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Biomedical subjects

J Walden

Publications and source records attributed to J Walden.

At least 37 records · Page 2Linked to original sources
PubMed2000

Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity.

Comparison of 19 aminoquinolines supports the hypothesis that chloroquine and related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)PPIX), inhibiting its conversion to beta-hematin (hemozoin) and hence its detoxification. The study suggests that a basic amino side chain is also essential for antiplasmodial activity. 2- And 4-aminoquinolines are unique in their strong affinity for Fe(III)PPIX, and attachment of side chains to the amino group has relatively little influence on the strength of complex formation. Association with Fe(III)PPIX is necessary, but not sufficient, for inhibiting beta-hematin formation. Presence of a 7-chloro group in the 4-aminoquinoline ring is a requirement for beta-hematin inhibitory activity, and this is also unaffected by side chains attached to the amino group. In turn, beta-hematin inhibitory activity is necessary, but not sufficient, for antiplasmodial activity as the presence of an aminoalkyl group attached to the 4-amino-7-chloroquinoline template is essential for strong activity. We thus propose that the 4-aminoquinoline nucleus of chloroquine and related antimalarials is responsible for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of beta-hematin formation, and the basic amino side chain is required for drug accumulation in the food vacuole of the parasite.

Aminoquinolines↗
PubMed2000

An open longitudinal study of patients with bipolar rapid cycling treated with lithium or lamotrigine for mood stabilization.

OBJECTIVES: Patients with rapid cycling bipolar disorder are frequently observed to fail conventional treatment. We conducted a preliminary study to explore the potential efficacy of lamotrigine in the treatment of this refractory patient population. METHODS: In an open longitudinal investigation, 14 patients with rapid cycling bipolar disorder were treated for 1 year with either lithium or lamotrigine as mood stabilizer. RESULTS: Out of the seven patients with lithium, three out of seven (43%) had less than four and four out of seven (57%) had four or more episodes. In the lamotrigine group, six out of seven (86%) had less than four and one out of seven (14%) had more than four affective episodes (depressive, manic, hypomanic or mixed). In fact, three out of seven (43%) of the patients who were on lamotrigine therapy were without any further affective episodes. There was no evidence of a preferential antidepressant versus antimanic efficacy. CONCLUSIONS: Although the study is limited by the small number of patients, the results are in line with other investigations, suggesting efficacy for lamotrigine and a suboptimal response for lithium in rapid cycling bipolar disorder. These preliminary data need to be confirmed with controlled double blind studies.

Adult↗
PubMed2000

[Effectiveness, safety and practicality of delayed-release minitablets of valproate in bipolar affective disorders].

UNLABELLED: Valproate has recently emerged as a drug of first choice in treating acute mania because of its efficacy and relative safety. It can be administered as an intravenous, oral non-sustained release or oral sustained release loading therapy. A new sustained release formulation of valproate consists of "mini-tablets" with the possible advantage of a less problematic and more reliable administration of the drug. We report on eleven patients with an acute manic exacerbation who were investigated for sufficient control of manic symptoms and the duration of building up and maintaining sufficient blood levels of valproate in once/d versus twice/d administration of valproate delayed release mini-tablets (VPA mrt.). Acute and prophylactic effectiveness in mania were rated with the Young-Mania Rating Scale (YMRS), respectively the Global Clinical Impression Scale for Bipolar Disorder (CGI-BP). RESULTS: Within a short period of time sufficient blood levels in both groups (once/d versus twice/d administration) were built up. Seven of eleven patients were responders according to a reduction of 50% of the YMRS. In respect of prophylactic treatment all of the ten patients showed satisfactory results and no re-exacerbation of manic symptoms or depression.

Adult↗
PubMed2000

Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group.

To compare the efficacy of sodium valproate administered as adjunct to neuroleptic medication for patients with acute mania with the efficacy of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind, parallel-group, placebo-controlled trial. The study design closely reflected a clinical psychiatric setting in Europe where patients with acute mania commonly receive neuroleptic medication. In this trial, 136 hospitalized patients met the ICD-10 criteria for acute manic episodes; these patients received a fixed dose of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably haloperidol and/or perazine. The primary outcome measure was the mean dose of neuroleptic medication (after conversion into haloperidol-equivalents) for the 21-day study period. Severity of symptoms was measured using the Young Mania Rating Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression Scale. Intent-to-treat analysis was based on 69 patients treated with valproate and 67 patients who received placebo. Groups were comparable with regard to demographic and clinical baseline data. Premature discontinuations occurred in only 13% of the patients. The mean neuroleptic dose declined continuously in the valproate group, whereas only slight variations were observed in the placebo group; the difference was statistically significant (p = 0.0007) for study weeks 2 and 3. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or neuroleptics; the only adverse event was asthenia, which occurred more frequently with the combination therapy. Valproate represents a useful adjunct medication for the treatment of acute manic symptoms. Valproate is beneficial because it allows the administration of fewer neuroleptic medications and produces improved and quicker remission of manic symptoms.

Acute Disease↗
PubMed2000

Bupropion-induced isolated impairment of sensory trigeminal nerve function.

Bupropion is increasingly used for nicotine withdrawal and in the treatment of major depression, especially in bipolar patients. We present the case of a 38-year-old female schizoaffective, rapid-cycling patient treated with bupropion for a depressive episode. After 4 weeks of successful treatment (300 mg/day), the patient developed a circumscribed unilateral impairment of sensory trigeminal nerve function. Symptoms completely recovered after discontinuation of bupropion. When re-exposed to bupropion, mild symptoms reappeared, leading to final discontinuation of bupropion. With this natural on-off-on-off design, a causative role of bupropion for trigeminal impairment in this patient can be assumed. To our knowledge, a similar side-effect of bupropion has not been described to date.

Adult↗
PubMed2000

Effects of lamotrigine on field potentials and long-term potentiation in guinea pig hippocampal slices.

PURPOSE: To investigate the effects of lamotrigine (LTG), a new anticonvulsant, on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) in guinea pig hippocampal slices. METHODS: Electrically evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) were investigated in the CA1 region of the hippocampus. RESULTS: The concentration-response curves showed different actions of LTG in concentrations near therapeutic plasma levels (10 microM) on fEPSPs and PSs. The initial slopes of fEPSPs were not affected, whereas the amplitudes of PSs were significantly decreased. Higher concentrations of LTG decreased both fEPSP slopes and PS amplitudes; however, the effects on PSs were much stronger. Also, there were no differences in fEPSP slopes or PS amplitudes compared with controls when LTP was induced in the presence of LTG (10 microM). CONCLUSIONS: Our data are in contrast to previous findings that suggest LTG acts primarily on presynaptic sites by blocking the release of excitatory amino acids. Further, LTP was not affected by LTG.

Animals↗
PubMed2000

New insights into the mechanisms and sites of action of lamotrigine.

This study was aimed at investigating the effects of lamotrigine (LTG) on electrically evoked field excitatory postsynaptic potentials (fEPSP) and population spikes in the CA1 hippocampal region of guinea pigs. The concentration response curves showed different actions of LTG on fEPSP and on population spikes. The data are in contrast to previous findings that suggest the drug acts primarily on presynaptic sites via a blockade of the release of excitatory amino acids. In the range of therapeutic plasma levels, synaptic transmission was not affected.

Animals↗
PubMed2000

Modulation of neural cell membrane conductance by the herbal anxiolytic and antiepileptic drug aswal.

To evaluate the effects of aswal on ionic fluxes and neuronal excitation, we performed extracellular and whole cell patch clamp recordings on CA1 pyramidal neurons of guinea pigs and Long-Evans rats. Aswal (100- 250 mg/l) was administered systemically, and its effects on the rate of synchronized extracellular field potentials (EFP), membrane parameters, action potentials and postsynaptic potentials were recorded. The extracellular results obtained are consistent with calcium antagonistic properties. Intracellular recordings suggest that a direct sodium antagonistic effect as seen in many antiepileptic drugs plays no significant role. Further effects on ligand gated ion channels are discussed controversially. In summary, the cellular action of aswal appears heterogeneous with calcium antagonism playing a prominent role in counteracting excitation which may be a common feature in epilepsy and different psychiatric conditions as mood and anxiety disorder.

Animals↗
PubMed2000

New perspectives in the acute treatment of bipolar depression.

In contrast to mania, bipolar depression is usually characterised by longer-lasting episodes and a higher incidence of treatment refractoriness. Additionally, the risks of antidepressive standard treatment regimens are increasingly recognised, especially the risk of a switch into mania or induction of a rapid cycling course. Mood stabilisers, e.g. lithium, and some anticonvulsants, appear to have at least some antidepressant efficacy, which, however, may not be sufficient for treating severe depression. Currently, their use as a monotherapy of mild depression and at the start as a co-medication to antidepressants in severe depression is under consideration. The potential usefulness and risks of currently applied antidepressive treatment strategies as well as potential future developments will be reviewed in this article. At this stage, at least in severe depression, the use of true antidepressants still appears to be mandatory, especially because of the risk of suicide. However, initial combination with a mood stabiliser can be recommended. The treatment of depressive episodes only responsive to ECT should include combination with a mood stabiliser, in this case lithium, right from the start. In patients with lithium refractoriness, mood stabilising anticonvulsants should be initiated directly after the end of the ECT cycle. In order to reach sufficient plasma levels and thus reduce the risk of a switch, a loading therapy is recommended.

Algorithms↗
PubMed1999

The 6-min walk and peak oxygen consumption in advanced heart failure: aerobic capacity and survival.

BACKGROUND: This study sought to determine to what extent the 6-min walk (6MW) distance in advanced heart failure predicts aerobic capacity and provides comparable information regarding survival. Peak oxygen uptake ( VO(2)) and the 6MW both describe function and predict outcome over a wide range of heart failure, but their determinants and implications may differ within a narrower clinical spectrum. This study compared 6MW with aerobic capacity both at peak exercise and during low-level cycling. METHODS AND RESULTS: Both the 6MW and symptom-limited cycle ergometry were performed by 307 patients of whom 264 patients additionally performed 6 min of 20-W cycling to estimate aerobic capacity during sustained low-level activity. In the first 198 patients, multivariate analysis of survival was performed with the 6MW and peak VO (2). Patients achieved the 6MW of 393 +/- 104 m and peak VO (2) of 14 +/- 5 mL/kg per minute. Although low peak VO (2) was more likely with the shorter 6MW, the relation was weak within peak VO (2) range of 10 to 20 mL/kg per minute (n = 213, 69% of patients, r = 0.28). During 20-W exercise, VO (2) was 9.2 +/- 2.0 mL/kg per minute, with respiratory exchange ratio poorly correlated with the 6MW. In contrast to peak VO (2), the 6MW in meters did not predict survival. Division into short, medium, and long walks, however, supplemented simple clinical description. CONCLUSIONS: Although helpful in broader populations for identification of patients with obvious clinical compromise, the 6MW distance is not a surrogate for peak VO (2) in assessing aerobic capacity or prognosis for individuals with advanced heart failure.

Exercise Test↗
PubMed1999

Effects of (+/-)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats.

Kava pyrones extracted from pepper Piper methysticum are pharmacologically active compounds. Since kava pyrones exhibit anticonvulsive, analgesic and centrally muscle relaxing properties, the influence of a synthetic kava pyrone, (+/-)-kavain, on voltage-dependent ion channel currents was studied. Effects of (+/-)-kavain on voltage-activated inward currents were analysed in cultured dorsal root ganglion cells derived from neonatal rats. Voltage-activated Ca2+ and Na+ currents were elicited in the whole-cell configuration of the patch clamp technique. Extracellularly applied (+/-)-kavain dissolved in hydrous salt solutions reduced voltage-activated Ca2+ and Na+ channel currents within 3-5 min. As the solubility of (+/-)-kavain in hydrous solutions is low, dimethyl sulfoxide (DMSO) was added to the saline as a solvent for the drug in most experiments. When (+/-)-kavain was dissolved in DMSO, the drug induced a fast and pronounced reduction of both Ca2+ and Na+ currents, which partly recovered within 2-5 min even in the presence of the drug. The present study indicates that (+/-)-kavain reduces currents through voltage-activated Na+ and Ca2+ channels.

Animals↗
PubMed1999

[Predictors of response to phase prophylactics (mood stabilizers) in bipolar affective disorders].

Since the introduction of lithium ions in the acute treatment and in the prophylaxis of bipolar disorders the antiepileptic drugs valproate and carbamazepine have been in use for several years as mood stabilizers. In a number of open and controlled clinical studies predictors of response for the single drugs were investigated. These studies indicated that valproate was a predictor of good response in mixed (dysphoric) mania and bipolar rapid cycling. Moreover, valproate has a better response than lithium in secondary mania (organic origin) and atypical mania (episode sequence: depression-mania-euthymia rather than mania-depression-euthymia). The preferential efficacy in the spectrum of bipolar disorders of the new antiepileptic drugs lamotrigine and gabapentin must be analysed in more detail in future studies.

Affect↗
PubMed1999

[Gabapentin in the treatment of mania].

We present the case of a 60-year old bipolar-I-patient showing a rapid antimanic response to gabapentin after having been non-responsive to lithium and perazine. This case encouraged us to further evaluate the antimanic potency of gabapentin in an open label trial. 20 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Ten patients were treated with gabapentin as add-on medication and ten patients were treated with a high dose of gabapentin alone. The BRMAS score declined significantly in patients with moderate mania, whereas gabapentin alone was not efficacious in patients with very severe mania. Keeping in mind the limitations of an open study, it can still be said that gabapentin as add-on medication with other effective mood stabilizers appears to be safe and efficacious in the treatment of moderate mania.

Acetates↗
PubMed1999

Intravenous valproate loading in acutely manic and depressed bipolar I patients.

Recently, valproate has emerged as a drug of primary choice for the treatment of acute mania, especially mixed mania and, partially, rapid cycling. Because of its relative safety, it can be administered in high doses as an oral loading therapy, with approximately 60% to 70% of patients showing a favorable response. Here we report on seven bipolar I patients, two of which have euphoric mania, three have a mixed manic state (including one patient with ultra-rapid cycling and one with very prominent depressed features), and two have solely depressed mood. All but one of the manic patients showed a rapid and favorable response to intravenous valproate loading, which built up sufficient blood levels that were maintained by subsequent oral treatment. Of the two patients with solely depressed mood, however, one experienced only minor benefits and the other showed no change in the depressive symptomatology. Intravenous valproate was tolerated without problems and also led to a drastic reduction in and eventual withdrawal of benzodiazepine treatment in two cases. All of the patients showed a drastic remission of mania with valproate blood levels at or only slightly above 50 microg/mL (blood drawn 12 hours after last application). It is interesting to note that one patient who was previously nonresponsive to oral valproate loading responded well to intravenous valproate. Besides the obvious efficacy and safety of this treatment regimen, these findings may also imply that a difference in pharmacokinetics with intravenous loading may result in a quick saturation of plasma-binding proteins, and hence, peak concentrations of valproate may be reached rapidly, which could contribute to the beneficial action, even in patients previously nonresponsive to oral valproate.

Acute Disease↗
PubMed1999

Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients.

The objective of this study was to compare the effects of carbamazepine (CBZ) and valproate (VPA) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders. In this controlled clinical trial, 27 patients with an ICD-10 diagnosis of schizophrenia (N = 24) or schizoaffective disorder (N = 3) were randomly assigned to receive 4 weeks of treatment with either haloperidol alone, haloperidol with CBZ, or haloperidol with VPA. Whereas the haloperidol dose remained stable, the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels. Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale. The use of CBZ was associated with significantly lower haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy. VPA had no significant effect on either plasma levels or on psychopathology. Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure. This might be a result of a pharmacokinetic interaction on the hepatic level. The concomitant use of VPA with neuroleptic therapy is not impaired by clinically significant drug interactions, but it is not associated with a better outcome under our conditions.

Adult↗
PubMed1999

Ventricular response in atrial fibrillation: random or deterministic?

The ventricular response in atrial fibrillation is often described as "chaotic," but this has not been demonstrated in the strict mathematical sense. A defining feature of chaotic systems is sensitive dependence on initial conditions: similar sequences evolve similarly in the short term but then diverge exponentially. We developed a nonlinear predictive forecasting algorithm to search for predictability and sensitive dependence on initial conditions in the ventricular response during atrial fibrillation. The algorithm was tested for simulated R-R intervals from a linear oscillator with and without superimposed white noise, a chaotic signal (the logistic map) with and without superimposed white noise, and a pseudorandom signal and was then applied to R-R intervals from 16 chronic atrial fibrillation patients. Short-term predictability was demonstrated for the linear oscillators, without loss of predictive ability farther into the future. The chaotic system demonstrated high short-term predictability that declined rapidly further into the future. The pseudorandom signal was unpredictable. The ventricular response in atrial fibrillation was weakly predictable (statistically significant predictability in 8 of 16 patients), without sensitive dependence on initial conditions. Although the R-R interval sequence is not completely unpredictable, a low-dimensional chaotic attractor does not govern the irregular ventricular response during atrial fibrillation.

Aged↗