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  • 1.
    Abdal Hadi, Jehan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hur skiljer sig traditionella från nyare generationer antipsykotika åt vad gäller biverkningen viktökning?2008Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpStudent thesis
    Abstract [sv]

    Antipsykotiska läkemedel är basen för behandling av schizofreni, en psykisk sjukdom som uppträder redan hos unga människor. Symtomen vid schizofreni brukar delas in i positiva symtom (hallucinationer, vanföreställningar, paranoida tankar), negativa symtom (koncentrationssvårigheter, nedsatt språk- och tankeförmåga, minskat intresse för omgivningen, och initiativlöshet), samt kognitiva symtom (minnesproblem, problem med uppmärksamhet och koncentration).

    Antipsykotiska läkemedel delas in i typiska (den äldre generationen) och atypiska (den nyare generationen) antipsykotika. För båda grupperna antipsykotiska läkemedel finns det risk för biverkningar. De vanligaste biverkningarna vid behandling med den äldre generationen antipsykotika är extrapyramidala biverkningar. En biverkning som förefaller mer specifik för de nya atypiska preparaten är viktökning, vilken även kan orsaka utveckling av många allvarliga sjukdomstillstånd.

    Syftet med detta arbete var att jämföra typiska och atypiska antipsykotiska läkemedel med avseende på utveckling av viktökning.

    För att få svar på min frågeställning har en litteraturstudie av fem vetenskapliga artiklar genomförts. De vetenskapliga artiklarna har hittats genom databassökningar i PubMed, medan övriga fakta har hämtats från andra källor.

    Resultatet av de vetenskapliga artiklarna visar att det finns skillnader mellan traditionella och nyare generationer antipsykotika vad gäller tendens att orsaka viktökning. Med några undantag, är flera antipsykotiska läkemedel, som tillhör den nyare generationen, associerade med högre risk för utveckling av viktökning jämfört med den äldre generationen antipsykotika. Viktökning orsakas mest av klozapin, följt av olanzapin och risperidon. Quetiapin orsakar, i likhet med haloperidol, mindre viktökning.

    På grund av detta faktum, forskar man numera kring orsakerna till denna skillnad för att förbättra biverkningsprofilen hos framtida antipsykotika.

    2008:F2

  • 2.
    Angviken, Åsa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    SSRIs effekt och säkerhet hos barn och ungdomar2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Depression är den näst mest kostsamma sjukdomen för samhället efter hjärt-kärlsjukdom, främst på grund av långa sjukskrivningsperioder. Sjukdomen kan uppstå när som helst från sex månaders ålder, men prevalensen ökar med åldern. Det finns ett antal stressrelaterade faktorer som skulle kunna leda till depression, så som stor sorg, verbala eller fysiska övergrepp samt en svår barndom. Vad som orsakar sjukdomen är ännu inte helt känt, men det finns teorier att halterna av serotonin och noradrenalin är lägre hos deprimerade personer. Behandling som används är olika former av samtalsterapi, men även läkemedel så som selektiva serotoninåterupptagshämmare (SSRI). Det finns teorier som sammankopplar användandet av SSRI med självmord, framförallt hos personer ≤19 år. Syftet med detta litteraturarbete var att undersöka om SSRI preparat har någon effekt på depression hos barn och ungdomar och om de är säkra eller kan få allvarliga konsekvenser så som självmord. Sökningar i PubMed gjordes för att hitta relevanta artiklar. Fem av de åtta inkluderade studierna rapporterade olika effekter och säkerhet hos olika SSRI preparat bland barn och ungdomar, jämfört med placebo. Två andra studier undersökte förekomsten av suicidalitet till följd av läkemedlen. Den sista studien jämförde toxikologiska data från Rättsmedicinalverket med receptregistret på antidepressiva läkemedel från  Socialstyrelsen. Endast två av de fem studerade preparaten (fluoxetin och citalopram) hade en bättre effekt än placebo i hela populationen och ytterligare ett (sertralin) hade bättre effekt hos ungdomar. Det begicks inga självmord i studierna.    De studier som har granskats i detta arbete tyder på att olika SSRI preparat har olika bra effekt samt olika säkerhetsprofiler. Det sågs inget tydligt samband mellan behandlingen och självmord, men en något förhöjd risk för suicidalitet.     

  • 3.
    Davidsson, Mattias
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Är olika statiner ekvipotenta: en analys av kontemporär evidens inklusive farmakologi och läkemedelskemi2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Statins are among the most used drugs in Sweden. There are currently four statins available on the Swedish market; atorvastatin, simvastatin, pravastatin and rosuvastatin. Statins act by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme-A reductase, also known as HMG-CoA-reductase. HMG-CoA-reductase is the rate-limiting enzyme of the cholesterol synthesis. Decreased hepatic cholesterol leads to increased low-density lipoprotein (LDL) clearance from plasma to liver cells. Having a high level of LDL cholesterol is potentially dangerous as it can lead to atherosclerosis and cardiovascular disease. Statins significantly reduce cardiovascular morbidity and mortality in patients with and without coronary heart disease.

    Purpose: The aim of this work was to investigate if there are any differences between the different statins according to contemporary evidence.

    Method: This is a literary analysis. Studies included were searched from PubMed. A total of five studies were included.

    Results: The result of this study indicates rosuvastatin to be most efficacious in lowering LDL cholesterol (LDL-C), triglycerides and total cholesterol. It also improved the high-density lipoprotein cholesterol (HDL-C) better than atorvastatin, simvastatin and pravastatin. Study 1 showed rosuvastatin to lower LDL-C with statistical significance (P<0.001) across dose ranges (10-40 mg) after 12 weeks. Study 2 compared a dose ratio of 1:2 between rosuvastatin and simvastatin in lowering LDL-C with a 3.24% (95% CI 4.10 to 2.38) favor of rosuvastatin. Study 4 compared effects of atorvastatin 80 mg and rosuvastatin 20 mg in patients with ST elevation myocardial infarction in a 4-week therapy. Rosuvastatin 20 resulted in a 35% compared with atorvastatin 80 mg 34% (P=0.59) reduction in LDL-C levels. Study 1 demonstrated rosuvastatin to improve HDL-C levels in daily doses of 40 mg with statistical significance compared with atorvastatin, simvastatin and pravastatin. Study 1 demonstrated rosuvastatin to lower total cholesterol with statistical significance (P<0.002) across doses compared with atorvastatin, simvastatin and pravastatin. Study 1 also demonstrated rosuvastatin to lower triglycerides more. In daily doses of 40 mg rosuvastatin had a statistical significance (P<0.002) versus simvastatin and pravastatin, but not atorvastatin. The P value between rosuvastatin and atorvastatin was not mentioned, neither the P-value between atorvastatin, simvastatin and pravastatin.

    Conclusion: Statins are not equipotent. Rosuvastatin showed greater results in reducing LDL-C, triglycerides and total cholesterol with no increased risk of adverse events compared with atorvastatin, simvastatin and pravastatin. Rosuvastatin still lacks in clinical experience which makes needs for further studies on this topic.

  • 4.
    Eltayb, Amani
    et al.
    Karolinska Institutet.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Schilström, Björn
    Karolinska Institutet.
    Svensson, Torgny
    Karolinska Institutet.
    Antipsychotic-like effect by combined treatment with citalopram and WAY 100635: involvement ofthe 5-HT2C receptor.2007In: The Int J neuropsychopharmacol, ISSN 1461-1457, Vol. 10, no 3, p. 405-410Article in journal (Refereed)
    Abstract [en]

    Catalepsy occurs following high dopamine (DA) D2 blockade by typical antipsychotic drugs (APDs). We showed that a combination of a high dose of citalopram, a selective serotonin reuptake inhibitor (SSRI) and the selective 5-HT1A receptor antagonist WAY 100635 produces significant catalepsy in rats, similar to APDs. Here, we investigated the potential antipsychotic activity of lower doses of citalopram+WAY 100635, using the conditioned avoidance response (CAR) test. Cataleptogenic liability of the combination was evaluated with the catalepsy test. Citalopram and WAY 100635 in combination, but not when givenalone, prod uced a significant antipsychotic action in CAR without significant catalepsy, similar to the effect selective 5-HT2C receptor antagonist, SB , completely prevent 242084ed the citalopram/WAY 100635-induced suppression of CAR indicating an involvement of the 5-HT2C receptor. In summary, treatment with an SSRI/5-HT1A antagonist combination might prove beneficial in psychiatric disorders withpsychotic/depressive symptoms. 

  • 5.
    Fernando, Cathrine
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mipomersen, an apolipoprotein B synthesis inhibitor: A literature study analyzing efficacy and safety when used for treating patients with familial hypercholesterolemia2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Familial hypercholesterolemia is a genetic disease affecting about 10 million people around the world. Those who carry the disease have a very high risk of developing cardiovascular diseases and commonly encounter myocardial infarction at the early age of 40. Therefore, a diagnosis and immediate treatment are very important for these patients. Despite many combinations of available drugs, there are many patients who still cannot reach the desired cholesterol levels.

    Mipomersen is a new lipid-lowering drug which inhibits the synthesis of apolipoprotein B, a common component of lipoproteins such as low-density lipoprotein. Inhibition of this protein leads to reduced production of these lipoproteins and reduces the risk of cardiovascular diseases. The drug is currently only indicated for treating patients with homozygous familial hypercholesterolemia.  Unfortunately, there have been many reports of adverse events in patients using mipomersen which has proven problematic.        

    The aim of this thesis is to analyze the efficacy and safety of mipomersen when treating patients with familial hypercholesterolemia. This has been done by searching for five clinical trials in the database Web of Science. The studies were required to include patients with familial hypercholesterolemia, use mipomersen as the study drug and analyze its effect and safety.  

    The studies showed that mipomersen has a very good effect in decreasing low-density lipoproteins as well as other lipoproteins in comparison to placebo. Many of the patients who were treated with mipomersen displayed several adverse events and the most common were injection-site reaction and influenza-like symptoms. Elevated levels of aminotransaminase and increased fat deposit in the liver were also common.

    Based on the five clinical trials analyzed in this thesis, mipomersen is an effective lipid-lowering drug which reduces low density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a) in patients with familial hypercholesterolemia. Elevations in alanine aminotransferase and aspartate aminotransferase are common in patients treated with mipomersen. This could indicate a negative impact on the liver. To be more certain of its safety profile, more research could be needed. There are however, new treatments that combines statins and a proprotein convertase subtilisin/kexin 9 inhibitor, which could be the future of lipid-lowering treatments and mipomersen would then likely be substituted. 

  • 6. Garcia-Pascual, A
    et al.
    Persson, Katarina
    Department of Clinical Pharmacology, University Hospital of Lund .
    Holmquist, F
    Andersson, K-E
    Endothelin-1-induced phosphoinositide hydrolysis and contraction in isolated rabbit detrusor and urethral smooth muscle1993In: General Pharmacology, ISSN 0306-3623, E-ISSN 1879-0011, Vol. 24, no 1, p. 131-138Article in journal (Refereed)
    Abstract [en]

    1. Endothelin-1 (ET-1) caused a concentration-dependent increase in the formation of inositol phosphates (IPs) in isolated rabbit detrusor and urethral smooth muscle preparations prelabelled with myo-[H-3]inositol. 2. The increase in accumulation of IPs was slow in onset in both detrusor and urethra, with no significant accumulation demonstrable during the first 30 min. The increase in IPs accumulation found after exposure of detrusor tissue to ET-1 (10(-7) M) for 2 hr (250 +/- 38%, n = 7) was not significantly different from that found in the urethra (279 +/- 40%, n = 6), when expressed as per cent of corresponding control values. 3. Pretreatment with nifedipine (10(-6) M) did not reduce IPs formation. In contrast, no increase in IPs formation was demonstrated in Ca2+-free medium. 4. ET-1 (10(-11) - 10(-7) M) produced concentration-dependent, slowly developing contractions in both detrusor and urethral preparations. Pretreatment with H-7 (3 x 10(-5) M) for 30 min before ET-1 application resulted in a non-parallel shift of the ET-1 concentration-response curve with significant reductions in maximal responses in both tissues. 5. ET-1-induced contractions in urethral preparations were markedly inhibited by Ni2+ (3 x 10(-4) M), whereas the effect of Ni2+ in the detrusor was less pronounced. 6. The results suggest that ET-1 stimulates phosphoinositide hydrolysis in the rabbit detrusor and urethra. Both IPs formation and contractile activation evoked by ET-1 are dependent on extracellular Ca2+. Ca2+-entry pathways seem to be differently activated in the detrusor and urethra, since Ca2+-influx through dihydropyridine-sensitive channels is involved in the ET-1-induced contraction of the detrusor, whereas a Ni2+-sensitive, nifedipine-resistant pathway seems to dominate in the urethra. 

  • 7.
    Göransson, Ulf
    et al.
    Uppsala University.
    Jacobsson, Erik
    Uppsala University.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The toxins of nemertean worms2019In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 11, no 2, p. 1-36, article id 120Article in journal (Refereed)
    Abstract [en]

    Most ribbon worms (phylum: Nemertea) are found in marine environments, where they act as predators and scavengers. They are characterized by an eversible proboscis that is used to hunt for prey and thick mucus covering their skin. Both proboscis and epidermal mucus mediate toxicity to predators and preys. Research into the chemical nature of the substances that render toxicity has not been extensive, but it has nevertheless led to the identification of several compounds of potential medicinal use or for application in biotechnology. This review provides a complete account of the current status of research into nemertean toxins.

  • 8.
    Hasan, Badrul
    et al.
    Uppsala Univ.
    Melhus, Åsa
    Uppsala Univ.
    Sandegren, Linus
    Uppsala Univ.
    Alam, Munirul
    Int Ctr Diarrhoeal Dis Res, Bangladesh.
    Olsen, Björn
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Uppsala Univ.
    The Gull (Chroicocephalus brunnicephalus) as an Environmental Bioindicator and Reservoir for Antibiotic Resistance on the Coastlines of the Bay of Bengal2014In: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448, Vol. 20, no 5, p. 466-471Article in journal (Refereed)
    Abstract [en]

    The presence and frequency of multiresistant bacteria in wild birds act as indicators of the environmental contamination of antibiotic resistance. To explore the rate of contamination mediated by Escherichia coli, 150 fecal samples from the brown-headed gull (Chroicocephalus brunnicephalus) and 8 water samples from the Bay of Bengal area were collected, cultured, and tested for antibiotic susceptibility. Special attention was paid to extended-spectrum beta-lactamase (ESBL)-producing isolates, which were further characterized genetically. Antibiotic resistance was found in 42.3% (36/85) of the E. coli isolates and multidrug resistance in 11.8%. Isolates from the area with a higher human activity were more resistant than those from an area with a lower level of activity. Most frequent was resistance to ampicillin (29.4%), followed by trimethoprim-sulfamethoxazole (24.7%) and quinolones (22.4%). Carriage of ESBL-producing E. coli was relatively high (17.3%) in the gulls, whereas no ESBL producers were found in the water. All ESBL-producing E. coli isolates, but one, carried bla(CTX-M-15) or bla(CTX-M-15)-like genes. A bla(CTX-M-14)-like enzyme was found as an exception. Gulls from two different colonies shared E. coli clones and harbored the clinically relevant sequence types ST10, ST48, and ST131. The high frequency of antibiotic resistance and ESBL production among E. coli isolates from gulls indicates that the environmental contamination of antibiotic resistance has already gone far on the coastlines of the Bay of Bengal. Considering the limited control over the antibiotic consumption and waste from human activities in Bangladesh, there is no easy solution in sight.

  • 9.
    Holmgren, Christina M.
    et al.
    University of Gothenburg, Sweden;County Hospital Ryhov, Sweden.
    Abdon, Nils J.
    Hudiksvall Hospital, Sweden.
    Bergfeldt, Lennart B.
    University of Gothenburg, Sweden.
    Edvardsson, Nils G.
    University of Gothenburg, Sweden.
    Herlitz, Johan D.
    University of Borås, Sweden;Sahlgrenska University Hospital, Sweden.
    Karlsson, Thomas
    University of Gothenburg, Sweden.
    Svensson, Leif G.
    Karolinska Institutet, Sweden.
    Åstrand, Bengt
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry.
    Changes in Medication Preceding Out-of-hospital Cardiac Arrest Where Resuscitation Was Attempted2014In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 63, no 6, p. 497-503Article in journal (Refereed)
    Abstract [en]

    Objective: To describe recent changes in medication preceding out-of-hospital cardiac arrest (OHCA) where resuscitation was attempted. Methods: OHCA victims were identified by the Swedish Cardiac Arrest Register and linked by means of their unique 10-digit personal identification numbers to the Prescribed Drug Register. We identified new claimed prescriptions during a 6-month period before the OHCA compared with those claimed in the period 12 to 18 months before. The 7-digit Anatomical Therapeutical Chemical codes of individual drugs were used. The study period was November 2007-January 2011. Results: OHCA victims with drugs were (1) older than those who did not claim any drugs in any period (70 +/- 16 years vs. 54 +/- 22 years, P < 0.001), (2) more often women (34% vs. 20%, P < 0.001), and (3) had more often a presumed cardiac etiology (67% vs. 54%, P < 0.001). The OHCA victims were less likely to have ventricular tachycardia/ventricular fibrillation as the first recorded ;rhythm (26% vs. 33%, P < 0.001) or to survive 1 month (9% vs. 17%, P < 0.0001). New prescriptions were claimed by 5122 (71%) of 7243 OHCA victims. The most frequently claimed new drugs were paracetamol (acetaminophen) 10.3%, furosemide 7.8%, and omeprazole 7.6%. Of drugs known or supposed to cause QT prolongation, ciprofloxacin was the most frequent (3.4%) altogether; 16% had a new claimed prescription of a drug included in the "qtdrugs.org" lists. Conclusions: Most OHCA victims had new drugs prescribed within 6 months before the event but most often intended for diseases other than cardiac. No claims can be made as to the causality.

  • 10.
    Hovstadius, Bo
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Petersson, Göran
    Linnaeus University, Faculty of Health, Social Work and Behavioural Sciences, School of Health and Caring Sciences.
    Adherence, therapeutic intensity, and the number of dispensed drugs2011In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 20, no 12, p. 1255-1261Article in journal (Refereed)
    Abstract [en]

    Purpose

    To estimate non-adherence in relation to the therapeutic intensity (TI) and the number of dispensed drugs per individual and studywhether the TI can be used as an estimator of non-adherence with an increasing number of drugs.

    Methods

    The study comprised an individual-based register of all dispensed outpatient prescriptions in Sweden in 2006, including6.2 million individuals. The applied definition of drug was the chemical entity or substance comprising the fifth level in the World HealthOrganisation’s Anatomic, Therapeutic, Chemical classification. The defined daily dosage per individual during 12 months was applied asan indicator of the TI.

    Results

    We found a positive linear relation between the TI and the increasing number of dispensed drugs per individual, both for men andwomen. We found a slightly diminishing TI with an increasing number of drugs only for the age groups above 70 years, at a level above 13drugs per individual.

    Conclusions

    The linear relationship between the TI and the increasing number of dispensed drugs per individual provides poor support forusing decreasing TI as an estimator of non-adherence. The low rate of cost-related non-adherence in Sweden might contribute to explainingthe linear relationship.

  • 11.
    Hovstadius, Bo
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Petersson, Göran
    Linnaeus University, Faculty of Health, Social Work and Behavioural Sciences, School of Health and Caring Sciences.
    Factors leading to excessive polypharmacy.2012In: Clinics in Geriatric Medicine, ISSN 0749-0690, E-ISSN 1879-8853, Vol. 28, no 2, p. 159-172Article in journal (Refereed)
    Abstract [en]

    There are numerous risk factors for patients to develop excessive polypharmacy. The most prominent risk factors are associated with sociodemographics and the patients’ conditions. Risk factors associated with patient behavior, such as patient’s self medication with all types of medications, have not been observed to the same extent but might be at the same level of importance for patients developing excessive polypharmacy. Risk factors related to physicians, and the interaction between patient and physician, are studied to a much lesser extent. The few studies conducted regarding the large variation in physicians’ individual prescribing practices, in terms of polypharmacy, add another perspective to the complexity of the area. Interventions aiming to improve communication between GP and hospital specialist, to create support systems for medical reviews that include all patients’ medications, and to improve the knowledge of multiple prescribing might have the largest potential to better manage excessive polypharmacy.

  • 12.
    Hovstadius, Bo
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Tågerud, Sven
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Petersson, Göran
    Linnaeus University, Faculty of Health, Social Work and Behavioural Sciences, School of Health and Caring Sciences.
    Åstrand, Bengt
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Prevalence and therapeutic intensity of dispensed drug groups for individuals with multiple medications: a register-based study of 2.2 million individuals2010In: Journal of Pharmaceutical Health Services Research, ISSN 1759-8885, Vol. 1, no 4, p. 145-155Article in journal (Refereed)
    Abstract [en]

    Objectives  To assess the prevalence and the therapeutic intensity of dispensed drug groups for individuals receiving multiple medications.

    Methods  The individual-based data of all dispensed outpatient prescriptions in Sweden in 2006 were analysed. Five or more dispensed drugs (DP ≥ 5) during a 12-month period were applied as an indicator of multiple medications. The drugs were categorized according to the second level of the World Health Organization's Anatomic, Therapeutic, Chemical classification. The defined daily dosage per individual during 12 months was applied as an indicator of the therapeutic intensity.

    Key findings  For the 2.2 million individuals with DP ≥ 5, the drug groups with the highest prevalences were antibacterials (48.2%), analgesics (40.3%), psycholeptics (35.9%), antithrombotic agents (33.4%) and beta-blocking agents (31.7%). As examples, the level of prevalence increased with age for analgesics, psycholeptics, antithrombotic agents and diuretics, and decreased with age for antibacterials, drugs for obstructive airway diseases and antihistamines for systemic use. Substantial differences in the level of prevalence between women and men were observed for several drug groups; for example, thyroid therapy (13.3 vs 3.6%), psychoanaleptics (26.3 vs 18.2%), drugs used in diabetes (9.1 vs 15.7%) and lipid-modifying agents (18.1 vs 30.7%). Generally, the therapeutic intensity increased with the increasing number of dispensed drugs. For a third of the most common drug groups, the therapeutic intensity increased with an increasing age above the 60–69-year age group.

    Conclusion  The number of drugs taken not only increases the potential risks associated with multiple drug use, but also increases the potential burden of an increased therapeutic intensity, especially for older people. The reported findings may enlighten physicians and healthcare stakeholders concerning the complex patterns of multiple drug use in the entire population and the associated expenses. The findings may also be used as a base for interventions aiming to bring about the most appropriate and balanced prescription of medicines to individuals with multiple diseases.

  • 13. Jardemark, Kent
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Grillner, Pernilla
    Svensson, Torgny
    Dopamine D3 and D4 receptor antagonists in the treatment of schizophrenia.2002In: Curr Opinion in Investigational Drugs, Vol. 3, no 1, p. 101-105Article, review/survey (Other academic)
    Abstract [en]

    The findings that dopamine D3 and D4 receptors are highly expressed in limbic and cortical areas (D4 more than D3), and the fact that the atypical drug clozapine has preferential affinity for the D4 receptors have suggested an involvement of these receptors in schizophrenia. Subsequently, many pharmaceutical companies have pursued the approach of developing selective dopamine D3 or D4 antagonists as potential antipsychotics. This review will discuss the current status of selective dopamine D3 and D4 receptor antagonists for the treatment of schizophrenia.

  • 14.
    Jokela, Päivi
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Computer Science, Physics and Mathematics.
    Rydbrink, Morgan
    Linnaeus University, Faculty of Science and Engineering, School of Computer Science, Physics and Mathematics.
    Att minska läkemedelsförväxlingar med hjälp av ändrad design av förpackningar2012Report (Other academic)
    Abstract [sv]

    Nätverket för patientsäkerhet (2011) har uppmärksammat det faktum att läkemedelsförväxlingar medför ett stort antal vårdskador varje år, både i Sverige och i andra länder. Problemet är mångfacetterat och situationen kan förbättras genom organisatoriska åtgärder såsom goda arbetsrutiner, ändamålsenlig placering av läkemedel i förråden, egen färgmarkering på sjukhus samt genom tekniska lösningar såsom automatiserad läkemedelsdosering och scanning av streckkoder.

    Nätverket för patientsäkerhet (2011) har dock dragit slutsatsen att en enhetlig och bättre utformning av läkemedelsförpackningar och etiketter är en nödvändig åtgärd för att snabbare och effektivare minska risken för läkemedelsförväxlingar. Nätverket har även i samverkan med Läkemedelsverket tagit fram ett antal faktorer som kan minska risken för förväxlingar:

    • Det generiska namnet samt styrka/enhet anges med störst och tydligast text på förpackningen. 
    • Bakom styrkan finns skuggning i avvikande färg – i regel finns dock ingen standardisering av färgerna. 
    • Särskild markering för läkemedel som ska spädas införs. 
    • Typsnittet måste vara lättläst och texten tillräckligt stor. 
    • Tall Man lettering kan användas i generiska namn som liknar varandra, med andra ord skrivs avvikande bokstäver med versaler.

    Den aktuella studien fokuserar på de effekter som kan uppnås genom att variera läkemedelsförpackningens design.

  • 15. Libelius, Rolf
    et al.
    Lundquist, I
    Tågerud, Sven
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Thesleff, S
    Endocytosis and lysosomal enzyme activities in dystrophic muscle: The effect of denervation1981In: Acta Physiologica Scandinavica, Vol. 113, no 2, p. 259-261Article in journal (Refereed)
  • 16. Libelius, Rolf
    et al.
    Tågerud, Sven
    Department of Pharmacology, University of Lund.
    Uptake of horseradish peroxidase in denervated skeletal muscle occurs primarily at the endplate region1984In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 66, p. 273-281Article in journal (Refereed)
    Abstract [en]

    The spatial distribution of horseradish peroxidase (HRP) uptake has been studied by light- and electron microscopy in the denervated hemidiaphragm of the mouse. Segments with high HRP uptake were observed in a band centrally located in the denervated muscle. This distribution is similar to the well-known innervation pattern of the diaphragm. Ultrastructural studies demonstrated a high incidence of postsynaptic folds in close proximity of fibre areas with high intracellular content of HRP. 8–12 days after denervation a large number of fibres showed segments of high HRP uptake. 2–4 days after denervation very few such segments were observed. Biochemical studies also demonstrated an increase in HRP uptake after denervation occurring primarily in the endplate region. The activities of the lysosomal enzymes N-acetyl-β-d-glucosaminidase, acid phosphatase and cathepsin D all increased after denervation, most prominently in the endplate region.It is suggested that the observed segmental uptake of HRP and lysosomal activation reflects a process for rapid membrane turnover in denervated muscle. 

  • 17.
    Mohamed, Diana
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Kan GABA-transporthämmare fungera som läkemedel mot epilepsi?2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Epilepsy is not a specific disease but a symptom of brain injury or impaired nerve cell function in the brain. Epileptic seizures are symptoms of abnormal activity in the brain neurons. Today, about 60 000 i.e. 0.5-1% of the Swedish population live with epilepsy. The risk of being affected is greatest during the first year of life and after the age of 65 years when the risk for stroke is greatest. The treatment of epilepsy is used in order to prevent the onset of seizures and to allow the patient to live a relatively normal life. Anticonvulsants dampen the activity in the brain and thus reduce the risk of seizures.

    During many years, attempts have been made to develop new anticonvulsants against other potential targets than those that exist today, for example GABA-transporter inhibitors. The only presently used medicine with GABA-transporter inhibiting effect is tiagabine, but this is not licensed as a pharmaceutical drug in Sweden.

    The aim of this study was to investigate whether GABA-transport inhibitors could be used as medication for epilepsy. The method that was used was a literature study in which scientific articles were chosen from PubMed, ELIN, Cochrane and Google Scholar. The work is based on 4 original research articles and one meta-analysis. The articles describe antiepileptic effects and/or related properties of various substances with inhibitory actions on different GABA-transporters. These inhibitors, alone or in combination, were shown to have anticonvulsant effects in several different animal models of epilepsy. Inhibitors of different GABA transporters, such as tiagabine and EF1502, resulted in synergistic effects, while inhibitors of the same GABA transporter, such as tiagabine and LU-32-176 B, resulted in additive effects. Inhibition of various GABA transporters in different cell types in and around synapses therefore seems to provide synergistic effects. No synergistic effect was observed for toxic effects. There is reason to believe that additional drugs with effects on GABA transporters may be used in the future for the treatment of epilepsy.

  • 18.
    Nordqvist, Ola
    Kalmar County Council, Sweden.
    Pharmaceuticals increasing the risk of vitamin D deficiency- an overlooked issue among Swedish physicians2014In: Presented at IOF Regionals 5th Asia-Pacific Osteoporosis Meeting, 2014, Taipei, Taiwan, 2014Conference paper (Other academic)
  • 19.
    Norrby, Marlene
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Tågerud, Sven
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mitogen-activated protein kinase-activated protein kinase 2 (MK2) in skeletal muscle atrophy and hypertrophy2010In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 223, no 1, p. 194-201Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle is a highly plastic tissue. Overall muscle growth (hypertrophy) or muscle wasting (atrophy) results from alterations in intracellular signaling pathways with important regulatory steps occurring in the nucleus as well as in the cytoplasm. Previous studies have identified components of the Akt/mTor pathway as well as the p38 MAPK pathway as important for skeletal muscle hypertrophy and/or atrophy. The present study tests the hypothesis that MK2, a substrate of p38 which following phosphorylation, can be exported from the nucleus in a complex with p38, may be important for skeletal muscle growth. The expression of MK2 was examined in denervated mouse hind-limb (atrophic) and hemidiaphragm (transiently hypertrophic) muscles. MK2 mRNA expression decreased after denervation in both atrophic (48% of innervated controls, P < 0.001) and hypertrophic muscle (34% of innervated controls, P < 0.01) but MK2 protein expression decreased only in atrophic muscle (32% of innervated controls, P < 0.01). The level of T205 phosphorylated MK2 increased after denervation in both atrophic (fourfold increase, P < 0.01) and hypertrophic muscles (almost sevenfold increase, P < 0.001) whereas the level of T317 phosphorylated MK2 (necessary for nuclear export) increased after denervation in hypertrophic muscle (nearly threefold increase, P < 0.001) but not in atrophic muscle. Logarithmically transformed relative changes in MK2 phosphorylated at T317 correlated well (r2 = 0.7737) with relative changes in muscle weight. The results suggest a role for MK2 in the regulation of muscle mass, a role which, at least in part, may be related to determining the subcellular localization of p38 in muscle fibers. J. Cell. Physiol. 223: 194–201,

  • 20.
    Novotny, Ann
    et al.
    University of Gothenburg.
    Edsparr, Karin
    University of Gothenburg.
    Nylund, Gunnar
    Södra Älvsborg's Hospital.
    Khorram-Manesh, Amir
    University of Gothenburg.
    Albertsson, Per
    University of Gothenburg.
    Nordgren, Svante
    University of Gothenburg.
    Delbro, Dick S
    University of Gothenburg ; Karlstad University.
    A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator, and plasminogen activator inhibitor-1 secretion in the human colon cancer cell line, HT-292010In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 646, no 1-3, p. 22-30Article in journal (Refereed)
    Abstract [en]

    Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the α7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24 h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10 nM. This effect was markedly inhibited by α-Bungarotoxin, thus showing the involvement of α7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer.

  • 21.
    Persson, Katarina
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Alm, P
    Johansson, K
    Larsson, B
    Andersson, K-E
    The L-arginine/nitric oxide pathway in pig lower urinary tract: nitric oxide synthase immuno-histochemistry, NADPH-diaphorase activity and functional effects1994In: The biology of nitric oxide: 3, physiological and clinical aspects, Portland Press, 1994, p. 413-417Conference paper (Other academic)
  • 22.
    Persson, Katarina
    et al.
    Department of Clinical Pharmacology, University Hospital of Lund .
    Andersson, K-E
    Nitric oxide and relaxation of pig lower urinary tract1992In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 106, no 2, p. 416-422Article in journal (Refereed)
    Abstract [en]

    1 We studied the non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation induced by electrical stimulation in pig isolated lower urinary tract smooth muscle, and the possible involvement of the L-arginine (L-ARG)/nitric oxide (NO) pathway in this response. 2 Trigonal strips, precontracted by noradrenaline (NA), carbachol or endothelin-1 (ET-1), relaxed frequency-dependently in response to electrical stimulation. Maximum relaxation was obtained at 6-8 Hz, and amounted to 56 +/- 2%, 77 +/- 3% and 62 +/- 6% of the agonist-induced tension in preparations contracted by NA, carbachol, or ET-1, respectively. Exposure to N(G)-nitro-L-arginine (L-NOARG; 10(-7) - 10(-5) M) concentration-dependently reduced the relaxant response in preparations contracted by NA. L-NOARG (10(-6) M) reduced the maximal response to 51 +/- 8% of control. L-NOARG (10(-5) M) abolished all relaxation, and unmasked a contractile component; D-NOARG had no effect. Also in trigonal preparations. where the tension had been raised by carbachol or ET-1, L-NOARG (10(-5) M) markedly reduced relaxations evoked by electrical stimulation. 3 In trigonal preparations contracted by NA, maximal relaxation was increased after pretreatment with L-ARG (10(-3) M), and the inhibitory effect of L-NOARG (10(-6) M) was prevented. Incubation of the trigonal strips with methylene blue had no effect on relaxations elicited at frequencies <6Hz, but a small inhibition was observed at higher frequencies. 4 Administration of NO (present in acidified solution of NaNO2) induced concentration-dependent relaxations in trigonal preparations contracted by NA, carbachol, or ET-1. L-NOARG (10(-5) M) and L-ARG (10(-3) M) had no effect on these relaxations. However, methylene blue (10(-5) M) significantly shifted the concentration-response curve for NO to the right. NANC-relaxation and NO-induced relaxation of trigonal preparations were both inhibited by oxyhaemoglobin (10(-5) M) and pyrogallol (10(-4) M). 5 In urethral preparations precontracted by NA, electrical stimulation caused frequency-dependent relaxations. A maximum relaxation of 73 +/- 4% was obtained at 10 Hz. Also in the urethra, NANC-relaxation was blocked by L-NOARG (10(-5) M), and a contractile response generally appeared. 6 Detrusor strips treated with alpha-beta-methylene ATP (10(-5) M) and atropine (10(-6) M), and then contracted by ET-1, showed relaxations (19 +/- 3% of the induced tension) in response to electrical field stimulation (2-20 Hz) only when the tension was high. No response at all, or small contractions, were found in response to electrical stimulation in K+ (35 mM)-contracted detrusor strips. Detrusor preparations contracted by carbachol were concentration-dependently relaxed by exogenously administered NO, SIN-1 (NO-donor), and isoprenaline, whereas vasoactive intestinal polypeptide had minor effects. NO and SIN-1 induced maximal relaxations of 63 +/- 3% and 70 +/- 4%, respectively, of the tension induced by carbachol. Isoprenaline produced an almost complete relaxation (96 +/- 4%). 7 The results suggest that NANC-nerve mediated relaxation, involving the L-ARG/NO pathway, can be demonstrated consistently in the pig trigonal and urethral, but not in detrusor smooth muscle. The importance of this pathway for lower urinary tract physiology and pathophysiology remains to be established. 

  • 23.
    Persson, Katarina
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Garcia-Pascual, A
    Andersson, K-E
    Difference in the actions of calcitonin gene-related peptide on pig detrusor and vesical arterial smooth muscle1991In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 143, no 1, p. 45-53Article in journal (Refereed)
    Abstract [en]

    Calcitonin gene-related peptide has been demonstrated in urinary bladder nerves, and suggested to play a role in local control of bladder motility. In isolated strips of pig detrusor muscle, calcitonin gene-related peptide did not affect spontaneous contractile activity, or contractions induced by high K+, carbachol, substance P, and electrical field stimulation. In contrast, calcitonin gene-related peptide elicited a concentration-dependent and pronounced (78–99%) relaxation of vesical arteries precontracted with endothelin-1, noradrenaline or prostaglandin F2x. As a vasodilator, CGRP was approximately 50 times more potent than acetylcholine. Removal of the endothelium abolished acetylcholine-induced relaxation, but did not affect the relaxation produced by calcitonin gene-related peptide. Pretreatment with methylene blue, glibenclamide or indomethacin had no influence on CGRP's ability to relax the vessels. The inhibitor of NO-synthesis, NG-nitro-L-arginine, had no effect on the maximum vascular relaxation induced by calcitonin gene-relate peptide.

    It is concluded that in the pig, calcitonin gene-related peptide has no functionally important mechanical effects on isolated detrusor muscle strips, but is a potent dilator of vesical arteries. The vascular effects of the peptide are endothelium-independent, and seem to be exerted directly on the vascular smooth muscle. 

  • 24.
    Persson, Katarina
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Garcia-Pascual, A
    Forman, A
    Tottrup, A
    Andersson, K-E
    Nitric oxide and non-adrenergic, non-cholinergic nerve-mediated relaxation of isolated rabbit and pig urethral and trigonal smooth muscle1992Other (Other academic)
  • 25.
    Persson, Katarina
    et al.
    Department of Clinical Pharmacology, University Hospital of Lund .
    Igawa, Y
    Mattiasson, A
    Andersson, K-E
    Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro1992In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 107, p. 178-184Article in journal (Refereed)
    Abstract [en]

    1 The present study was performed to investigate how blockade of the L-arginine/nitric oxide (NO)pathway influences the function of the lower urinary tract in vivo, as studied by cystometry in consciousrats and in vitro, in isolated muscle preparations from the rat detrusor and urethra.2 L-N0-nitro arginine methyl ester (L-NAME), 10 and 20 mg kg-, administered intra-arterially,decreased micturition volume and bladder capacity, and increased spontaneous bladder contractions.D-NAME (20mgkg-') had no effect. No changes in the urodynamic parameters were recorded ifL-NAME (20mgkg-') was administered in combination with L-arginine (200mgkg-').3 Cystometries performed after intra-arterial administration of sodium nitroprusside (SNP) (3mgkg-') and 3-morpholino-sydnonimin hydrochloride (SIN-1, 2mgkg-') showed a decrease in bladdercapacity, micturition volume and threshold pressure. SIN-1, but not SNP, induced spontaneous bladdercontractions.4 Isolated precontracted urethral preparations responded to electrical stimulation with a frequencydependenttetrodotoxin-sensitive relaxation. L-NAME (10-4 M), but not D-NAME, reduced the maximalrelaxation to 31 ± 8% (n = 8) of the response prior to drug administration. The inhibition induced byL-NAME was completely reversed by L-arginine (10-3 M). SNP (10-1 10-4 M), SIN-1 (10-6-3 x l0-4M) and NO (10-5-10-3M; present in acidified solution of NaNO2), caused relaxation (93-100%) ofurethral preparations. L-NAME did not affect these relaxations.5 Detrusor strips contracted by carbachol or K' showed contractions in response to electricalstimulation, even when pretreated with a,p-methylene ATP and/or atropine. Small relaxations (14-41%)of detrusor strips were evoked by SNP (10-6-10-4M), SIN-1 (10-5-3 x 10-4M) and NO (10-5-10-3M). Electrically (20 Hz) induced contractions of the detrusor muscle were unaffected by addition ofL-NAME (10-6_10-4 M) or L-arginine (10-3 M).6 The present results suggest that the L-arginine/NO pathway is of functional importance for thebladder outlet region, but that its role in the detrusor is questionable. They also suggest that the site ofaction of L-NAME for inducing bladder hyperactivity in the rat is the outlet region rather than thedetrusor muscle. 

  • 26. Sellin, L C
    et al.
    Libelius, Rolf
    Lundquist, I
    Tågerud, Sven
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Thesleff, S
    Membrane and biochemical alterations after denervation and during reinnervation of mouse skeletal muscle1980In: Acta Physiologica Scandinavica, Vol. 110, no 2, p. 181-186Article in journal (Refereed)
    Abstract [en]

    Denervation of the extensor digitorum longus (EDL) muscle of the mouse by either nerve crush or nerve section produced: a reduction of the resting membrane potential (Em), alterations in the properties of muscle fibre action potentials and the development of tetrodotoxin (TTX)-resistant action potentials. These changes in membrane electrical properties were accompanied by an increase in the endocytic activity of the muscle and an increase in the activities of the lysosomal enzymes cathepsin D and N-acetylglucosaminidase (NAGA). Reinnervation of muscle was indicated at 9 days after nerve crush by the presence of miniature end-plate potentials. The recovery of membrane electrical properties, beginning with the onset of reinnervation, were not temporally related. The Em increased in two stages: an early rapid repolarization and a later slower repolarization. The muscle fibers were sensitive to the blocking action of TTX by 12 days after nerve crush, whereas the rate of rise (dV/dt) of the action potential did not approach values of innervated muscles until 21 days. Reinnervation resulted in a decrease in endocytosis and a decrease in the activities of cathepsin D and NAGA toward innervated values by 21 days after nerve crush. The results suggest that membrane alterations after denervation and during reinnervation may occur by endo- and exocytosis of membrane constituents and that the lysosomal system may play a role in the breakdown and/or recycling of these structures. 

  • 27.
    Snyder, Gretchen L.
    et al.
    Intra-Cellular Therapies Inc, USA.
    Prickaerts, Jos
    Maastricht University, The Netherlands.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Zhang, Lei
    Intra-Cellular Therapies Inc, USA.
    Zheng, Hailin
    Intra-Cellular Therapies Inc, USA.
    Yao, Wei
    Intra-Cellular Therapies Inc, USA.
    Akkerman, Sven
    Maastricht University, The Netherlands.
    Zhu, Hongwen
    Tianjin Hospital, China.
    Hendrick, Joseph P.
    Intra-Cellular Therapies Inc, USA.
    Vanover, Kimberly E.
    Intra-Cellular Therapies Inc, USA.
    Davis, Robert
    Intra-Cellular Therapies Inc, USA.
    Li, Peng
    Intra-Cellular Therapies Inc, USA.
    Mates, Sharon
    Intra-Cellular Therapies Inc, USA.
    Wennogle, Lawrence P.
    Intra-Cellular Therapies Inc, USA.
    Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 17, p. 3113-3124Article in journal (Refereed)
    Abstract [en]

    Rationale: Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed.

    Objective: The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1).

    Methods: ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1–10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments.

    Results: ITI-214 inhibited PDE1A (Ki = 33 pmol) with &gt;1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR.

    Conclusions: ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1–10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.

  • 28. Steers, W D
    et al.
    Persson, Katarina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Neurophysiology of bladder and urethral function1998In: Textbook of genitourinary surgery / [ed] Whitfield, Hugh N., Oxford, England: Blackwell Publishing, 1998, p. 891-905Chapter in book (Other academic)
  • 29.
    Svensson, Anna
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Norrby, Marlene
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Libelius, Rolf
    Tågerud, Sven
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle.2008In: Journal of Molecular Histology, ISSN 1567-2379, E-ISSN 1567-2387, Vol. 39, no 3, p. 329-337Article in journal (Refereed)
    Abstract [en]

    Wnts are secreted proteins with functions in differentiation, development and cell proliferation. Wnt signaling has also been implicated in neuromuscular junction formation and may function in synaptic plasticity in the adult as well. Secreted frizzled-related proteins (Sfrps) such as Sfrp1 can function as inhibitors of Wnt signaling. In the present study a potential role of Wnt signaling in denervation was examined by comparing the expression levels of Sfrp1 and key proteins in the canonical Wnt pathway, Dishevelled, glycogen synthase kinase 3 beta and beta-catenin, in innervated and denervated rodent skeletal muscle. Sfrp1 mRNA and immunoreactivity were found to be up-regulated in mouse hemidiaphragm muscle following denervation. Immunoreactivity, detected by Western blots, and mRNA, detected by Northern blots, were both expressed in extrasynaptic as well as perisynaptic parts of the denervated muscle. Immunoreactivity on tissue sections was, however, found to be concentrated postsynaptically at neuromuscular junctions. Using beta-catenin levels as a readout for canonical Wnt signaling no evidence for decreased canonical Wnt signaling was obtained in denervated muscle. A role for Sfrp1 in denervated muscle, other than interfering with canonical Wnt signaling, is discussed.

  • 30.
    Svensson, Anna
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Tågerud, Sven
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Galectin-1 expression in innervated and denervated skeletal muscle2009In: Cellular & Molecular Biology Letters (Druk), ISSN 1425-8153, E-ISSN 1689-1392, Vol. 14, no 1, p. 128-138Article in journal (Refereed)
    Abstract [en]

    Galectin-1 is a soluble carbohydrate-binding protein with a particularly high expression in skeletal muscle. Galectin-1 has been implicated in skeletal muscle development and in adult muscle regeneration, but also in the degeneration of neuronal processes and/or in peripheral nerve regeneration. Exogenously supplied oxidized galectin-1, which lacks carbohydrate-binding properties, has been shown to promote neurite outgrowth after sciatic nerve sectioning. In this study, we compared the expression of galectin-1 mRNA and immunoreactivity in innervated and denervated mouse and rat hind-limb and hemidiaphragm muscles. The results show that galectin-1 mRNA expression and immunoreactivity are up-regulated following denervation. The galectin-1 mRNA is expressed in the extrasynaptic and perisynaptic regions of the muscle, and its immunoreactivity can be detected in both regions by Western blot analysis. The results are compatible with a role for galectin-1 in facilitating reinnervation of denervated skeletal muscle.

  • 31. Svensson, Torgny
    et al.
    Mathe, Jan
    Nomikos, George
    Marcus, Monica
    Hygge-Blakeman, Karin
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Brain dopaminergic dysfunction in psychotic behaviour: stabilization by 5-HT2A and a1-receptor antagonistic drugs1999In: Interactive Monoaminergic Disorders / [ed] T Palomo, R Beninger & T Archer, Spain: Foundacion Cerebro Y Mente , 1999Chapter in book (Other academic)
  • 32. Thesleff, S
    et al.
    Sellin, L C
    Tågerud, Sven
    Department of Pharmacology, University of Lund .
    Tetrahydroaminoacridine (tacrine) stimulates neurosecretion at mammalian motor endplates1990In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 100, no 3, p. 487-490Article in journal (Refereed)
    Abstract [en]

    1. Tacrine (20 microM) induced, like 4-aminoquinoline (4-AQ, 200 microM), the appearance of a population of miniature endplate potentials (m.e.p.ps) with more than twice the normal amplitude or time-to-peak. The times-to-peak of nerve impulse-evoked endplate potentials were not similarly affected. 2. Cholinesterase inhibition by edrophonium (25 microM) did not prevent tacrine or 4-AQ from inducing this population of m.e.p.ps. 3. Nerve-muscle preparations in which the normal calcium-sensitive quantal release of acetylcholine had been blocked by botulinum neurotoxin type A also responded to tacrine by an increase in the frequency of giant or slow m.e.p.ps. 4. Reduction of the temperature from 30 degrees to 14 degrees C reduced the frequency of giant or slow m.e.p.ps induced either by tacrine or by 4-AQ. A similar effect was obtained by colchicine (5 mM). This supports the idea that proximo-distal axonal transport is required for the secretory activity. 5. The neurosecretion evoked by tacrine could explain the therapeutic effects of the drug claimed in the treatment of Alzheimer's type of dementia. 

  • 33.
    Tågerud, Sven
    et al.
    MRC Neurochemical Pharmacology Unit, Department of Pharmacology, Medical School, Hills Road, Cambridge, U.K..
    Cuello, A C
    Dopamine release from the rat substantia nigra in vitro. Effect of raphe lesions and veratridine stimulation1979In: Neuroscience, Vol. 4, no 12, p. 2021-2029Article in journal (Refereed)
    Abstract [en]

    In order to eliminate the 5-hydroxytryptaminergic input to the substantia nigra lesions were placed in the dorsal and medial raphe nuclei in a number of rats. The release of exogenously applied [3H]dopamine from the partially denervated substantia nigra was determined in vitro and found to be very similar to the release observed from slices of control substantia nigra. These results lend further support to the theory that the release of exogenously applied [3H]dopamine at the level of the substantia nigra occurs mainly from dopaminergic dendrites, rather than from terminals of 5-hydroxytryptamine-containing neurons.

    A veratridine-induced release of [3H]dopamine from the pars reticulata of the substantia nigra is also described. An almost complete blockade of veratridine (3.0 μM) stimulation was observed with 100 nM tetrodotoxin. Similar effects of veratridine and tetrodotoxin were also observed on [3H]dopamine release from slices of corpus striatum. These results suggest that dendrites of the dopaminergic neurones in the substantia nigra contain fast, tetrodotoxin-sensitive sodium channels.

  • 34.
    Tågerud, Sven
    et al.
    Department of Pharmacology, University of Lund, Lund Sweden.
    Jirmanovà, I
    Libelius, Rolf
    Biochemical and ultrastructural effects of chloroquine on horseradish peroxidase uptake and lysosomal enzyme activities in innervated and denervated mouse skeletal muscle1986In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 75, no 2, p. 159-171Article in journal (Refereed)
    Abstract [en]

    The effects of chloroquine treatment on horseradish peroxidase (HRP) uptake and lysosomal enzyme activities in innervated and denervated mouse skeletal muscle have been studied using biochemical, histochemical and ultrastructural techniques.Chloroquine treatment caused a large (59–101%) increase in the activity of cathepsin D in both innervated and denervated muscle. The activity of N-acetyl-β-d-glucosaminidase also increased slightly in denervated muscle. No effect was observed on acid phosphatase activity. The in vivo uptake of HRP in innervated and denervated muscle was unaffected by chloroquine treatment. The results show that the activities of certain lysosomal enzymes may increase in skeletal muscle without an increase in endocytic activity. This is discussed in comparison to what is seen in denervated and dystrophic muscle.Histochemical and ultrastructural studies showed the HRP uptake to occur segmentally in denervated muscle fibres from untreated as well as chloroquine-treated animals. Ultrastructurally the peroxidase-positive phagosomes occurring in these segments were found to contain increased levels of undegraded material after chloroquine treatment suggesting that these phagosomes are of a lysosomal nature and also participate in autophagic processes. 

  • 35.
    Tågerud, Sven
    et al.
    UNIV LUND, DEPT PHARMACOL, S-22362 LUND, SWEDEN .
    Libelius, Rolf
    Lysosomes in skeletal muscle following denervation. Time course of horseradish peroxidase uptake and increase of lysosomal enzymes1984In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 236, no 1, p. 73-79Article in journal (Refereed)
    Abstract [en]

    The in-vivo uptake of exogenously applied horseradishperoxidase and the activities of the lysosomal enzymesacid phosphatase and cathepsin D were studied histochemicallyand/or biochemically in innervated and2-14 day-denervated tibialis anterior muscles of the mouse.The biochemically determined uptake of horseradish peroxidaseshowed a large increase already 4 days after denervation.The activities of the lysosomal enzymes increased ina more gradual fashion, and only cathepsin D showed anincrease in activity when expressed as total activity per muscle.Histochemically horseradish peroxidase was found tobe localized in muscle fibres in characteristic spindle-shapedsegments after denervation. The main increase in thenumber of such segments per transverse section of the muscleoccurred between 3 and 6 days after denervation. Inserial sections these segments frequently showed positivestaining also for acid phosphatase.It is concluded that exogenously applied horseradishperoxidase is taken up into the lysosomal system, whichafter denervation becomes organized into characteristicspindle-shaped segments in the muscle fibres. The endocyticactivity of muscle fibres increases early after denervation.This is followed by a more gradual increase in activity oflysosomal enzymes and finally by an organization of thelysosomal system into characteristic spindle-shaped segments.The results are compatible with the working hypothesisthat increased endocytosis may initiate lysosomal activationin denervated skeletal muscle. 

  • 36.
    Tågerud, Sven
    et al.
    Department of Pharmacology, University of Lund, S-223 62, Lund, Sweden.
    Libelius, Rolf
    Receptor-mediated uptake of horseradish peroxidase in innervated and denervated skeletal muscle1985In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 160, no 1, p. 95-105Article in journal (Refereed)
    Abstract [en]

    The in vitro uptake of [3H]inulin and horseradish peroxidase (HRP) has been studied in innervated and 6 days denervated extensor digitorum longus muscle of the mouse. Both markers were taken up at a higher rate in denervated muscle. The increase in uptake after denervation was, however, larger for HRP than for [3H]inulin. After 2 h incubation at 37 °C, pH 7.3, in the presence of equimolar concentrations of HRP and [3H]inulin (approx. 2.1 μM), the uptake of HRP was approx. 8 times as great as the uptake of [3H]inulin in the same innervated muscles. In denervated muscle the HRP uptake was approx. 19 times as great as the [3H]inulin uptake in the same muscles. Various possible explanations of these differences in uptake have been considered and tested experimentally. [3H]Inulin uptake in skeletal muscle has previously been shown to obey bulk kinetics. The present investigation shows the HRP uptake to obey saturation kinetics. The HRP uptake shows dependency on divalent cations and is reduced if incubation is carried out at pH 6.4. The uptake of HRP, when used at a low, non-saturating concentration (10 μg/ml approx. 0.25 μM), is inhibited 60% by yeast mannan (0.1 mg/ml), ribonuclease B (0.1 mg/ml, approx. 7.4 μM), mannose (30 mM), monodansylcadaverine (1 mM), chloroquine (100 μM), trifluoperazine (25 μM) or maleic acid (2 mM). It is concluded that HRP is taken up in innervated and denervated skeletal muscle by a process of receptor-mediated endocytosis and that this uptake is under neurotrophic control. 

  • 37.
    Tågerud, Sven
    et al.
    Department of Pharmacology, University of Lund.
    Libelius, Rolf
    Shainberg, A
    High endocytotic and lysosomal activities in segments of rat myotubes differentiated in vitro1990In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 259, p. 225-232Article in journal (Refereed)
    Abstract [en]

    Endocytosis and the lysosome system have beenstudied in rat myotubes differentiated in vitro. Horseradishperoxidase was used as marker for endocytosis and wasfound to accumulate unevenly in the myotubes. Small segmentsof myotubes display very high endocytotic activity.Similar segments contained numerous lysosomes, as seenby the accumulation of neutral red or histochemical stainingfor acid phosphatase. The segments also contained accumulationsof acetylcholine receptors as determined by bindingof tetramethyl rhodamine-labelled c~-bungarotoxin. Unstainedsegments in living cultures could be recognized byphase-contrast microscopy since they often appeared somewhatdilated and were not as well spread on the culturesurface as the main parts of the myotubes. Ultrastructurally,the segments contained an intensely proliferating tubularsystem in communication with the extracellular space,which therefore probably represents the developing transversetubular system. The segments also contained endocytosedmarker within large phagosomes. Contractile filamentsoccurred in the segments but were frequently lesswell-organized than in other parts of the myotubes. Thedescribed characteristics of the segments in rat myotubesdifferentiated in vitro bear resemblance to some of the characteristicsof the denervated endplate region of adult muscle. 

  • 38.
    Tågerud, Sven
    et al.
    Department of Pharmacology, University of Lund, Lund Sweden.
    Libelius, Rolf
    Thesleff, S
    An ultrastructural study of the segmental uptake of horseradish peroxidase in the endplate region of denervated skeletal muscle fibres1986In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 75, no 2, p. 141-157Article in journal (Refereed)
    Abstract [en]

    The segmental uptake of horseradish peroxidase (HRP) in the endplate region of denervated skeletal muscle fibres has been studied ultrastructurally using a method for selecting single muscle fibres with high segmental peroxidase staining from denervated mouse tibialis anterior muscle.Segments containing large peroxidase positive phagosomes could already be seen 10–15 min after i.v. injection of HRP. Such segments were still present 24 h after HRP injection. The localization of phagosomes, deep in the fibres rather than immediately under the sarcolemma, suggests that the uptake occurs from t-tubuli. Vivid proliferation of t-tubuli, consisting of vesiculation, enlargement and encircling of cytoplasmic components, was also observed. The HRP accumulates in phagosomes of varying size and shape. Similar membrane-limited bodies without or with very weak peroxidase staining were also observed. The peroxidase-positive phagosomes participate in autophagic processes as suggested by their content of undegraded cellular material. Golgi profiles, which occurred deep in the muscle fibres, and enlarged components of the sarcoplasmic reticulum were frequently encountered in the segments. Myofibrillar degeneration occurs in the segments and progresses with time after denervation.The described segments may be related to the increased membrane turnover in denervated muscle fibres and/or they may be related to processes aimed at establishing new synaptic contacts. 

  • 39.
    Tågerud, Sven
    et al.
    1Department of Pharmacology, University of Lund, Lund Sweden.
    Libelius, Rolf
    Thesleff, S
    Effects of botulinum toxin induced muscle paralysis on endocytosis and lysosomal enzyme activities in mouse skeletal muscle1986In: Pflügers Archive European Journal of Physiology, ISSN 0031-6768, Vol. 407, no 3, p. 275-278Article in journal (Refereed)
    Abstract [en]

    The effects of botulinum toxin (type A) induced muscle paralysis on endocytosis and lysosomal enzyme activities in skeletal muscle were compared with the effects of surgical denervation. Muscle atrophy, measured as decrease in total muscle protein content, was as large or larger after botulinum toxin treatment as after denervation. Endocytic activity, measured as the in vitro uptake of horseradish peroxidase, and the specific activities of the lysosomal enzymes N-acetyl--d-glucosaminidase and cathepsin D were all increased six days after denervation. Only the specific activity of cathepsin D was increased six days after botulinum toxin poisoning. The uptake of horseradish peroxidase and the specific activity of N-acetyl--d-glucosamidase were also increased eleven days after poisoning. Transverse sections of eleven days botulinum poisoned muscles from animals injected with horseradish peroxidase showed fibres with dense peroxidase staining similar to those seen in denervated muscle although they seemed to occur less frequently.The results show that increases in endocytic activity and lysosomal enzyme activities may occur in skeletal muscle without the presence of degenerating axons. The differences in effects of surgical denervation and botulinum toxin induced paralysis are discussed in terms of what is known about the mechanism of action of botulinum toxin and the possible functional roles of the two lysosomal enzymes studied. 

  • 40.
    Tågerud, Sven
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Magnusson, Caroline
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Norrby, Marlene
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Libelius, Rolf
    The nifk gene is widely expressed in mouse tissues and is up-regulated in denervated hind limb muscle2003In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 27, no 6, p. 469-475Article in journal (Refereed)
    Abstract [en]

    Denervation of skeletal muscle alters the expression of many genes, which may be important for establishing optimal conditions for reinnervation. Using the differential display technique we have attempted to discover neurally regulated genes in skeletal muscle. An mRNA that is up-regulated in denervated hind limb muscle was identified and cloned. The cDNA encodes an RNA-binding protein, which was discovered during the course of this work to be a nucleolar protein interacting with the fork-head associated domain of the proliferation marker protein Ki-67, and named NIFK. We show that the nifk gene is widely expressed in adult mouse tissues and that the expression is up-regulated in denervated hind limb muscle. No difference between expression in perisynaptic and extrasynaptic portions of muscle was observed. The widespread expression in adult tissues suggests that the NIFK protein has other functions in addition to its interaction with Ki-67, which is only expressed in proliferating cells.

  • 41.
    Vumma, Ravi
    et al.
    Örebro University.
    Bang, Charlotte Sahlberg
    Örebro University.
    Kruse, Robert
    Örebro University.
    Johansson, Kjell
    Örebro University.
    Persson, Katarina
    Örebro University.
    Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization: a comparison with nitrofurantoin2016In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 69, no 3, p. 183-186Article in journal (Refereed)
    Abstract [en]

    Uropathogenic Escherichia coli (UPEC) is the predominant causative organism of urinary tract infections (UTI) with a high recurrence rate.1 Recurrence of UTI may involve intracellular localization of bacterial colonies within the bladder mucosa, a process that could benefit the bacteria in terms of protection against antibiotics and host immune cells.2, 3 Once internalized, UPEC may multiply and form intracellular bacterial communities with biofilm-like properties4 and/or enter a non-replicating stable and quiescent state that may serve as a source for recurrent UTI.2, 5, 6 A wide range of antimicrobial agents is used for the treatment of UTI but many antibiotics are unable to penetrate biofilm matrix or inhibit bacteria in a metabolically quiescent state. A recent study demonstrated that of seven different functional classes of antibiotics only a few, including nitrofurantoin and some fluoroquinolones, were able to eliminate internalized UPEC within bladder epithelial cells. Nitric oxide (NO) is a small hydrophobic molecule with antibacterial properties that readily diffuses through lipid bilayer membranes. During infection various host cells produce NO enzymatically from inducible nitric oxide synthase and NO has a key role in the innate immune response. It has been shown previously that NO has antibacterial activity against UPEC isolates, including multidrug-resistant extended spectrum beta-lactamase-producing isolates. Although NO can interact directly with bacteria, it can also be oxidized to reactive nitrogen species.

  • 42.
    Wadenberg, Marie-Louise
    Karolinska Inst, Sect Neuropsychopharmacol, Stockholm, Sweden.
    A Review of the Properties of Spiradoline: A Potent and Selective Kappa-Opioid Receptor Agonist.2003In: CNS Drug Reviews, Vol. 9, no 2, p. 187-198Article, review/survey (Other academic)
  • 43.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Active Avoidance2010In: Encyclopedia of Psychopharmacology: Part 1 / [ed] Ian P Stolerman, Heidelberg: Springer, 2010, p. 15-19Chapter in book (Other academic)
  • 44.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bifeprunox: a novel antipsychotic agent with partial agonist properties at dopamine D2 and serotonin 5-HT1A receptors2007In: Future Neurology, ISSN 1479-6708, Vol. 2, no 2, p. 153-165Article in journal (Refereed)
  • 45.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Conditioned avoidance response in the development of new antipsychotics.2010In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 16, no 3, p. 358-370Article, review/survey (Refereed)
    Abstract [en]

    Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.

  • 46.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Current Pro-Cognitive Therapeutic Strategies for Improved Pharmacological Treatment in Schizophrenia2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 31, p. 5045-5045Article in journal (Other academic)
    Abstract [en]

    Cognitive impairment influencing memory, attentional focus and executive functions in schizophrenia have a significant impact on social functioning and quality of life. Cognitive functions depend on normal functioning of brain prefrontal cortex. Attempts to explain cognitive impairment in schizophrenia include hypotheses (based on among others post-mortem, genetic and imaging data) of dysfunctions involving dopamine, glutamate, GABA as well as acetylcholine neural transmission. Current antipsychotic drugs are not sufficiently effective against cognitive symptoms. Thus, while pharmacological treatment strategies earlier primarily focused on managing psychotic (so called positive) symptoms, current pharmacological strategies aim at identifying compounds with pro-cognitive properties, suitable for treatment of cognitive symptoms as manifested in schizophrenia. To this end, scientists are primarily working along two lines: i) developing animal models/tests in rodents with relevance either to cognitive symptoms as presented in schizophrenia and/or to brain abnormalities in schizophrenia believed to be causing these symptoms; ii) identifying pro-cognitive compounds with pharmacological properties acting on brain neurotransmitter functions believed to be involved in cognitive dysfunction in schizophrenia. The present special issue on ‘Current pro-cognitive therapeutic strategies for improved pharmacological treatment in schizophrenia’ includes presentation and discussion of the use of the attentional set-shifting test as a relevant model for attentional/executive functioning in schizophrenia as well as for the identification of pro-cognitive compounds with relevance to schizophrenia treatment Tait et al. [1] and Goetghebeur and Dias [2], presentation of the neurodevelopmental prenatal methylazoxymethanol acetate (MAM) model of schizophrenia by Gill and Grace [3], and discussion of the novel object recognition (NOR) task for memory functions by Rajagopal et al. [6]. In addition, putative procognitive treatment strategies for schizophrenia treatment such as the use of GABAA receptor agonists [3], the use of compounds acting at nicotinic acetylcholine receptors from a clinical perspective Boggs et al. [4], as well as the therapeutic significance of compounds (phosphodiesterase, PDE, inhibitors) influencing intracellular signaling Snyder and Vanover [5] are presented and discussed. Finally, data on the effects of atypical antipsychotics, as well as 5-HT1A partial agonists, 5-HT7 antagonists, and D1 agonists in the NOR test are reviewed by Rajagopal et al. [6]. The contributors are all distinguished scientists, and issues discussed in the articles are timely and of great importance for the advancement of effective schizophrenia treatment strategies. Therefore, this special issue will hopefully be well received and appreciated in the scientific community dealing with these issues.

  • 47.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Drug Evaluation: Iloperidone1998In: Curr Res in Serotonin, Vol. 3, p. 66-69Article, review/survey (Other academic)
  • 48.
    Wadenberg, Marie-Louise
    UNIV STOCKHOLM, DEPT PSYCHOL, S-10691 STOCKHOLM, SWEDEN.
    Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat.1996In: Neurosci and Biobehav Reviews, Vol. 20, p. 325-339Article, review/survey (Other academic)
    Abstract [en]

    The present paper reviews a series of experiments aimed at elucidating the interaction between specific dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors in the mediation of extrapyramidal motor functions in the rat. There is strong evidence to suggest that (1) the catalepsy produced by dopamine D-1 or D-2 receptor antagonists can be completely antagonized by the administration of 5-HT1A receptor agonists acting at 5-HT autoreceptors in the median raphe nucleus; (2) the catalepsy produced by a dopamine D-2 receptor antagonist can be completely antagonized by treatment with a 5-HT2A/C receptor agonist; and (3) the catalepsy produced by blockade of either dopamine D-1 or D-2 receptors is not affected by the administration of a 5-HT2A/C receptor antagonist. The emerging picture of DA/5-HT receptor interactions in the mediation of extrapyramidal motor functions is of great interest in relation to present efforts to develop new atypical neuroleptics with affinity for brain 5-HT receptor subtypes, and also for the observations that new serotonin selective re-uptake inhibiting antidepressants can produce parkinson-like symptoms in vulnerable individuals.

  • 49.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm .
    Ahlenius, Sven
    Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: Enhancement of antipsychotic-like effects without catalepsy.1991In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 83, p. 43-53Article in journal (Refereed)
    Abstract [en]

    The administration of the 5-HT1A agonist 8-OH-DPAT,0.1 mg kg- 1 sc - - 20 min, produced a moderate suppression of conditionedavoidance behavior (60% of controls) in the rat. This effect, however, was notseen after administration of higher doses, 0.4 and 1.6 mg kg- 1 sc. The numberof intertrial crosses were not affected by the lower dose but significantly increasedby administration of the two higher doses of 8-OH-DPAT. The dopamineD 2 receptor blocking agent raclopride, 0.05 mgkg-t, by itself did notsuppress the avoidance behavior, but in combination with 8-OH-DPAT producedsuppression of avoidance behavior (30% of controls) as well as intertrialcrosses. Open field locomotor activity was suppressed by raclopride,0.1 mg kg- 1 sc, or by 8-OH-DPAT, 0.1 mg kg- 1 sc. The combined treatmentproduced a further suppression of locomotor activity and a marked increasein "immobility" (stationary movements). Treadmill locomotion, however, wasnot affected by either compound by itself, whereas the combined treatmentimpaired treadmill performance. Suppression of treadmill performance by ahigher dose of raclopride, 0.4mgkg-~sc, was not altered by the additionaltreatment with 8-OH-DPAT, 0.1 mg kg- 1. In contrast to the additive effects of8-OH-DPAT and raclopride on conditioned avoidance behavior, open fieldlocomotion and treadmill performance, the catalepsy produced by raclopride,16mgkg -1 was completely antagonised by treatment with 8-OH-DPAT0.1 mg kg-1. Taken together, the present findings demonstrate strong interactionsbetween a 5-HT agonist and a DAD 2 antagonist on some critical testsfor antipsychotic-like actions and extrapyramidal motor effects in rats, andsuggest new possibilities in the search for new antipsychotic drugs with higherclinical efficacy and less extrapyramidal side effects. 

  • 50.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm .
    Ahlenius, Sven
    Effects of raclopride and haloperidol on spontaneous motor activity and on conditioned avoidance behavior in rats: A comparison of potency, efficacy and time-course of action.1991In: Arzneimittel-Forschung / Drug Res, ISSN 0004-4172, Vol. 41, no 7, p. 692-695Article in journal (Refereed)
    Abstract [en]

    The spontaneous locomotor activity of rats was used as an index of centrally mediated of raclopride (CAS 84225-95-6). The results indicate a duration of less than 2 h after s.c administration of 2 μmol kg-1. In support of a rapid first-pass metabolism in the rat, the effect was considerably weaker after i.p. administration. This difference was further supported by comparing the dose-effect curves after s.c. and i.p. raclopride administration. Halopéridol appears to be slightly more potent than raclopride 

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