A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

Henry, Michael E.; Schmidt, Mark E.; Hennen, John; Villafuerte, Rosemond A.; Butman, Michelle L.; Trân, Pierre V.; Kerner, Lynn T; Cohen, Bruce M.; Renshaw, Perry F.

doi:10.1038/sj.npp.1300749

Cited by 75 publications

(54 citation statements)

References 26 publications

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“…The proton image intensity in Fig. 1 reflects the 19 F MRS sensitivity profile, which shows maximal coil sensitivity as the brightest region localized mainly in the occipital lobe and the major signal contribution from brain tissue. The sensitivity profile of the coil minimized sensitivity at the coil surface region, which also contains minor contributions from occipital bone, scalp, blood, and other nonbrain tissue.…”

Section: Methodsmentioning

confidence: 99%

“…All MRS recordings were performed at the McLean Hospital Brain Imaging Center on a 4T horizontal bore, wholebody magnetic resonance system (Agilent Technologies, Santa Clara, CA) using a dual-tuned ( 19 F-1 H) 12-cm-diameter circular surface coil, built and validated in-house, tuned to 160.2 MHz for 19 F detection and 170.3 MHz for 1 H detection. The surface coil was placed with its center at the back of the head (occiput) and its sensitive region covering the occipital lobe.…”

Section: Methodsmentioning

confidence: 99%

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Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Henry

Bolo

Chen

et al. 2013

Antimicrob Agents Chemother

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Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the bloodbrain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid, so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open-label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 h on day 1, followed by 200 mg every 12 h administered orally over a 3-day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the MIC for Aspergillus. The brain/plasma ratios were 3.0 at steady state on day 3 (predose) and 1.9 postdose. We found that voriconazole is able to penetrate the brain tissue, which can be quantified using a noninvasive MRS technique. (This study has been registered at ClinicalTrials.gov under registration no. NCT00300677.) C entral nervous system (CNS) fungal infections often occur in immunocompromised individuals and historically have been associated with high mortality rates. Although invasive aspergillosis only involves the CNS in 4 to 6% of cases, the mortality rates range from 80% to close to 100% (1). The number of cases of invasive aspergillosis has risen in recent decades due to greater numbers of transplant patients, as well as more aggressive chemotherapy and immunosuppressive treatments (1). Historically, amphotericin B was the standard of care with itraconazole as an alternative (2). However, the clinical efficacy of standard antifungal agents, including amphotericin B, triazoles, and echinocandins, is generally poor for CNS infections. Most antifungal agents are large molecules that cannot easily penetrate the blood-brain barrier and enter the CNS (3).Voriconazole is a newer broad-spectrum derivative of fluconazole that can be administered both intravenously and orally (4). It is indicated as a first-line treatment for invasive aspergillosis, as well as for other fungal infections that are refractory to other treatments. It is better tolerated and has been associated with improved survival rates in CNS infections compared to other antifungal agents (5). A randomized clinical trial comparing voriconazole to amphotericin B for invasive aspergillosis, including patients with cerebral infections, demonstrated a higher response rate and survival rate for patients who received voriconazole, with fewer serious adverse events (6). The ability of voriconazole to penetrate the blood-brain barrier more effectively than other antifungal agents likely accounts for its greater clinical efficacy.A variety of techniques have been used to study the ability of antifungal medications, inclu...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Henry

Bolo

Chen

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…These concentrations can be easily achieved in the brain at therapeutic dosages since these compounds are preferentially taken up and enriched in brain tissue with 10-20 fold higher concentrations in the human brain compared to plasma [43]. Steady state levels are achieved over several weeks to months [44]. These studies also show that the SSRI are evenly distributed throughout the brain.…”

Section: Discussionmentioning

confidence: 73%

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

et al. 2015

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There are severe neurological complications that arise from HIV infection, ranging from peripheral sensory neuropathy to cognitive decline and dementia for which no specific treatments are available. The HIV proteins secreted from infected macrophages, gp120 and Tat, are neurotoxic. The goal of this study was to screen, identify and develop neuroprotective compounds relevant to HIV-associated neurocognitive disorders (HAND). We screened more than 2000 compounds that included FDA approved drugs for protective efficacy against oxidative stress-mediated neurodegeneration and identified selective serotonin reuptake inhibitors (SSRIs) as potential neuroprotectants. Numerous SSRIs were then extensively evaluated as protectants against neurotoxicity as measured by changes in neuronal cell death, mitochondrial potential, and axodendritic degeneration elicited by HIV Tat and gp120 and other mitochondrial toxins. While many SSRIs demonstrated neuroprotective actions, paroxetine was potently neuroprotective (100 nM potency) against these toxins in vitro and in vivo following systemic administration in a gp120 neurotoxicity model. Interestingly, the inhibition of serotonin reuptake by paroxetine was not required for neuroprotection, since depletion of the serotonin transporter had no effect on its neuroprotective properties. We determined that paroxetine interacts selectively and preferentially with brain mitochondrial proteins and blocks calcium-dependent swelling but had less effect on liver mitochondria. Additionally, paroxetine induced proliferation of neural progenitor cells in vitro and in vivo in gp120 transgenic animals. Therefore, SSRIs such as paroxetine may provide a novel adjunctive neuroprotective and neuroregenerative therapy to treat HIVinfected individuals.

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“…Moreover, the brain concentration of fluoxetine and its metabolites keep on increasing through at least the first 5 weeks of treatment [Henry et al 2005]. This means that the full benefits of the current dose received by a patient are not realized for at least a month after initiation.…”

Section: A Putative Mechanism and Argumentmentioning

confidence: 99%

A new logical insight and putative mechanism behind fluoxetine-induced amenorrhea, hyperprolactinemia and galactorrhea in a case series

Mondal¹,

Saha

Das³

et al. 2013

Therapeutic Advances in Psychopharmacology

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Clinical casesCase one A 35-year-old married woman consulted the psychiatry department in February 2010 for depression for the past 1.5 years which had become aggravated during the past 3 months. Using the Montgomery-Åsberg Depression Rate Scale (MADRS) [Montgomery and Åsberg, 1979] the patient scored 25 points and was diagnosed having depression and was prescribed fluoxetine 20 mg/day. After 21 days, the dose was increased to 40 mg/day along with alprazolam 0.5 mg/day for poor treatment response and persistent insomnia. After 2 weeks, she showed significant improvement although she experienced slight nausea and headache. During her subsequent follow up, the dose of alprazolam was reduced to 0.25 mg/day and tapered to complete cessation over the next week, and fluoxetine was continued with excellent therapeutic response.However, in July 2011, she complained of amenorrhea for five consecutive cycles and her serum prolactin level was found to be 25 ng/ml (normal 0-20 ng/ml). The dose of fluoxetine was reduced A new logical insight and putative mechanism behind fluoxetine-induced amenorrhea, hyperprolactinemia and galactorrhea in a case series Somnath Mondal, Indranil Saha, Saibal Das, Abhrajit Ganguly, Debasis Das and Santanu Kumar Tripathi Abstract: With the exception of fluoxetine, all selective serotonin reuptake inhibitors (SSRIs) commonly cause hyperprolactinemia through presynaptic mechanisms indirectly via 5-hydroxytryptamine (5-HT)-mediated inhibition of tuberoinfundibular dopaminergic neurons. However, there is little insight regarding the mechanisms by which fluoxetine causes hyperprolactinemia via the postsynaptic pathway. In this text, analysis of five spontaneously reported clinical cases of hyperprolactinemia resulting in overt symptoms of amenorrhea with or without galactorrhea, were scrupulously analyzed after meticulously correlating relevant literature and an attempt was made to explore the putative postsynaptic pathway of fluoxetine inducing hyperprolactinemia. Hypothetically, serotonin regulates prolactin release either by increasing oxytocin (OT) level via direct stimulation of vasoactitive intestinal protein (VIP) or indirectly through stimulation of GABAergic neurons. The pharmacodynamic exception and pharmacokinetic aspect of fluoxetine are highlighted to address the regulation of prolactin release via serotonergic pathway, either directly through stimulation of prolactin releasing factors (PRFs) VIP and OT via 5-HT 2A receptors predominantly on PVN (neurosecretory magnocellular cell) or through induction of 5-HT 1A -mediated direct and indirect GABAergic actions. Prospective molecular and pharmacogenetic studies are warranted to visualize how fluoxetine regulate neuroendocrine system and cause adverse consequences, which in turn may explore new ways of approach of drug development by targeting the respective metabolic pathways to mitigate these adverse impacts.

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A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

Cited by 75 publications

References 26 publications

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

A new logical insight and putative mechanism behind fluoxetine-induced amenorrhea, hyperprolactinemia and galactorrhea in a case series

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