New antipsychotics: preclinical and clinical research.
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Animals↗
Biomedical subjects
J Gerlach
Publications and source records attributed to J Gerlach.
Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects.
Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n = 100) and perphenazine, flupenthixol or zuclopentixol (controls, n = 100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3-19 years for clozapine, 0.3-24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P < 0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P < 0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P = 0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.
Adult↗
Digital movement analysis, a new objective method of measuring tardive dyskinesia and drug-induced parkinsonian tremor: acceptability, reliability and validity.
Digital movement analysis (DMA) is a new instrumental approach to assessing oral tardive dyskinesia (TD) by means of digital image processing of a video signal, tracking five paper dots placed around the patient's mouth. A total of 40 schizophrenic patients, 30 with and 10 without TD, were examined twice (with a 3-month interval) with this new device. The patients were further examined with two TD rating scales: the St. Hans Rating Scale for extrapyramidal syndromes (SHRS) and the Abnormal Involuntary Movement Scale (AIMS). The schizophrenic patients accepted the instrumental assessment without any anxiety or resistance. The internal reliability of the apparatus was high, with correlation coefficients of 0.80-0.99. The DMA TD values correlated with the SHRS and AIMS scores with correlation coefficients of 0.48-0.73 indicating an acceptable, although not strong, concurrent validity. Fluctuations occurred from the first to the second examination independent of medication. For these fluctuations no correlation was found between DMA values and rating scores. Finally, the DMA device was able to detect perioral tremor as a sign of parkinsonism. It has been concluded that DMA is a useful supplement to classical TD rating, although further validity evaluation is warranted.
Adult↗
Extrapyramidal symptoms during long-term treatment with antipsychotics: special focus on clozapine and D1 and D2 dopamine antagonists.
In schizophrenic patients in maintenance treatment, clozapine, compared to classic neuroleptics, induces relatively few extrapyramidal syndromes (EPS), especially less akathisia and tremor and usually no dystonia or rigidity. In patients with dyskinetic movements (acute or tardive) induced by other neuroleptics, clozapine may reduce or even remove dyskinesia or permit it to disappear. It cannot, however, be excluded that clozapine can induce dyskinesia in extremely rare cases, but it seems more likely that this is due to previous treatment with classic neuroleptics. The earlier clozapine is started, the less chance of development of dyskinesia. The low level of EPS with clozapine may be linked to the special receptor-binding profile of this drug: during treatment with therapeutic doses of clozapine, the level of D2 receptor blockade is too low (40% to 50% occupancy by positron emission tomography) to induce EPS, and the D1 receptor blockade (also 40% to 50% occupancy) has a lower EPS potential than D2 blockade. This binding profile may at the same time contribute to the special antipsychotic properties of clozapine. Other receptor affinities may contribute to the beneficial effect of clozapine in EPS and schizophrenia.
Antipsychotic Agents↗
Subjective experience of treatment, side-effects, mental state and quality of life in chronic schizophrenic out-patients treated with depot neuroleptics.
Attitude towards treatment, side-effects, mental state and quality of life was assessed in 53 chronic schizophrenic out-patients on maintenance treatment with depot neuroleptics. It was found that 60% of the patients viewed depot medication positively, while only 8% viewed it negatively. Only 70% of patients complained about side-effects, even though 94% had scored as having them. Hypokinesia and hyperkinesis were the side-effects least noticed by the patients, but most noticed by the treating physician, while the opposite was the case with psychic side-effects. Only 49% of patients thought they had a psychotic illness, and there was no correlation between the patients' own evaluation of the severity of their illness and their score on the Positive and Negative Symptom Scale (PANSS) or the treating physician's evaluation. Quality of life did not correlate with either side-effect score or PANSS score. The schizophrenic patients' assessment of their condition was therefore in general different both from that of the treating physician and from that determined using rating scales.
Adult↗
Fulminant liver failure: relevance of extracorporeal hybrid liver support systems.
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Cell Transplantation↗
D1 receptor antagonists in schizophrenia.
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Animals↗
NNC 01-0687, a selective dopamine D1 receptor antagonist, in the treatment of schizophrenia.
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Adult↗
Depot neuroleptics in relapse prevention: advantages and disadvantages.
Non-compliance is a major problem in the treatment of schizophrenic patients, a problem which is due to the patient's mental condition, to disturbing side effects of the medication, to a defective doctor-patient relationship, and to a general scepticism towards chemical treatment of mental symptoms. The major advantage of depot administration of neuroleptic drugs is the assurance of compliance leading to fewer relapses and rehospitalizations. Depot neuroleptics also eliminate bioavailability problems related to absorption and first pass metabolism and give a stable plasma concentration. Finally, depot neuroleptics provide a better and safer way to use the lowest effective dose principle thereby reducing the frequency of side effects, including the subjectively distressing mental side effects such as akathisia, dysphoria and neuroleptic-induced deficit syndrome. Disadvantages include delayed disappearance of potentially irreversible and unpleasant side effects after discontinuation and, for many patients, a feeling of being controlled. Administered in the proper way, with suitable information to the patient and relatives, depot neuroleptics improve the quality of antipsychotic treatment, reduce relapse frequency, stabilize the therapeutic effect and diminish the level of side effects.
Adult↗
New antipsychotics: the present status.
Until antipsychotics can be subdivided according to differentiated effects on psychic functions (for example on positive/negative symptoms and cognitive functions), the best classification seems to be one based upon receptor-binding profiles and the side effects that follow. Such a combined pharmacological-clinical approach appears fruitful to clinicians as well as pharmacologists. According to this classification the new antipsychotics can be subdivided into three main categories: the relatively pure dopamine antagonists (D2 antagonists, including sulpiride and amisulpiride); the dopamine (D2)-serotonin (5-HT2)-norepinephrine (alpha 1) antagonists (risperidone, ziprazidone and sertindole); and the multireceptor antagonists (clozapine, olanzapine and seroquel). Clozapine is still the most potent antipsychotic and the least potent at inducing extrapyramidal symptoms. New drugs such as olanzapine, seroquel and sertindole represent the further development of clozapine's positive qualities, while risperidone and ziprasidone are dominated to a greater extent by relatively traditional dopamine D2 receptor blockade.
Antipsychotic Agents↗
[The electrolyte composition of liver preservation solutions for hepatocytes in a model of in vitro preservation and reoxygenation].
The cation and anion content in liver preservation solutions have been investigated in order to justify the use of "intracellular" or "extracellular" electrolyte compositions. Various concentrations of sodium and potassium with chloride or lactobionate as anions and with added calcium and/or magnesium were made up as preservation solutions and incubated with in vitro adherent cultures of pig hepatocytes. In vitro hypoxia and hypothermia (4 degrees C, PO2 < 0.1 mmHg) for 24 h, with reoxygenation for 3 h, in standard culture medium was used as a model for preservation. Measurements of cell viability and detachment rate by light microscopy and of LDH and GOT liberation were used as parameters of cell damage. Cell swelling was estimated in suspension cultures of isolated hepatocytes. When chloride was used as the anion, significant cell toxicity from potassium concentrations over 75 mM was found within 6 h of preservation. Enzyme liberation decreased with increasing content of sodium cations in the preservation solution. Calcium ions had a protective effect at a concentration of 0.8 mM. Addition of magnesium to an "intracellular" ion composition minimized the toxic effect of potassium cations. Using lactobionate as an impermeant anion, there was no difference between the sodium and the potassium salt and the choice of cation had no effect on enzyme leakage or cell volume. An "extracellular" solution with high sodium chloride content and 0.8 mM calcium resulted in better preservation than was obtained with lactobionate solutions. With chloride as the anion, a significant increase in cell swelling was found when potassium replaced sodium in the solutions. Cell swelling decreased with increasing concentration of sodium cations.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
[The effect of buffers in liver preservation solutions on hepatocytes in a model of in vitro preservation and reoxygenation].
In order to answer the question of whether there is an optimal buffer system for the preservation and reoxygenation period in liver transplantation, sodium/potassium phosphate, HEPES, TRIS (THAM), MOPS and histidine/His-HCl buffers were investigated. The buffers were added to an "extracellular" electrolyte composition of preservation solution. The solutions were incubated with in vitro cultures of pig hepatocytes in two different models. I: during cold hypoxia (4 degrees C, PO2 < 0.1 mmHg) for 24 h, and II. during the reoxygenation period of 3 h after preservation in UW solution. Cell viability, cell detachment rate, and LDH and GOT liberation were used as parameters of cell alteration. The lowest amount of enzyme release during the preservation period and reoxygenation was obtained using sodium or potassium phosphate buffer. Rising LDH and GOT liberation rates during preservation and reoxygenation were observed with HEPES and TRIS buffer. The enzyme release induced by these three buffer systems correlated with their pKa values. Higher pH of the preservation solution resulted in higher enzyme leakage from the cells. In contrast, the Histidine/HCl buffer system with low pH led to striking cell damage during preservation as well as during reoxygenation. MOPS, a weak acid with the lowest pH in solution, led to the lowest enzyme release during the preservation period, but to high enzyme release after reoxygenation with standard medium. Incubation of the cultures with MOPS after UW preservation resulted in lower enzyme levels in comparison to the controls. In summary, PBS had the best results in our study.
Acid-Base Equilibrium↗
[Addition of an osmotic agent to liver preservative solutions in a model of in vitro preservation of hepatocytes].
To avoid hypoxic cell swelling during liver preservation followed by reduced perfusion in the reoxygenation period, osmotic substances such as mannitol, sucrose and raffinose, and the impermeant anion lactobionate are used in established liver preservation solutions. The various osmotic agents were investigated at concentrations of 60, 140, 260 and 300 mM, the solutions being kept isotonic by substitution with sodium and potassium chloride to 300 mosmol/l. Cultures of adherent pig hepatocytes were incubated in an in vitro model of cold hypoxia (4 degrees C, PO2 < 0.1 mmHg) for 24 h and reoxygenated with standard culture medium for 3 h. After each incubation period, light microscopy was performed to estimate cell viability and detachment rate. LDH and GOT liberation were also measured. To estimate the change in cell volume, isolated hepatocytes were incubated in suspension for 24 h of cold hypoxia. The cell volumes were compared after centrifugation and measurement of the pellet and the solute levels. Rising concentrations of osmotic substances resulted in increasing liberation of LDH and GOT. The levels of LDH and GOT release from cultures incubated with 60 mmol/l sucrose or raffinose were comparable to those in a preservation solution of "extracellular" ion composition. Addition of mannitol to the preservation solution resulted in cell damage. At high concentrations, sucrose did not affect the hepatocytes as much as raffinose. While mannitol can permeate the hepatocytes and lead to cell swelling, a cell-shrinking effect was observed when sucrose was used, and even more pronounced cell shrinking was seen with raffinose, to which the hepatocyte membrane is known to be permeable.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Long-term treatment with low doses of the D1 antagonist NNC 756 and the D2 antagonist raclopride in monkeys previously exposed to dopamine antagonists.
Eight Cebus apella monkeys previously exposed to D1 and D2 antagonists were treated subcutaneously for 8 weeks with the D1 antagonist NNC 756 (0.01 mg/kg), followed by a wash-out period of 4 weeks and treatment with the D2 antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia-inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D1 agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D2/D3 agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D1 antagonists may induce less dystonia and oral dyskinesia as compared with D2 antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D1 and D2 receptor systems.
Animals↗
Zuclopenthixol decanoate in maintenance treatment of schizophrenic outpatients. Minimum effective dose and corresponding serum levels.
23 schizophrenic outpatients in maintenance treatment with zuclopenthixol decanoate were included in a study aimed at finding the minimum effective dose and corresponding serum concentration of zuclopenthixol. Every three months the dose was gradually reduced until prodromal symptoms appeared, indicative of an incipient relapse. A slightly higher dose was then promptly reinstituted (the minimum effective dose). At each dose level, two blood samples were drawn to determine the serum concentration. This dose reduction principles proved feasible. Only one patient had a clear-cut relapse. The condition of the remaining patients was acceptably maintained by a dose increase. The minimum effective dose of zuclopenthixol was 200 mg/2 weeks (range 60-400), with a serum concentration of 22 nmol/l (7.1-69.7). There was a significant correlation between the administered dose and the corresponding serum level of the drug (r = 0.66, P < 0.01). A trend towards a positive correlation was found between the serum level at the minimum effective dose and the BPRS score (r = 0.42, P < 0.1). No correlation was found between the serum level and the side-effects or length of neuroleptic treatment. It is concluded that routine serum drug monitoring is hardly indicated in the long-term depot-neuroleptic treatment of schizophrenic patients. A strategy aiming at continually seeking the lowest effective dose on the basis of clinical parameters appears more appropriate, especially in case of depot-neuroleptic treatment.
Adult↗
Hepatocyte isolation from pig livers after warm ischaemic injury.
Hepatocyte cultures have been used extensively for a wide variety of physiological, pharmacological and experimental studies. The warm ischaemic period before isolation is kept to a minimum to achieve a high yield of cells isolated and a good viability for culture. We have recently introduced a new concept of liver resuscitation after warm ischaemia that is based on a 3-h reperfusion period with an improved perfusate and simultaneous dialysis. In this study, we applied the new technique for hepatocyte isolation from livers subjected to 80 min of complete ischaemia at 37 degrees C. Cell yield was improved by a resuscitating perfusion from 58% to 73% and viability from 39% to 76%.
Alanine Transaminase↗
Hepatocyte culture between woven capillary networks: a microscopy study.
A multi-compartment capillary membrane culture model with independently perfused three-dimensionally woven capillaries was developed for immobilization of hepatocytes in bioreactors. This enables spatial restructuring of cells and enhanced mass transfer performance with more efficient oxygenation and metabolite exchange. Seeding density defines cell behaviour in this model. With low densities cells attach to the membranes and flatten. Increasing density leads to spontaneous formation of aggregates which are immobilized between the capillaries.
Animals↗