Challenges in psychopharmacology: a drug information centre perspective.

WHAT IS KNOWN AND OBJECTIVE: Questions about psychotropic drugs are frequently submitted to drug information centres (DICs). Twenty years' experience from Norwegian DICs was used to identify particular challenges in responding to those questions. COMMENT: Questions about psychopharmacological therapy are usually patient-related and are often difficult to answer. Frequent questions about psychotropic drugs come from experienced senior physicians in disciplines like psychiatry, geriatrics, general practice and neurology. The physicians often ask about specific drug use in pregnancy or breastfeeding, drug combinations and interactions, drug switching and formulations, and drug-withdrawal reactions. WHAT IS NEW AND CONCLUSION: There is a lack of relevant information in drug monographs and guidelines to inform answers to the questions posed for the care of individual patients. There is a clear need for these topics to be highlighted in the pre- and postgraduate teaching of physicians. The issues highlighted are likely to be of international relevance based on our experience of the use of international sources of drug information.

Tamoxifen administration and metabolism in nude mice and nude rats.

We investigated the kinetics of tamoxifen (tam) in immunodeficient mice and rats after oral treatment and compared drug and metabolite profile in nude rat serum and tissues after oral and subcutaneous (s.c.) routes of administration. The serum levels were compared to those observed in man. After oral dosing in mice, tam and the potent metabolite 4-hydroxytamoxifen (4-hydroxytam), were detectable in liver and lung tissue, but not in serum. The levels of 4-hydroxytam in these tissues were significantly higher than those of tam, a profile opposite to that observed in rat and man. In rats and man, the 4-hydroxytam/tam serum concentration ratios were 0.16 and 0.02, respectively. Compared to oral route, the s.c. pellets yielded only trace amounts of the demethylated derivatives of tam in rats. Thus, the kinetics of tam observed in the present study suggest that the nude rat may represent a preferable animal model in studying the pharmacokinetics of tam and that, the oral route yielded higher serum and tissue levels of tam and metabolites than equivalent s.c. pellet implants.

Polypharmacy among patients admitted to hospital with rheumatic diseases.

AIM: This study describes polypharmacy among patients admitted to hospital with rheumatic diseases. METHODS: The study was performed in departments of rheumatology at nine Norwegian hospitals during five weeks in 1998. Pharmacists recorded all drugs on admittance among patients 18 years or older with rheumatic diseases. RESULTS: Sixty percent of 313 patients had polypharmacy defined as the concurrent use of five or more drugs, and this was most frequent among the older patients. However, they used fewer antirheumatic drugs compared to the younger patients. With regard to the three most common drug groups, older patients used more corticosteroids, and less nonsteroidal antiinflammatory drugs (NSAIDs) and disease modifying antirheumatic drugs (DMARDs), compared to the younger. Eighty-four percent of patients on methotrexate used folic acid, but only 52% of the patients who used corticosteroids used calcium supplements. CONCLUSION: Polypharmacy among patients with rheumatic diseases is common, and the present description could be useful for drug-related interventions.

Assessing the effects of an intervention by a pharmacist on prescribing and administration of hypnotics in nursing homes.

INTRODUCTION: We have previously reported sub optimal use of hypnotics in geriatric institutions. In the present study we examined the intervention by a pharmacist on the prescribing and administration of hypnotics in nursing homes. Thus a follow up study was performed in 5 nursing homes included in the previous study. METHOD: In the period between the two surveys the pharmacist provided drug information on the rational use of hypnotics, both written and verbal, to the staff of the institutions. Data on the administration of hypnotics was obtained from the Cardex system in the institutions. Data were compared to a control group in other nursing homes, where no intervention was carried out. RESULTS: Although the population was older in 2000 than in 1995, the proportion of patients using hypnotics (24%) was similar. Use of benzodiazepines was reduced from 81% to 40%, use of long acting benzodiazepines was reduced from 62% to 22%, and use of short-acting hypnotics (zopiclone, zolpidem) increased from 9% to 53%. Furthermore, hypnotics administered before 9 p.m. were reduced from 40% to 14%, and the time of administration showed less variation than before. In the control population we also observed the use of short acting hypnotics in favour of benzodiazepines, similar to the results in the 5 institutions. However, in this population a significantly higher proportion of patients used hypnotics, used more than 1 hypnotic and the hypnotics were administered earlier in the evening. CONCLUSION: The results demonstrate an important effect of written and verbal drug information provided by a pharmacist to improve the prescribing and administration on the use of hypnotics in nursing homes.

Sustained activation of hippocampal Lp-type voltage-gated calcium channels by tetanic stimulation.

The molecular heterogeneity of voltage-gated calcium channels is mirrored by extensive biophysical diversity. Subtype-selective antagonists have been used to place different kinds of calcium channels in functional categories. Dihydropyridine (DHP) antagonists have been used, for example, to implicate L-type calcium channels in the induction of NMDA receptor-independent forms of synaptic plasticity. DHPs, however, do not discriminate between the recently identified Lp and Ls subtypes of L-type calcium channel. The different properties of the two kinds of L-type channels suggest that they may have different functional roles. Ls channels are comparable with cardiac L-type channels, whereas Lp channels show low-threshold voltage-dependent potentiation. To clarify the potential roles of Lp and Ls channels in the induction of synaptic plasticity, we studied the responses of these channels to trains of action potentials. The frequency and duration of the trains were chosen to mimic the stimuli used to induce changes in synaptic strength. Cell-attached single-channel recordings from cultured hippocampal neurons revealed that both Lp and Ls channels responded to these trains, but only Lp channels showed persistent activation that outlasted the train. The magnitude of Lp channel activity increased with increasing action potential frequency and train duration. Stimuli that reproduced the postsynaptic response to action potential trains were also examined, and Lp channels were found to show much greater responses than were Ls channels. These results suggest that the Lp channel may play a critical role in the induction of long-lasting changes in synaptic strength.

[What do health professionals ask RELIS Vest service and how satisfied are they with the answers?]. / Hva spør helsepersonell RELIS Vest om og hvor fornøyde er de med svarene?

RELIS Vest provides drug information by answering questions from mainly physicians and pharmacists. In the present paper we evaluated this service. All questions to RELIS Vest during the 1995-98 period were systematically categorized and analysed. The quality of the service was assessed by evaluation forms. Of a total of 875 queries, 393 came from physicians and 370 from pharmacists. 42% were about psychoactive drugs; the most frequent types of queries concerned documentation and adverse effects. Analysis of 180 evaluation forms showed that 79% of the physicians and 56% of the pharmacists found the answers fast enough, relevant, adequately comprehensive and with valuable references while 16% of the physicians and 29% of the pharmacists found that the answers satisfied three of these four criteria. We conclude that problem-oriented drug information based on actual cases of prescribing is highly appreciated.

Hyperosmotic perfusion of the beating rat heart and the role of the Na+/K+/2Cl- co-transporter and the Na+/H+ exchanger.

The aim of the present study was to investigate the role of the Na+/K+/2Cl- co-transporter and the Na+/H+ exchanger on contractile function and electrolyte regulation during hyperosmotic perfusion of the heart. Langendorff perfused rat hearts were subjected to hyperosmolal perfusion in 10-min intervals. Perfusates were made hyperosmotic by adding mannitol to the buffer (370, 450 and 600 mOsmol/kg H2O). Cardiac contractile function was monitored with a balloon in the left ventricle (LV) coupled to a pressure transducer. Cardiac effluent was sampled repeatedly throughout and after hyperosmotic perfusion and analysed for content of Na+, K+, and Cl-. All three hyperosmotic perfusates initially reduced LV developed pressure (LVDP), but for 370 and 450 mOsmol/kg H2O, LVDP recovered to baseline within 4 min of perfusion. With 600 mOsmol/kg H2O, LVDP recovered slowly and was 50% below baseline after 10 min of hyperosmotic perfusion. Inhibition of the Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methylsulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694) abolished the recovery of LVDP to the 600 mOsmol/kg H2O perfusate, whereas inhibition of the Na+/K+/2Cl- co-transporter had no impact on LVDP. Potassium was taken up by the heart during hyperosmotic perfusion and this uptake was significantly reduced with inhibition of the Na+/H+ exchanger. Intracellular pH was assessed with 31p magnetic resonance spectroscopy and hyperosmolality induced a significant alkalosis that was dependent upon the Na+/H+ exchanger. The rat heart responds to moderate elevations in osmolality with a transient reduction in contractile function, whereas an elevation of 300 mOsmol/kg H2O persistently reduces contractile function. The Na+/H+ exchanger, but not the Na+/K+/2Cl- co-transporter, is of importance in contractile recovery and electrolyte regulation during hyperosmotic perfusion in the rat heart.

Protective effects of repetitive injections of radiographic contrast media on the subsequent tolerance to ischemia in the isolated rat heart.

PURPOSE: Despite detailed knowledge of the effects of X-ray contrast media on cardiac function, no studies have examined the effect of contrast media injections on the subsequent tolerance to ischemia in the heart. METHODS: Isolated perfused rat hearts were exposed to repetitive injections of iohexol, iodixanol, or ioxaglate before 30 min of global ischemia and 120 min of reperfusion. These groups were compared with control (no pretreatment) and ischemic preconditioning known to reduce infarct size. Physiologic variables and infarct size were measured RESULTS: Pretreatment with iodixanol reduced infarct size significantly compared with control and thus afforded protection against ischemia. Injections with iohexol and ioxaglate reduced infarct size, although not significantly, compared with control. CONCLUSION: Pretreatment of the isolated rat heart with commonly used contrast media enhances the cardiac tolerance to subsequent ischemia. The mechanism behind this protective effect could not be determined, but could involve stretching of the heart and/or generation of nitric oxide.

A survey of hypnotic use in geriatric institutions in Sogn og Fjordane, Norway.

We investigated the use of hypnotics in nursing homes and old age homes in the county of Sogn og Fjordane, Norway. Data on administration of hypnotics on 3 separate days within a week in August 1995 was obtained from the drug administration records in 31 institutions. Twenty-five percent of the 1062 patients in the institutions used hypnotics, with no difference between patients from nursing homes and old age homes. The number of patients treated with hypnotics, the doses administered, and the time of administration were similar for weekends and workdays. About 100% of the hypnotics were used as scheduled, and 29% of the doses administered were higher than the recommended lowest dose for elderly patients. Furthermore, about 50% of the hypnotics administered were long-acting benzodiazepines. The results indicate a need for a review of the prescribing of hypnotics in geriatric institutions.

Hyperosmotic pretreatment reduces infarct size in the rat heart.

Preconditioning of the heart can be achieved by an ischemia/reperfusion stimulus, but also by stretching of the heart by an acute volume overload. Since manipulations of the extracellular osmolality affects cell size, we hypothesized that hyperosmotic pretreatment of the isolated perfused rat heart could reduce infarct size following regional ischemia (RI). Langendorff perfused rat hearts were subjected to 30 min RI by ligature of the main branch of the left coronary artery followed by 120 min reperfusion (control group). Ischemic preconditioning (IP-5') was achieved by 5 min total global ischemia and 5 min reperfusion prior to RI. Hyperosmotic pretreatment was accomplished by perfusion with a hyperosmotic buffer (600 mOsm/kg H2O by adding mannitol) for 1 min, 2 min or 5 min. At the end of the experiments, the hearts were cut into 2 mm slices, incubated with triphenyltetrazoliumchloride before scanning and computerized for estimation of infarct size. The average infarct size (as percentage of area at risk) in the control group was 42% and was significantly reduced to 16% by ischemic preconditioning and to 17% by 2 min hyperosmotic pretreatment. Neither 1 min nor 5 min hyperosmotic pretreatment reduced infarct size as compared to the controls. The infarct reducing effect of 2 min hyperosmotic pretreatment was not blunted by inhibition of protein kinase C (chelerytrine chloride), the Na+/H+-exchanger (HOE 694) or stretch-activated anion channels (gadolinium chloride). The results indicate that short-lasting hyperosmotic perturbations of the extracellular environment may precondition the heart to a subsequent ischemic insult.

Use of hypnotics among patients in geriatric institutions.

A survey of hypnotic use in geriatric institutions outside hospitals was performed in the county of Hordaland, Norway. The data were obtained from the cardex system in 67 institutions and represented administration of hypnotics to the patients on 3 separate days within a week. About 24% of 2802 patients in the institutions used hypnotics. The number of patients treated with hypnotics, the doses administrated and the time of administration were similar for weekends and workdays. About 98% of the hypnotics were used as scheduled, and 41% of the doses administrated were higher than the recommended lowest dose for elderly patients. Long-acting benzodiazepines constituted about 62% of the hypnotics. A significantly higher proportion of patients in old age homes used hypnotics compared to patients in nursing homes (30.7% versus 22.9%, respectively, p < 0.01). Furthermore, higher doses, administration later in the evening and use of additional hypnotics were more common in old age homes compared to nursing homes. The results indicate a need for frequent reevaluation of prescribing of hypnotics in geriatric institutions.

Effects of MnDPDP, DPDP--, and MnCl2 on cardiac energy metabolism and manganese accumulation. An experimental study in the isolated perfused rat heart.

RATIONALE AND OBJECTIVES: Recent studies indicate that manganese dipyridoxyl diphosphate (MnDPDP) may function as a slow release agent for manganese ions (Mn++) and that MnDPDP is approximately 10 times less potent than manganese chloride (MnCl2) in depressing cardiac function. The authors examined the possibility that MnDPDP and MnCl2 may influence cardiac metabolism and enzyme release and lead to a tissue accumulation of Mn. METHODS: Manganese DPDP, DPDP--, or MnCl2 (1000 microM) was infused in isolated rat hearts, which were freeze-clamped at various time intervals during infusion (5 minutes) and recovery (14-minute washout). Enzyme (lactate dehydrogenase) release, tissue high energy phosphates, Mn contents, and physiologic indices were measured at various time intervals. RESULTS: No significant differences were noted for: lactate dehydrogenase in the treated groups; tissue creatine phosphate (CrP) and adenosine triphosphate in MnDPDP, DPDP--, and control groups; and tissue Mn in DPDP-- and control groups. Manganese-chloride and MnDPDP-treated hearts accumulated and retained Mn in an 8:1 ratio. Manganese chloride depressed cardiac function more effectively than MnDPDP. CONCLUSIONS: The study has shown that: heart tissue uptake and retention of Mn++ is rapid and effective; MnCl2 is approximately eight times more potent than MnDPDP in promoting these effects; and a rise in tissue Mn content to eight to nine times (MnDPDP) or 60 to 70 times (MnCl2) the normal level does not lead to acute side effects on cardiac energy metabolism, function, and enzyme release. The study indicates that MnDPDP may act like a slow release compound for Mn++ ions.

Manganese and the heart: acute cardiodepression and myocardial accumulation of manganese.

The aim of study was to assess acute effects of the divalent manganese ion (Mn2+) in an intact but isolated heart preparation. Rat hearts were perfused in the Langendorff mode at constant flow rate. Left ventricular (LV) developed pressure (LVDP). LV pressure first derivatives (LVdp/dt max and min), heart rate (HR) and aortic pressure (AoP) were recorded. Ventricular contents of high energy phosphate compounds (HEP) and Mn metal were measured at the end of experiment. Infusion of MnCl2 for 5 min with perfusate concentrations 1-3000 microM induced an immediate depression of contractile function at and above 30 microM and negative chronotropy at and above 300 microM. These IC50 values were found (microM): LVDP 250; LVdp/dt max 160; LVdp/dp min 120; HR 1000; and increase in AoP 80. Recovery of function during a 14 min washout period was rapid and extensive except for Mn2+ 3000 microM. Somewhat unexpected, Mr2+ 30-1000 microM raised coronary vascular resistance up to about twice the control level, whereas the vasoconstrictory response was overcome at 3000 microM. Mn2+ 3000 microM reduced tissue HEP Ventricular Mn content rose stepwise for perfusate Mn2+ above 1 microM up to about 55 times the control level for perfusate Mn2+ 3000 microM. It is concluded that: acute effects of Mn2+ like depression of contractility and rate is rapidly reversible; and rat hearts accumulate and buffer large amounts of Mn2+ without affecting cardiac function or energy metabolism in the acute stage.

Protection induced by a brief ischemic episode in the Langendorff perfused rat heart.

RATIONALE AND OBJECTIVES: Ischemic episodes lasting approximately 1 min may be associated with coronary angioplasty. We explored whether such episodes could induce myocardial protection against prolonged ischemic episodes in an ex vivo model. METHODS: Protection afforded by pretreatment with a 1-min ischemic episode (ischemic preconditioning) against prolonged ischemia was investigated in the isolated rat heart. Left ventricular developed pressure (LVDP; LV systolic pressure-LV end-diastolic pressure), heart rate (HR), and enzyme leakage (lactate dehydrogenase) were indexes of protection. RESULTS: An increased recovery of LVDP x HR after 16 and 19 min of ischemia of 37% and 28%, respectively, paralleled by reduced enzyme leakage, was observed in preconditioned hearts after 10 min of reperfusion. However, the difference between preconditioned and control hearts was lost after 30 min of reperfusion. CONCLUSION: Ischemic episodes lasting approximately 1 min are not sufficient to initiate stable protection even if initial functional and metabolic indexes suggest a protective effect.

Effects of eicosapentaenoic acid and docosahexaenoic acid diet supplement on tolerance to the cardiotoxicity of epirubicin and to ischaemia reperfusion in the isolated rat heart.

We compared the effects of 2 weeks dietary supplement of docosahexaenoic acid, eicosapentaenoic acid or olive oil on myocardial tolerance to the cardiotoxicity of the anthracycline epirubicin and to ischaemia reperfusion. Isolated rat hearts from the dietary groups were perfused at a constant flow rate of 12.5 ml/min. The hearts were subjected to a 20 min. period of epirubicin infusion by a side arm of the perfusion system at a rate of 0.2 mg/min. or a 20 min. period of global ischaemia. After 10 min. of epirubicin infusion a significantly (P < 0.05) higher aortic pressure (an index of coronary resistance during constant flow perfusion) was observed in the olive oil group; 130 +/- 22% (mean +/- S.D.) compared to hearts in the docosahexaenoic acid; 108 +/- 9% (mean +/- S.D.), and eicosapentaenoic acid; 105 +/- 7% (mean +/- S.D.), group. Hearts from docosahexaenoic acid-fed rats showed a significantly increased left ventricular end-diastolic pressure (an index of contracture); of 66 +/- 30 mmHg (mean +/- S.D.) after 15 min. of global ischaemia compared to eicosapetaenoic acid fed rats; 37 +/- 18 mmHg (mean +/- S.D.), and significantly higher release of lactate dehydrogenase during the following 30 min. period of reperfusion compared to olive oil-fed rats. We conclude that eicosapentaenoic acid and docosahexaenoic acid could be useful during epirubicin infusion and that docosahexaenoic acid could be harmful during ischaemia reperfusion.

Pretreatment with ischaemia attenuates acute epirubicin-induced cardiotoxicity in isolated rat hearts.

We investigated whether a brief ischaemic episode (ischaemic pretreatment) preconditioning might attenuate the acute cardiotoxicity of the anthracycline, epirubicin. Isolated rat hearts perfused at a constant flow rate of 10 ml/min, were preconditioned with 5 min. of global ischaemia and 10 min. of reperfusion (preconditioned hearts), or were perfused for 15 min. (control hearts). The hearts were then subjected to 20 min. of infusion with epirubicin (2 mg/ml) or vehicle by a side arm of the perfusion system at a rate of 0.1 ml/min. (0.2 mg epirubicin/min.). Attenuation of cardiotoxicity of a total dose of 4 mg of epirubicin was assessed by functional and metabolic parameters during infusion and during the following 30 min. recovery period. Cardiotoxic effects were reduced in preconditioned hearts compared to control hearts. Thus left ventricular developed pressure and heart rate product after 20 min. of epirubicin infusion was depressed to 27 +/- 7% (mean +/- S.D.) and 40 +/- 4% (mean +/- S.D.) of baseline values in the control group and the preconditioned group, respectively (P < 0.05). Furthermore, we observed less contracture during epirubicin infusion and more effective reversal of contracture during the recovery period in the preconditioned hearts. Improvement in cardiac function was associated with a significantly lower (P < 0.05) myocardial content of epirubicin in the preconditioned group at the end of the infusion period. We conclude that ischaemic preconditioning attenuates the acute cardiotoxicity of epirubicin, probably by reducing the myocardial accumulation of the anthracycline.

Effects of manganese dipyridoxyl diphosphate, dipyridoxyl diphosphate--, and manganese chloride on cardiac function. An experimental study in the Langendorff perfused rat heart.

RATIONALE AND OBJECTIVES: Manganese dipyridoxyl diphosphate (MnDPDP) is a promising contrast agent for magnetic resonance imaging of the liver. The authors explored the possibility that high concentrations of MnDPDP may cause manganese ion (Mn++)-induced side effects on cardiac function. METHODS: Potential cardiodepression by MnDPDP, DPDP--, and manganese chloride (MnCl2) (100-3,000 mumol/L) was investigated in the isolated rat heart, with left ventricular developed (systolic--end-diastolic) pressure and heart rate as the primary indices of cardiac function. RESULTS: During 5-minute exposures, 10% and 50% decreases in left ventricular developed pressure were observed for MnDPDP, 250 mumol/L and 1580 mumol/L; DPDP--, less than 100 mumol/L and 1000 mumol/L; MnCl2, 30 mumol/L and 250 mumol/L. Heart rate changes were not observed with MnDPDP. Cardiodepression was reversed within 2 minutes during a 14-minute recovery period for all investigated concentrations of MnDPDP and was less rapid for the highest concentrations of MnCl2. CONCLUSIONS: Manganese dipyridoxyl diphosphate is well tolerated in the rat heart at concentrations as high as 200 to 250 mumol/L and is approximately 10 times less cardiotoxic than MnCl2. Cardiodepressive effects of MnDPDP in the present rat heart model, perfused in the absence of blood and proteins, are related primarily to the release of free Mn++ ions and in part to the simultaneous release of DPDP--.

Contractile responses to electrolyte changes during coronary bolus perfusion. A comparative study in isolated rat, guinea pig, and rabbit hearts.

RATIONALE AND OBJECTIVES: The authors studied cardiac contractile responses during coronary bolus perfusion, as in coronary angiography, in three species and related the responses to the bolus content of electrolytes and to patterns of cardiac electrolyte regulation. METHODS: Isolated, paced hearts from the rat, guinea pig, and rabbit were subjected to coronary perfusion in the global mode with recording of left ventricular developed pressure during exposure (< 7.5 seconds) and recovery (30 seconds). RESULTS: In series 1 of the experiments, the perfusate reduction to one fifth of normal Ca, Na, K, Mg, and Ca/Na/K/Mg, and the removal of all ions, led to the following percentage changes in left ventricular developed pressure: rat -64, +84, -38, +7, +40, and +79; guinea pig -43, +48, +18, +5, +28, and +37; and rabbit -32, +60, +14, +4, +22, and +33. CONCLUSIONS: Except for K reduction, inducing negative inotropy in the rat but positive inotropy in the guinea pig and the rabbit, the three species responded similarly. Thus, changes in left ventricular developed pressure were related to changes in direction and rate of the sarcomal Na-Ca exchange. In series 2 of the experiments, iohexol (150 mg I/mL) +/- minor electrolyte additives were studied. Additives with Na 30 mmol/L only or with Na, Ca, K, and Mg carefully balanced reduced positive and negative inotropic responses in all three species.