACKGROUND: At excitatory synapses, glutamate released from neurons is taken up by glial cells and converted to glutamine, which is cycled back to neurons. Alterations in this system are believed to play a role in the pathophysiology of bipolar disorder, but they have not been characterized in vivo. We examined the glutamine/glutamate ratio and levels of other metabolites in acute mania and schizophrenia in this exploratory study. METHODS: Data were obtained from 2 x 2 x 2 cm voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 Tesla and analyzed using LCModel. Fifteen bipolar disorder patients with acute mania and 17 schizophrenia patients with acute psychosis were recruited from an inpatient unit; 21 matched healthy control subjects were also studied. Glutamine/glutamate ratio and N-acetylaspartate, creatine, choline, and myo-inositol levels were evaluated in a repeated measures design. Medication effects and relationship to demographic and clinical variables were analyzed. RESULTS: Glutamine/glutamate ratio was significantly higher in ACC and POC in bipolar disorder, but not schizophrenia, compared with healthy control subjects. N-acetylaspartate was significantly lower in the ACC in schizophrenia. Patients on and off lithium, Anticonvulsants, or benzodiazepines had similar glutamine/glutamate ratios. CONCLUSIONS: The elevated glutamine/glutamate ratio is consistent with glutamatergic overactivity and/or defective neuronal-glial coupling in acute mania, although medication effects cannot be ruled out. Abnormalities in glutamatergic neurotransmission and glial cell function in bipolar disorder may represent targets for novel therapeutic interventions.

Science. 2008 Jul 4; 321(5885): 31-3
Couzin J

Pediatrics. 2008 Jul; 122(1): e223-31
Newport DJ, Pennell PB, Calamaras MR, Ritchie JC, Newman M, Knight B, Viguera AC, Liporace J, Stowe ZN

OBJECTIVE. Although lamotrigine use during pregnancy has substantially increased over the past decade secondary to accumulated reproductive safety data, systematic data on lamotrigine during breastfeeding remains sparse. We sought to characterize the determinants of lamotrigine concentrations in breast milk and nursing-infant plasma. PATIENTS AND METHODS. Women who enrolled in a prospective investigation of perinatal medication pharmacokinetics, were treated with lamotrigine, and chose to continue lamotrigine while breastfeeding were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient and serial samples over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Lamotrigine concentrations in all of the samples were determined by using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. RESULTS. Thirty women and their nursing infants participated in the study, providing a total of 210 breast milk samples. The mean milk/plasma ratio was 41.3%. There was a nonsignificant trend for higher lamotrigine concentrations in breast milk 4 hours after the maternal dose. Infant plasma concentrations were 18.3% of maternal plasma concentrations. The theoretical infant lamotrigine dose was 0.51 mg/kg per day, and the relative infant lamotrigine dose was 9.2%. Mild thrombocytosis was present in 7 of 8 infants at the time of serum sampling. No other adverse events were observed or reported in the breastfed infants. CONCLUSIONS. Consistent with previous investigations of medications in breast milk, the lamotrigine milk/plasma ratio is highly variable. The rate of lamotrigine excretion into human breast milk is similar to that observed with other antiepileptic drugs. These data expand the extant literature on lamotrigine in breastfeeding and demonstrate relatively comparable nursing-infant exposure to lamotrigine compared with other antiepileptic drugs.

Rev Invest Clin. 2008 Jan-Feb; 60(1): 15-20
Juárez-Olguín H, Belmont-Gómez A, Flores-Pérez J, Barranco-Garduño LM, Flores-Pérez C

AIM: The purpose of the present study is to determine the relationship between the anticonvulsant drug use during pregnancy and the presence of malformations in the newborns. METHODS: The frequency of malformations in the neonates of epileptic mothers under anticonvulsant treatment was analyzed in two periods, one from 1988 to 1992, which included 76 epileptic mothers, and another from 1996 to 2003 with 170 patients. RESULTS: In the first period, 51 (67.1%) of mothers received monotherapy and 25 (32.9%) received polytherapy of phenytoin with carbamazepine, valproic acid or phenobarbital. In this period, 4 newborns (16%) with congenital malformations were registered. In the second period, 159 (93.5%) of the epileptic mothers received monotherapy and 11 (6.5%) received polytherapy of valproic acid with carbamazepine or phenytoin. During this period only 3 newborns 27.3% with malformations were registered. DISCUSSION: Clinical treatment should consider the risk of using polytherapy, mainly if phenytoin or valproic acid are combined with other Anticonvulsants.

Enferm Infecc Microbiol Clin. 2008 Jun; 26(6): 348-55
Lana R, Lérida AI, Mendoza JL

Neuropathic pain of various etiologies is a frequent symptom in HIV-infected patients that is underdiagnosed and inadequately treated. It requires a multidisciplinary pain approach based on psychosocial factors, diet and exercise, etiologic treatment whenever possible, symptomatic medical treatment, and sometimes, interventional techniques. Medical treatment should be individualized and introduced gradually, with a mind to potential drug interactions. Neuropathic pain responds poorly to conventional analgesics, such as nonsteroidal antiinflammatory drugs and opiates; tricyclic antidepressants and Anticonvulsants are the drugs of choice. Before establishing an analgesic treatment, possible drug interactions should be ruled out, mainly those occurring with antiretroviral agents.

Indian J Dermatol Venereol Leprol. 2008 May-Jun; 74(3): 238-40
Sharma VK, Sethuraman G, Minz A

BACKGROUND AND AIMS: Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and SJS-TEN overlap are serious adverse cutaneous drug reactions. Drugs are often implicated in these reactions. METHODS: A retrospective analysis of inpatients' data with these dermatological diagnoses were carried out for three years, to study the causative drugs, clinical outcome, and mortality in these conditions. RESULTS: Thirty patients (15 TEN, nine SJS-TEN overlap, and six SJS) were admitted. In 21 cases, multiple drugs were implicated whereas single drugs were responsible in nine. Anticonvulsants (35.08%) were the most commonly implicated drugs followed by antibiotics (33.33%) and NSAIDS (24.56%). Twenty-five patients recovered whereas five died (four TEN, one SJS-TEN overlap). CONCLUSION: Anticonvulsants, antibiotics and NSAIDs were the most frequently implicated drugs. TEN causes higher mortality than both SJS and SJS-TEN overlap.

Anaesthesia. 2008 Jul; 63(7): 780; author reply 780-1
Rigby-Jones A, Sneyd JR

Anaesthesia. 2008 Jul; 63(7): 719-25
Thwaites CL, Yen LM, Cordon SM, Thwaites GE, Loan HT, Thuy TT, White NJ, Soni N, Macdonald IA, Farrar JJ

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Curr Treat Options Neurol. 2008 Jul; 10(4): 246-52
Krishnamurthy KB

In the United States, about 1 million women of childbearing age have epilepsy. Estimates vary as to the percentage of these women who consider pregnancy, but epilepsy is the most common neurologic condition encountered in pregnancy. Women with epilepsy express significant interest in receiving guidance about pregnancy and the effects of seizures and anticonvulsant treatments on the developing fetus, but clinicians often are hard-pressed to find accurate and relevant information to share. In our practice, we devote many hours of clinical time to the counseling required when such a request is made. We begin by providing information about the risks of pregnancy for any woman, comparing the data for women with and without epilepsy; this gives patients perspective on the increase in the risk of fetal malformations associated with anticonvulsant therapy. We then proceed with an evaluation of whether the patient could consider withdrawing one or more Anticonvulsants, particularly during the first trimester of gestation. For women who must continue taking Anticonvulsants to prevent seizures, we explain that the increase in metabolism during pregnancy will require an increase in oral dosing to maintain prepregnancy concentrations of Anticonvulsants. It is hoped that by maintaining prepregnancy blood levels during pregnancy, a woman with epilepsy can maintain the same level of seizure control during pregnancy that she had before conception. Additional time is spent discussing the need for adequate hydration, regular meals, and proper sleep during pregnancy and in the postpartum time to avoid behavioral alterations that can trigger seizures. As seizure medicines will need to be decreased after delivery, when a patient will be sleep-deprived and under the influence of hormonal changes that can increase the seizure tendency, our nurses meet with patients throughout pregnancy to develop plans for partner or family assistance with care of the neonate. Patients report appreciation for this type of personalized counseling but express frustration that we cannot provide absolute guidance with respect to the use of Anticonvulsants in pregnancy. Therefore we often have to return several times to the topic of the limitations of scientific research regarding decision-making in pregnancy. Much of the information we have about the safety of anticonvulsant use in pregnancy comes from the registry studies discussed in this article. These studies can be difficult to interpret and compare because of the diversity of the methods used.

Hiroshima J Med Sci. 2008 Mar; 57(1): 1-6
Kurokawa H, Matsunaga A, Tanaka H, Hamada H, Kawamoto M, Yuge O

Propofol has been shown to attenuate beta-adrenoreceptor-mediated signal transduction in cardiomyocytes. Cyclic adenosine monophosphate (cAMP) is an essential second messenger of beta-signal transduction, while olprinone, a phosphodiesterase-III inhibitor, improves poor cardiac performance by increasing cAMP levels. In the present study, we investigated the effects of olprinone toward the reducing effect of propofol on beta-adrenoreceptor-mediated increases in cAMP production. First, suspensions of rat ventricular myocytes were incubated with isoproterenol or olprinone and the effects on cAMP concentrations were assessed. Next, propofol was added prior to the addition of isoproterenol or olprinone. Finally, following preincubation with propofol, isoproterenol with or without olprinone was added. Both isoproterenol and olprinone increased cAMP production in a dose-dependent manner. However, clinically relevant concentrations of olprinone (up to 10(-7) M) did not cause a significant increase. Propofol (10(-7)-10(-4) M) attenuated isoproterenol-stimulated increases in cAMP production (decrease of 2 +/- 4% approximately 43 +/- 1%, as compared to the isoproterenol-stimulated state). However, the agent did not alter olprinone (10(-7) M)-stimulated cAMP production. Olprinone (10(-8)-10(-6) M) reversed the attenuating effect of propofol (10(-5) M) toward isoproterenol (10(-7) M)-stimulated cAMP production dose-dependently (increase of 10 +/- 5% approximately 79 +/- 4% as compared to the propofol-attenuated state). Our results suggest that an improvement in cardiac function is provided by olprinone when the beta-adrenoreceptor-mediated signaling pathway is inhibited by propofol.