How long does the pharmacokinetic interaction between carbamazepine and quetiapine last after carbamazepine withdrawal?

OBJECTIVES: Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. METHODS: In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal. RESULTS: No serum quetiapine was detected during concurrent use of carbamazepine and was lower than the therapeutic range almost 2 weeks after carbamazepine withdrawal. The patient suffered from sedation when her serum level of quetiapine was 181 ng/ml and because she was quiet we started slowly to decrease to a quetiapine dose of 600 mg. Her serum level (45 ng/ml) was again below therapeutic levels after 3 weeks of carbamazepine withdrawal. CONCLUSION: We hypothesize that induction of CYP3A lasts even after carbamazepine withdrawal. Our hypothesis was confirmed during the next treatment of mania. The patient had been off carbamazepine for 1 year and her serum level was four times higher (210 ng/ml) on 600 mg of quetiapine than 3 weeks after carbamazepine withdrawal. The influence of carbamazepine on CYP3A enzymes lasted at least 3 weeks after carbamazepine withdrawal which is in accordance with CYP3A de-induction lasting 3 weeks. This could be important information for psychiatrists to know that in some patients it is better to use a minimum washout period of 3 weeks for carbamazepine before new treatment with quetiapine.

Increased amisulpride serum concentration in a patient treated with concomitant pregabalin and trazodone: a case report.

We report on the case of a 46-year-old woman with generalized anxiety disorder, paranoid personality disorder, and mild reduction in glomerular filtration rate (GFR). She was treated with pregabalin, trazodone, hydroxyzine, and clonazepam before hospital admission. Pharmacotherapy for the patient was changed during her first week in the hospital. Dosing of hydroxyzine and clonazepam was gradually decreased, and then these two drugs were withdrawn. Treatment with amisulpride was started on the fourth day after admission, and amisulpride serum levels were then measured three times as a part of therapeutic drug monitoring (TDM). The serum concentration of amisulpride detected during concurrent use of trazodone and pregabalin was approximately twice the therapeutic range for amisulpride. When the dose of pregabalin was reduced by half, the serum concentration of amisulpride decreased to therapeutic serum levels. We hypothesize that an interaction between amisulpride and pregabalin was responsible for the increased amisulpride concentration since both drugs are almost exclusively excreted from the body by the renal route. Pregabalin-amisulpride interaction might also be influenced by concomitant therapy with trazodone or a mild reduction in GFR. However, we only have clinical evidence for an interaction between amisulpride and pregabalin because after we halved the dose of pregabalin, the amisulpride concentration decreased, and the C/D ratio normalized. This could be helpful information for psychiatrists in order to avoid drug-drug interactions between amisulpride and pregabalin. We recommend TDM of amisulpride in patients treated concomitantly with other drugs eliminated mainly by the kidneys.

Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes.

Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient's medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.

What combinations of agomelatine with other antidepressants could be successful during the treatment of major depressive disorder or anxiety disorders in clinical practice?

Even with many antidepressant and anxiolytic drugs available on the market, there are still patients who do not respond well to the standard first or second line treatments for affective or anxiety disorders. The antidepressant agomelatine has been used in Europe for several years. Agomelatine, an agonist at melatonin receptors and an antagonist at serotonin receptors, can be particularly useful in patients suffering from a major depressive disorder associated with insomnia. Some clinical data have shown a limited effect for agomelatine in a subset of patients with major depression. A number of case reports published in 2011-2016 describe the effect of agomelatine in combination with an established antidepressant, such as escitalopram, venlafaxine, duloxetine, moclobemide or bupropion. A successful combination of agomelatine was reported after adjunctive use of agomelatine combined with clomipramine, escitalopram, and venlafaxine in patients with major depression or obsessive-compulsive disorder. Moreover, bupropion or moclobemide augmentation with agomelatine in patients with major depressive disorder led to a significant improvement. Other supportive data have been published, such as analysis of the VIVALDI study, although it should be noted that the study was supported by the manufacturer of agomelatine. In this study, agomelatine in combination with other antidepressants was shown to be effective and well tolerated in practice, although the most effective antidepressant treatment in the study consisted of agomelatine alone and not in combination with other antidepressants. There have also been two published case reports about the concomitant use of duloxetine and agomelatine which were not efficacious. The positive results of agomelatine augmentation with other antidepressants should be confirmed through randomized, double-blind clinical trials.

Purine P1 receptor-dependent immunostimulatory effects of antiviral acyclic analogues of adenine and 2,6-diaminopurine.

Acyclic nucleoside phosphonates are widely recognised antivirals. The oral prodrugs of prototype compounds, e.g., 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; adefovir), and 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] were approved by FDA for treatment of hepatitis B (Hepsera), and acquired immunodeficiency syndrome (AIDS) (Viread), respectively. A number of acyclic nucleoside phosphonates possess immunostimulatory activity. The present experiments demonstrate that activation of cytokine and chemokine secretion is mediated by adenosine receptors. Included in the study were 9-(R)-[2-(phosphonomethoxy)propyl]adenine [tenofovir], N(6)-cyclopentyl-(R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine, N(6)-cyclopropyl-(R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine, and N(6)-isobutyl-9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine. All of them activate secretion of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), "regulated on activation of normal T cell expressed and secreted" (RANTES/CCL5), and macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) in murine macrophages. With exception of MIP-1alpha, the effects were inhibited by antagonists of adenosine A(1), A(2B), and A(3) receptors (not by adenosine A(2A) receptor antagonist). The adenosine A(1) receptor antagonist inhibited TNF-alpha, IL-10, and RANTES, adenosine A(2B) receptor antagonist inhibited TNF-alpha and RANTES, and adenosine A(3) receptor antagonist inhibited IL-10 and RANTES. The suppression is due to decreased transcription of cytokine mRNA. It may be suggested that acyclic nucleoside phosphonates are nonspecific ligands for purine P(1) receptors.

Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives.

Newly developed acyclic nucleoside phosphonates, derivatives of adenine and 2,6-diaminopurine bearing the 2-hydroxy-3-(phosphonomethoxy)propyl (HPMP) moiety at the N9-side chain (i.e., HPMPA and HPMPDAP, respectively) were screened for in vitro immunobiological activity, using mouse resident peritoneal macrophages and splenocytes. Both HPMPA and HPMPDAP augmented the interferon-gamma-triggered production of NO as well as expression of inducible nitric oxide synthase (iNOS) mRNA in macrophages. HPMPDAP activated secretion of tumor necrosis factor-alpha (TNF-alpha), chemokines "regulated-upon-activation, normal T cell expressed and secreted" (RANTES) and macrophage inflammatory protein-1alpha (MIP-1alpha), and marginally also secretion of interleukin-10 (IL-10) in both macrophages and splenocytes. The HPMPA, less prominently than HPMPDAP, elevated only secretion of RANTES and TNF-alpha. The compounds also activated secretion of TNF-alpha (HPMPDAP > HPMPA) in human peripheral blood mononuclear cells (PBMC). Distinct N6-substituted derivatives, i.e., N6-dimethyl-, N6-cyclopropyl-, N6-piperidin-1-yl-, N6-(2-methoxyethyl)-, N6-(2-hydroxyethyl)-, N6-allyl- and N6-2-(dimethylamino)ethyl-HPMPA/HPMPDAP as well as 6-thio and 6-hydroxy derivatives usually showed loss of the activity compared to the parent compounds. The immunomodulatory effects were found to be at least in part dependent on P1 purinoreceptors, and mediated by transcriptional factor nuclear factor-kappaB.

Immunobiological activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, and 2,6-diaminopurines.

Acyclic nucleoside phosphonates are novel class of virostatics effective against replication of both DNA-viruses and retroviruses. We found recently, that in addition to the antimetabolic mode of action, some acyclic nucleoside phosphonates such as 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir], which is used in treatment of human immunodeficiency virus (HIV) infection, possess immunostimulatory and immunomodulatory activities known to interfere with replication of viruses. The present experiments analyzed immunobiological effects of more than 70 novel derivatives of acyclic nucleoside phosphonates. They comprise substitutions at the N6-amino function of adenine (A) or 2,6-diaminopurine (DAP) by monoalkyl, dialkyl, cycloalkyl, alkenyl, alkynyl or substituted alkyl group, and at the N9-side chain represented by (R)- or (S)-enantiomeric 9-[2-(phosphonomethoxy)ethyl] (PME) and 9-[2-(phosphonomethoxy)propyl] (PMP) moieties. Their biological effects were investigated in vitro using mouse resident peritoneal macrophages. A number of the compounds under scrutiny, mainly the N6-cycloalkyl derivatives of 9-[2-(phosphonomethoxy)ethyl]2,6-diaminopurine (PMEDAP) and (R)-enantiomeric 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPDAP] stimulate secretion of cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10)] and chemokines ["regulated-upon-activation, normal T expressed and secreted" (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha)]. Moreover, they substantially augment production of nitric oxide (NO) triggered by interferon-gamma. The effects are produced in a dose-dependent fashion. The most potent derivatives, i.e. N6-isobutyl-PMEDAP, N6-cyclopentyl-PMEDAP, N6-cyclooctyl-PMEDAP, N6-dimethylaminoethyl-(R)-PMPDAP, N6-cyclopropyl-(R)-PMPDAP, and N6-cyclopentyl-(R)-PMPDAP are more effective than (R)-PMPA (tenofovir) itself. They exhibit immunostimulatory effects at concentrations as low as 1 to 5 microM. It is suggested that these compounds might be prospective candidates for antiviral therapeutic exploitation.

Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3.

Acyclic nucleoside phosphonates are potent antiviral agents effective against replication of DNA viruses and retroviruses including human immunodeficiency virus (HIV). In addition to their antimetabolic mode of antiviral action, acyclic nucleoside phosphonates also possess immunomodulatory properties. We have shown recently that a number of them stimulate secretion of cytokines including chemokines RANTES/CCL5 ("regulated upon activation, normal T cell expressed and secreted") and MIP-1 alpha/CCL3 (macrophage inflammatory protein-1 alpha) that may inhibit entry of HIV in cells. In present experiments we analyzed effects of acyclic nucleoside phosphonates on gene expression of other members of the beta family of chemokines, monocyte chemotactic proteins (MCPs), which have also been implicated in the control of HIV infection. The following compounds differing at the type of heterocyclic base, i.e. adenine (A), or 2,6-diaminopurine (DAP), at the 6-amino group of the base, and at the N ( 9 )-side chain represented by 9-[2-(phosphonomethoxy)ethyl] (PME) and 9-[2-(phosphonomethoxy)propyl] (PMP) moieties were included in the study: (1) (R)-PMPA, ie. tenofovir, (2) N ( 6 )-cyclopropyl-(R)-PMPDAP, (3) N ( 6 )-cyclopentyl-(R)-PMPDAP, (4) N ( 6 )-dimethylaminoethyl-(R)-PMPDAP, (5) N ( 6 )-cyclopentyl-PMEDAP, (6) N ( 6 )-isobutyl-PMEDAP, (7) N ( 6 ) -cyclohexylmetyl-PMEDAP, and (8) N ( 6 ) -cyclooctyl-PMEDAP. These compounds are able to activate production of MCP-1 and MCP-3, and none of them influences gene expression of MCP-2, and MCP-5. Enhancement of monocyte chemotactic protein expression was found to be mediated by transcriptional factor nuclear factor-kappaB (NF-kappaB).

In vivo effects of antiviral acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)ethyl]adenine (adefovir) on cytochrome P450 system of rat liver microsomes.

Interference of antiviral agent adefovir, i.e. 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with microsomal drug metabolizing system was investigated in rats. The content of total liver cytochrome P450 (CYP) was lowered while that of its denaturated form, P420, was elevated in animals intraperitoneally treated with PMEA (25 mg/kg). Similar effect was observed after treatment with a prodrug of adevofir, adefovir dipivoxil (bisPOM-PMEA). The CYP2E1-dependent formation of 4-nitrocatechol from p-nitrophenol was diminished, though the specific activity of p-nitrophenol hydroxylase remained unchanged. PMEA had no influence on expression of CYP2E1 protein and mRNA and mRNAs of other P450 isoenzymes (1A1, 1A2, 2C11, 3A1, 3A2, and 4A1). It may be concluded that repeated systemic administration of higher doses of PMEA results in a partial degradation of rat CYP protein to inactive P420.

Cytostatic activity of antiviral acyclic nucleoside phosphonates in rodent lymphocytes.

Acyclic nucleoside phosphonates (ANPs) inhibit replication of both DNA viruses and retroviruses, including HIV. The major mechanism of their antiviral action is inhibition of virus-induced DNA polymerases and/or of reverse transcriptases. We investigated the effects of ANPs on proliferation of mitogen-stimulated mouse and rat splenocytes. Included in the study were compounds differing at the heterocyclic base, i.e., adenine (A) and 2,6-diaminopurine (DAP), and at the N(9)-side chain, i.e., 9-[2-(phosphonomethoxy)ethyl] (PME) and (R)- or (S)-enantiomers of 9-[2-(phosphonomethoxy)propyl] (PMP) moieties, and their numerous N(6)-substituted derivatives. The medial inhibitory concentrations (IC50) of N(6)-nonsubstituted compounds range from 0.13 (PMEDAP) to 354 microM ((R)-PMPA). Antiproliferative effects are more pronounced in PME than in PMP series, and they are more prominent in DAP compared to A analogs. The (S)-enantiomers of PMP series are more effective than corresponding (R)-congers. The highest cytostatic potential is exhibited by N(6)-allyl-PMEDAP (IC50 = 0.017 microM) and N(6)-cyclopropyl-PMEDAP (IC50 = 0.036 microM). The N(6)-substituted derivatives of (S)-PMPA are virtually devoid of cytostatic activity. No tight correlation between the cytostatic and reported antiviral effects could be detected.