IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

BACKGROUND: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents. PATIENTS AND METHODS: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0. RESULTS: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab. CONCLUSIONS: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses.

Pregabalin has demonstrated anti-hyperalgesic properties and was introduced into acute pain treatment in 2001. Our aim was to evaluate the beneficial and harmful effects of pregabalin in postoperative pain management. We included randomized clinical trials investigating perioperative pregabalin treatment in adult surgical patients. The review followed Cochrane methodology, including Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and used trial sequential analyses (TSAs). The primary outcomes were 24 h morphine i.v. consumption and the incidence of serious adverse events (SAEs) defined by International Conference of Harmonisation Good Clinical Practice guidelines. Conclusions were based primarily on trials with low risk of bias. Ninety-seven randomized clinical trials with 7201 patients were included. The 24 h morphine i.v. consumption was reported in 11 trials with overall low risk of bias, finding a reduction of 5.8 mg (3.2, 8.5; TSA adjusted confidence interval: 3.2, 8.5). Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias, Peto's odds ratio was 2.9 (1.2, 6.8; TSA adjusted confidence interval: 0.1, 97.1). Based on trials with low risk of bias, pregabalin may have a minimal opioid-sparing effect, but the risk of SAEs seems increased. However, the GRADE-rated evaluations showed only moderate to very low quality of evidence. Consequently, a routine use of pregabalin for postoperative pain treatment cannot be recommended.

Low degree of satisfactory individual pain relief in post-operative pain trials.

BACKGROUND: The majority of clinical trials regarding post-operative pain treatment focuses on the average analgesic efficacy, rather than on efficacy in individual patients. It has been argued, that in acute pain trials, the underlying distributions are often skewed, which makes the average unfit as the only way to measure efficacy. Consequently, dichotomised, individual responder analyses using a predefined 'favourable' response, e.g. Visual Analogue Scale (VAS) pain scores ≤ 30, have recently been suggested as a more clinical relevant outcome. METHODS: We re-analysed data from 16 randomised controlled trials of post-operative pain treatment and from meta-analyses of a systematic review regarding hip arthroplasty. The predefined success criterion was that at least 80% of patients in active treatment groups should obtain VAS < 30 at 6 and 24 h post-operatively. RESULTS: In the analysis of data from the randomised controlled trials, we found that at 6 h post-operatively, 50% (95% CI: 31-69) of patients allocated to active treatment reached the success criterion for pain at rest and 14% (95% CI: 5-34) for pain during mobilisation. At 24 h post-operatively, 60% (95% CI: 38-78) of patients allocated to active treatment reached the success criterion for pain at rest, and 15% (95% CI: 5-36) for pain during mobilisation. Similar results were found for trials from the meta-analyses. CONCLUSION: Our results indicate that for conventional, explanatory trials of post-operative pain, individual patient's achievement of a favourable response to analgesic treatment is rather low. Future pragmatic clinical trials should focus on both average pain levels and individual responder analyses in order to promote effective pain treatment at the individually patient level.

Gabapentin for post-operative pain management - a systematic review with meta-analyses and trial sequential analyses.

BACKGROUND: Perioperative pain treatment often consist of combinations of non-opioid and opioid analgesics, 'multimodal analgesia', in which gabapentin is currently used. The aim was to document beneficial and harmful effects of perioperative gabapentin treatment. METHODS: Randomized clinical trials comparing gabapentin vs. placebo or active placebo in adult surgical patients receiving gabapentin perioperatively were included. This review was conducted using Cochrane standards, trial sequential analysis (TSA), and Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The primary outcomes were 24-h opioid consumption and incidence of serious adverse events (SAE). RESULTS: One hundred and thirty-two trials with 9498 patients were included. Thirteen trials with low risk of bias reported a reduction in 24-h opioid consumption of 3.1 mg [0.5, 5.6] [corrected]. In the analysis of gabapentin as add-on analgesic to another non-opioid analgesic regimen found a mean reduction in 24-h morphine consumption of 1.2 mg [-0.3, 2.6; TSA-adjusted CI: -0.3, 2.6] in trials with low risk of bias. [corrected]. Nine trials with low risk of bias reported a risk ratio of SAEs of 1.61 [0.91; 2.86; TSA-adjusted CI: 0.57, 4.57]. CONCLUSION: Based on GRADE assessment of the primary outcomes in trials with low risk of bias, the results are low or very low quality of evidence due to imprecision, inconsistency, and in some outcomes indirectness. Firm evidence for use of gabapentin is lacking as clinically relevant beneficial effect of gabapentin may be absent and harm is imminent, especially when added to multimodal analgesia.

microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors.

Adeno-associated virus (AAV) vectors with capsids of AAV serotype 9 enable an efficient transduction of the heart upon intravenous injection of adult mice but also transduce the liver. The aim of this study was to improve specificity of AAV9 vector-mediated cardiac gene transfer by microRNA (miR)-dependent control of transgene expression. We constructed plasmids and AAV vectors containing target sites (TSs) of liver-specific miR122, miR192 and miR148a in the 3' untranslated region (3'UTR) of a luciferase expression cassette. Luciferase expression was efficiently suppressed in liver cell lines expressing high levels of the corresponding miRs, whereas luciferase expression was unaffected in cardiac myocytes. Intravenous injections of AAV9 vectors bearing three repeats of miR122 TS in the 3'UTR of an enhanced green fluorescent expression (EGFP) expression cassette resulted in the absence of EGFP expression in the liver of adult mice, whereas the control vectors without miR TS displayed significant hepatic EGFP expression. EGFP expression levels in the heart, however, were comparable between miR122-regulated and control vectors. The liver-specific de-targeting in vivo using miR122 was even more efficient than transcriptional targeting with a cardiac cytomegalovirus (CMV)-enhanced myosin light chain (MLC) promoter. These data indicate that miR-regulated targeting is a powerful new tool to further improve cardiospecificity of AAV9 vectors.

[The Obeldicks concept. An example for a successful outpatient lifestyle intervention for overweight or obese children and adolescents]. / Das Obeldicks-Konzept. Beispiel eines erfolgreichen ambulanten Therapieprogramms für Kinder und Jugendliche mit Übergewicht oder Adipositas.

The outpatient lifestyle interventions Obeldicks (for 8- to 16-year-old obese children; 1-year intervention), Obeldicks Light (for 8- to 16-year-old overweight children; 6-month intervention), and Obeldicks Mini (for 4- to 7-year-old obese children; 1-year intervention) are based on nutrition education, physical activity, behavior therapy, and individual psychological care. Only 17% dropped out of the intervention, and 79% of the more than 1,000 participants reduced their degree of overweight. The mean SDS-BMI reduction was 0.4 (~1.5-2 kg/m(2) BMI reduction) and was associated with a significant improvement of hypertension, dyslipidemia, and disturbed glucose metabolism in the participants compared to an untreated control group. This efficiency was also proven by a multicenter randomized controlled trial. Furthermore, the quality of life of the participants improved significantly. Even 4 years after the end of intervention, the achieved weight loss was sustained. Training manuals and training seminars for professionals assist in the implementation of these lifestyle interventions at further locations.

Individual Goffin´s cockatoos (Cacatua goffiniana) show flexible targeted helping in a tool transfer task.

Flexible targeted helping is considered an advanced form of prosocial behavior in hominoids, as it requires the actor to assess different situations that a conspecific may be in, and to subsequently flexibly satisfy different needs of that partner depending on the nature of those situations. So far, apart from humans such behaviour has only been experimentally shown in chimpanzees and in Eurasian jays. Recent studies highlight the prosocial tendencies of several bird species, yet flexible targeted helping remained untested, largely due to methodological issues as such tasks are generally designed around tool-use, and very few bird species are capable of tool-use. Here, we tested Goffin's cockatoos, which proved to be skilled tool innovators in captivity, in a tool transfer task in which an actor had access to four different objects/tools and a partner to one of two different apparatuses that each required one of these tools to retrieve a reward. As expected from this species, we recorded playful object transfers across all conditions. Yet, importantly and similar to apes, three out of eight birds transferred the correct tool more often in the test condition than in a condition that also featured an apparatus but no partner. Furthermore, one of these birds transferred that correct tool first more often before transferring any other object in the test condition than in the no-partner condition, while the other two cockatoos were marginally non-significantly more likely to do so. Additionally, there was no difference in the likelihood of the correct tool being transferred first for either of the two apparatuses, suggesting that these birds flexibly adjusted what to transfer based on their partner´s need. Future studies should focus on explanations for the intra-specific variation of this behaviour, and should test other parrots and other large-brained birds to see how this can be generalized across the class and to investigate the evolutionary history of this trait.

Synergistic effects in apoptosis induction by taurolidine and TRAIL in HCT-15 colon carcinoma cells.

Induction of apoptosis in tumor cells by TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a promising therapeutic principle in oncology, although toxicity and resistance against TRAIL are limiting factors. Taurolidine (TRD), an antineoplastic agent with low toxicity, is a potential candidate for combined therapy with TRAIL. The aim of this study was to evaluate the apoptotic effects of a combined treatment with TRD and TRAIL in a human HCT-15 colon carcinoma cell line. HCT-15 cells were incubated with increasing concentrations of recombinant human TRAIL (50 ng/mL to 500 ng/mL) or TRD (50 micromol/L to 1000 micromol/L). In a second experiment, cells were furthermore exposed to a combination of both substances (TRAIL 50 ng/mL and TRD 100 micromol/L). At various time points (3 h to 36 h), cell viability, apoptosis, and necrosis were quantified by FACS analysis (propidium iodide/annexin V-FITC) and confirmed by TUNEL assay. Incubation with TRD resulted in cell death induction with maximum effects observed at 100 micromol/L and 1000 micromol/L after 36 h. TRAIL application led to dose-dependent cell death induction as early as 6 h. Combined treatment of TRD (100 micromol/L) and TRAIL (50 ng/mL) caused a sustained induction of apoptosis that was superior to single-agent application, exceeding a merely additive effect. Combinatory treatment of human colon carcinoma cells with TRD and TRAIL results in a synergistic effect on apoptosis induction with a significant increase of the apoptotic index. Combination of TRAIL with the nontoxic TRD might represent a novel therapeutic strategy in oncological therapy.

Measurement techniques for tracer kinetic studies with stable isotopes of zirconium.

Biokinetic models are used in radiation protection to assess internal radiation doses. Experiments with stable isotopes as tracers can be performed to obtain characteristic parameters of these models. Two methods for the measurement of zirconium isotopes in human biological samples are presented--thermal ionisation mass spectrometry (TIMS) and proton nuclear activation analysis (PNA). Descriptions include sample preparation, operating conditions, relative uncertainties and method detection limits as well as important properties of both methods.

Effects of GTP on hormone-stimulated adenylate cyclase activity in cerebral cortex, striatum, and hippocampus from rats treated chronically with lithium.

The effects of lithium on guanosine triphosphate (GTP) stimulated adenylate cyclase activity and hormone-induced GTP activation of the enzyme have been studied in three regions of the rat brain. Chronic treatment with lithium, giving a serum lithium level of 0.71 +/- 24 mmol/L, reduced isoprenaline-induced GTP stimulation of adenylate cyclase activity in cortical membranes at concentrations of GTP up to 2 microM. No effect of lithium was observed at higher concentrations of GTP. The enzyme activity stimulated by GTP alone was unaltered by lithium ex vivo. In striatal membranes, lithium ex vivo decreased both dopamine-induced GTP activation of adenylate cyclase and GTP-stimulated adenylate cyclase activity at concentrations of GTP below 2 microM. No effects of lithium ex vivo were found in striatum at 2 microM GTP and above. In hippocampal membranes, lithium ex vivo did not influence either serotonin-induced GTP stimulation of the adenylate cyclase or GTP-stimulated enzyme activity at low levels of GTP. However, at 50 microM GTP, lithium ex vivo enhanced serotonin-stimulated enzyme activity. The present results suggest that lithium ex vivo decreases neurotransmitter activation of the cortical beta-adrenergic adenylate cyclase by influencing the mechanisms by which receptor agonists enhance the GTP stimulation of the adenylate cyclase. Furthermore, lithium ex vivo exerts a region-specific action on the brain adenylate cyclases, but in the brain regions studied, an effect of lithium on N-protein level might be of significance for the action of lithium ex vivo on neurotransmitter activation.

Value of bronchial artery embolisation with platinum coils in tumorous pulmonary bleeding.

We performed bronchial artery embolizations (BAE) using platinum coils with Dacron fibres in 30 consecutive patients with haemoptysis due to bronchial carcinoma. The aim of the study was to compare immediate results of bleeding cessation, recurrence and survival rates with a historical control group of 15 patients with tumorous pulmonary bleeding who were treated conservatively (non-BAE-group). Bronchial artery embolisation with platinum coils stopped active bleeding in all patients immediately. Comparing the BAE group and controls the cessation of first time haemoptysis (BAE 100% versus non-BAE 93%) and the rates of bleeding recurrence (BAE 50% versus non-BAE 47%) were similar in either group. In case of recurrent bleeding, repeated BAE led to a definite cessation of pulmonary haemorrhage in every case. In contrast, all patients with recurrent haemoptysis without a repeated BAE (8 patients, 27%) and all patients with bleeding recurrence in the non-BAE group died from pulmonary haemorrhage (8 patients, 53%). The mean survival time of the BAE group was significantly longer compared with the non-BAE group, 139 (range: 1-818) days versus 62 (range: 1-186) days (P<0.05). We conclude that consistent BAE proved beneficial in tumorous pulmonary bleeding, particularly with regard to the permanent arrest of haemorrhage in case of recurrence.

Effects of minocycline on accumulation of cyclic AMP in cerebral cortex of rat. A comparison with lithium.

The tetracycline minocycline and lithium have been reported to share some biochemical properties. This study was aimed at investigating the effects of minocycline and lithium in vitro on accumulation of noradrenaline-, forskolin- and calcium-(Ca2+) stimulated cyclic AMP (cAMP) in the cerebral cortex of the rat. Minocycline and lithium dose-dependently inhibited noradrenaline-stimulated formation of cAMP in slices of cortex, but only lithium inhibited the formation of cAMP induced by forskolin. In contrast to lithium, minocycline did not affect either noradrenaline- or Ca(2+)-stimulated activity of adenylate cyclase in a preparation of cortical membranes. However, in slices of cortex ouabain-induced formation of cAMP (dependent on extracellular Ca2+ and blocked by the Ca2+ channel antagonist, verapamil) was reduced both by minocycline and lithium. The present results indicate that the mechanisms of action of minocycline and lithium on the cAMP signalling system in the brain of the rat differ. Minocycline does not seem to interact directly with the adenylate cyclase, as reported for lithium. The decreased agonist-stimulated production of cAMP in intact cells, in the presence of minocycline, might be due to the ability of minocycline to chelate Ca2+ ions.

The effects of lithium in vitro and ex vivo on adenylate cyclase in brain are exerted by distinct mechanisms.

The effects of lithium on basal and forskolin-stimulated activity of adenylate cyclase in membrane preparations from cerebral cortex of the rat have been studied. Chronic treatment with lithium, yielding a level of lithium in serum of 0.71 +/- 0.18 mmol/l, reduced forskolin-stimulated activity in total homogenates but exerted no effect on the basal activity. Lithium in vitro, at 2 and 10 mM, did not influence the basal enzyme activity in membranes from either control or lithium-treated animals. The sensitivity of forskolin-stimulated adenylate cyclase to lithium in vitro was unaltered after chronic treatment and the in vitro and ex vivo effects of lithium on this parameter were additive. The inhibitory ex vivo effect of lithium was not antagonized by increasing concentrations of magnesium and the inhibitory effect of lithium ex vivo was still persistent after washing of the membranes. The present results indicate that lithium exerts its ex vivo effect on the activated cyclase, independently of the in vitro effect. Both effects may, however, contribute to the in vivo effect of lithium during chronic treatment.

Effects of treatment with a lithium-imipramine combination on components of adenylate cyclase in the cerebral cortex of the rat.

This study was aimed at investigating the effects of treatment with a lithium-imipramine combination on the activity of adenylate cyclase in membranes from the cerebral cortex of the rat. Treatment with (1) lithium for 2 weeks, yielding a level of lithium in serum of 0.54 +/- 0.12 mmol/l, (2) imipramine for 4 weeks (10 mg/kg i.p. twice per day) and (3) a combination of the two drugs reduced isoprenaline-induced stimulation of adenylate cyclase by GTP, with a greater decrement with the combined treatment. None of the treatments exerted any effect on the activity of the enzyme stimulated by GTP alone. Lithium ex vivo inhibited the calcium (Ca2+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but imipramine ex vivo did not affect the activity of adenylate cyclase, stimulated by these activators. The lithium-imipramine treatment reduced Ca2(+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but this was not different from that observed in the lithium-treated group. In conclusion, the beta-adrenoceptor-stimulated adenylate cyclase was affected markedly by administration of lithium and imipramine together. In contrast to lithium ex vivo, imipramine ex vivo did not impair the activity of either the guanine nucleotide regulatory protein or the catalytic subunit, since no change in activity was observed in the presence of beta,gamma-imidoguanosine-5' triphosphate (Gpp(NH)p) or Ca2+. Furthermore, lithium ex vivo exerted its post-receptor effects on the adenylate cyclase, independent of imipramine. The decrement in activity of beta-adrenergic adenylate cyclase, induced by administration of the two drugs together may partly be involved in the therapeutic action of the augmentation of antidepressants by lithium in refractory depression.

Fluoride-stimulated adenylate cyclase activity in rat brain following chronic treatment with psychotropic drugs.

Chronic treatment with imipramine and reserpine increased fluoride-stimulated activity of adenylate cyclase in homogenates of cerebral cortex and "limbic" forebrain of the rat. Concomitant treatment with lithium counteracted this effect, while lithium alone had no effect on the activity of adenylate cyclase.

3,4-O-diacetylisoproterenol. Preparation, structure proof, and beta-receptor effect.

Direct acetylation of isoproterenol by selective O-acetylation using CH3COCl/CF3COOH was shown to lead to the formation of 2-(3,4-diacetoxyphenyl)-2-chloro-N-isopropyl-1-ethanamine and not to 3,4-O-diacetylisoproterenol. The latter was prepared by reduction of 3,4-diacetoxy(2-isopropylamino)acetophenone and its structure confirmed by IR, 1H, 13C NMR, mass spectral, and elemental analysis. The two compounds were tested for activity on beta-receptors. Efficacy and affinity on beta 1-receptors were found identical with the effect of isoproterenol. So was efficacy on beta2-receptors, while affinity was lower for the chloro compounds than for isoproterenol and diacetylisoproterenol which exhibited identical affinity.

Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase activity in rat brain.

The aim of this study was to investigate the effects of chronic lithium treatment on calcium (Ca2+)-stimulated adenylate cyclase activity in rat striatum and hippocampus, and to elucidate the effect of lithium treatment on the neurotransmitter/GTP-mediated inhibition of Ca2+-stimulated enzyme activity in the two brain areas. Lithium treatment, which gave a serum-lithium concentration of 0.9 +/- 0.16 mmol/l, enhanced Ca2+-stimulated enzyme activity in the hippocampus but reduced this activity in the striatum. Serotonin (5-HT) dose dependently reduced Ca2+-stimulated adenylate cyclase activity in the hippocampus, and chronic lithium administration reduced the ability of 1 microM 5-HT to inhibit Ca2+-stimulated enzyme activity. Furthermore, the 5-HT-induced GTP-mediated inhibition of Ca2+-stimulated adenylate cyclase activity in the hippocampus was markedly decreased by lithium. Increasing concentrations of dopamine in the striatum did not, however, affect Ca2+-stimulated adenylate cyclase activity and the inhibition of enzyme activity observed with increasing concentrations of GTP was not influenced by chronic lithium treatment. These results demonstrate that lithium ex vivo exerts dual and region-specific effects on Ca2+-stimulated adenylate cyclase in the brain. Furthermore, long-term administration of lithium could reduce the inhibitory effect of 5-HT on adenylate cyclase in the hippocampus, by influencing the inhibitory GTP-binding protein. The effects of lithium on serotonergic and dopaminergic neurotransmission could be involved in the therapeutic actions of lithium in manic-depressive illness.

5-Hydroxytryptamine receptor agonists influence calcium-stimulated adenylate cyclase activity in the cerebral cortex and hippocampus of the rat.

The effects of 5-hydroxytryptamine (5-HT) receptor agonists on calcium (Ca2+)-stimulated adenylate cyclase activity in the hippocampus and cerebral cortex of the rat were studied. In the presence of Ca2+ (1.5 microM), 5-HT dose dependently inhibited adenylate cyclase activity (EC50 = 10 +/- 2 nM). The inhibitory effect of 5-HT on Ca2(+)-stimulated adenylate cyclase was antagonized by spiperone (KB = 2 +/- 0.8 nM). The rank order of potency of 5-HT agonists to inhibit Ca2(+)-stimulated adenylate cyclase in the hippocampus was: 5-carboxamidotryptamine (5-CT) greater than 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) greater than 5-hydroxytryptamine (5-HT) = 5-methoxytryptamine (5-OCH3-T) greater than trifluoromethylphenylpiperazine (TFMPP) greater than m-chlorophenylpiperazine (mCPP). 2-Methyl-5-hydroxytryptamine (2-CH3-5-HT) did not exert an effect on Ca2(+)-stimulated enzyme activity. In the cerebral cortex 5-HT exerted a biphasic stimulatory effect on adenylate cyclase activity in the absence of Ca2+ (EC50 = 0.2 +/- 0.04 nM and 10 +/- 3 microM), whereas 8-OH-DPAT, 5-CT and 2-CH3-5-HT exerted a monophasic effect. In the presence of Ca2+ (1.5 microM), low concentrations of 5-HT, 8-OH-DPAT, 5-CT and 2-CH3-5-HT potentiated adenylate cyclase activity, whereas higher concentrations, except 2-CH3-5-HT, inhibited the enzyme activity. We propose that the 5-HT receptor mediating inhibition of Ca2(+)-stimulated adenylate cyclase in the rat hippocampus corresponds to the 5-HT1A subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study on the effects of tetracyclines and lithium on the cyclic AMP second messenger system in rat brain.

1. This study was aimed at investigating the effects of demeclocycline (DMC), minocycline (MC), and lithium (Li) in vitro on cyclic AMP (cAMP) accumulation in rat cerebral cortex stimulated by noradrenaline, forskolin, and ouabain. 2. DMC, MC, and Li dose-dependently reduced noradrenaline-stimulated cAMP formation in cortical slices, but only Li inhibited the cAMP formation induced by forskolin. 3. In contrast to Li, DMC and MC did not affect noradrenaline-stimulated adenylate cyclase activity in cortical membranes. 4. In cortical slices, ouabain stimulated the cAMP production (required the presence of extracellular Ca2+ and was blocked by verapamil). Ouabain-stimulated cAMP accumulation in cortical slices was inhibited by DMC, MC, and Li. 5. DMC and MC do not seem to interact directly with the adenylate cyclase as reported for Li. It is concluded that the tetracyclines, DMC and MC, affect the cAMP signaling system in rat brain by mechanisms that differ from that of Li. The decreased receptor agonist-stimulated cAMP production in cortical slices in the presence of DMC and MC may be due to the Ca(2+)-chelating ability of these tetracyclines.