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1.
Drugs ; 79(2): 161-171, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30617959

ABSTRACT

The inability to use powerful antituberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug regimens are being investigated for pulmonary TB to counteract emergence of drug resistance. Intensified regimens with high-dose anti-TB drugs during the first weeks of treatment are being investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin, gatifloxacin and levofloxacin are seen as core agents in case of resistance or intolerance against first-line anti-TB drugs. However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing could be optimized. We prepared a comprehensive summary of clinical trials investigating the outcome of TB regimens based on moxifloxacin, gatifloxacin and levofloxacin in recent years. In the majority of clinical trials, treatment success was not in favour of these drugs compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into the armamentarium of drug-development tools is needed to clarify the role of moxifloxacin, gatifloxacin and levofloxacin for TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability advocates for concentration-guided dosing in patients at risk for too low a drug-exposure.


Subject(s)
Antitubercular Agents/therapeutic use , Fluoroquinolones/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Antitubercular Agents/administration & dosage , Antitubercular Agents/adverse effects , Fluoroquinolones/administration & dosage , Fluoroquinolones/adverse effects , Gatifloxacin/administration & dosage , Gatifloxacin/adverse effects , Gatifloxacin/therapeutic use , Humans , Levofloxacin/administration & dosage , Levofloxacin/adverse effects , Levofloxacin/therapeutic use , Moxifloxacin/administration & dosage , Moxifloxacin/adverse effects , Moxifloxacin/therapeutic use , Treatment Outcome
2.
Ned Tijdschr Geneeskd ; 161: D1591, 2017.
Article in Dutch | MEDLINE | ID: mdl-28984212

ABSTRACT

BACKGROUND: Since the introduction of the electronic e-cigarette a few years ago, its use has greatly increased. The liquid formulations used in these e-cigarettes contain nicotine in high concentrations; ingestion of these liquids can be fatal. CASE DESCRIPTION: A 42-year-old male was admitted to the Intensive Care ward due to cardiac arrest. The patient had ingested highly concentrated liquid nicotine, originating from a vial with liquid for e-cigarettes. When the ambulance personnel found the patient he did not have a pulse; following CPR and administration of adrenaline his pulse returned. Upon admission, the plasma nicotine level was high at 3.0 mg/l (reference values for a smoker are 0.01-0.05 mg/l) and the patient's neurological function was poor. The patient was treated symptomatically, but eventually died of a postanoxic encephalopathy. CONCLUSION: Nicotine e-liquids are highly concentrated. Intentional ingestion can lead to toxic levels of nicotine which are associated with cardiac arrhythmias or arrest. Because even a few millilitres can be lethal, nicotine intoxication due to e-liquid ingestion should be considered potentially life-threatening.


Subject(s)
Electronic Nicotine Delivery Systems , Heart Arrest/chemically induced , Nicotine/toxicity , Adult , Fatal Outcome , Humans , Male
3.
Curr Pharm Des ; 17(27): 2900-30, 2011.
Article in English | MEDLINE | ID: mdl-21834759

ABSTRACT

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC- 159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug resistant TB treatment.


Subject(s)
Antitubercular Agents/pharmacology , Fluoroquinolones/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Antitubercular Agents/administration & dosage , Antitubercular Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Therapy, Combination , Fluoroquinolones/administration & dosage , Fluoroquinolones/pharmacokinetics , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/isolation & purification , Practice Guidelines as Topic , Tuberculosis, Multidrug-Resistant/microbiology
4.
Eur Respir J ; 38(4): 888-94, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21310881

ABSTRACT

Moxifloxacin (MFX) is a powerful second-line anti-tuberculosis (TB) agent, but the optimal dose has not yet been established and long-term safety data are scarce. We retrospectively reviewed the medical charts of TB patients treated at the Tuberculosis Centre Beatrixoord, University Medical Centre Groningen (Haren, the Netherlands) receiving MFX 400 mg once daily as part of their TB treatment between January 1 2006 and January 1 2009. Safety data and drug-drug interactions were evaluated. Efficacy was predicted based on the area under the concentration-time curve up to 24 h post-dosage (AUC(0-24h))/minimal inhibitory concentration (MIC) ratio. 89 patients were treated with a median dose of 6.9 mg · kg(-1) MFX once daily for a median period of 74 days. Discontinuation of therapy occurred in only three patients due to gastrointestinal side-effects and hypersensitivity. Pharmacokinetic analysis showed an AUC(0-24h)/MIC ratio <100 in eight out of 16 patients. A large variation in protein binding affected the unbound AUC(0-24h) considerably. These data show that MFX treatment was well tolerated in 89 patients receiving a dose of 400 mg once daily for a prolonged period. Considering the variability in (un)bound AUC(0-24h)/MIC ratio, therapeutic drug monitoring is recommended in selected patients (i.e. rifampicin co-medication; MIC ≥ 0.25 mg · L(-1)) to assess optimal therapy.


Subject(s)
Antitubercular Agents/administration & dosage , Aza Compounds/administration & dosage , Quinolines/administration & dosage , Tuberculosis, Pulmonary/drug therapy , Adult , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/adverse effects , Anti-Infective Agents/pharmacokinetics , Antitubercular Agents/adverse effects , Antitubercular Agents/pharmacokinetics , Aza Compounds/adverse effects , Aza Compounds/pharmacokinetics , Drug Interactions , Female , Fluoroquinolones , Humans , Male , Middle Aged , Moxifloxacin , Netherlands , Quinolines/adverse effects , Quinolines/pharmacokinetics , Retrospective Studies , Treatment Outcome
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