Frans M. Belpaire

Abrupt awakening phenomenon associated with gamma-hydroxybutyrate use : A case series

Case reports mention a sudden awakening from GHB-associated coma but do not specify its time course. The aim of the present case series was to investigate the time course of the awakening from GHB intoxication and the relationship to plasma concentrations of GHB and the presence of other drugs. Unconscious (GCS ≤8) participants at six large rave parties who were treated at medical stations were included. Serial blood samples were taken every 10 to 30 minutes for toxicological analysis. At the same time-points, the depth of coma was scored with the Glasgow Coma Score (GCS). Fifteen out of 21 unconscious patients proved to be positive for GHB. Fourteen of these had ingested one or more other drugs. The median GHB plasma concentration upon arrival in the medical station was 212 μg/ml (range 112 to 430 μg/ml). In 10 patients the GCS was scored more than twice, allowing study of the time course. The GCS of these patients remained ≤8 for a median time of 90 minutes (range 30 to 105 minutes). The duration of the transition between GCS of ≤8 and ≥12 was 30 minutes (range 10 to 50 minutes). A subgroup of five patients had a GCS of 3 upon arrival and remained at 3 for a median time of 60 minutes (range 30 to 110 minutes), while the median time for the transition between the last point with GCS 3 and the first with GCS 15 was 30 minutes (range 20 to 60 minutes). This case series illustrates that patients with GHB intoxications remain in a deep coma for a relatively long period of time, after which they awaken over about 30 minutes. This awakening is accompanied by a small change in GHB concentrations. A confounding factor in these observations is co-ingested illicit drugs.

Tolerance to the hypnotic and electroencephalographic effect of gamma-hydroxybutyrate in the rat: pharmacokinetic and pharmacodynamic aspects

Tolerance to gamma‐hydroxybutyrate (GHB) has been suggested in illicit users and has been described for the hypnotic effect in the rat. The aim of this study was to investigate whether tolerance is also observed for the EEG effect, and whether the EEG can give insight into the pharmacodynamic aspects of GHB tolerance. In three series of experiments, rats were pre‐treated with either the GHB precursor gamma‐butyrolactone (GBL) or saline intraperitoneally twice daily. In the first series, a reduction in sleeping time was observed in the GBL pre‐treated rats compared with controls. In the second series, a fast infusion of GHB (300 mg kg−1 over 5 min) was given after 10 days pre‐treatment. The GHB plasma concentration‐time curves showed a slightly faster decrease in GHB concentration in the GBL pre‐treated rats, suggesting a small induction of the GHB metabolism (Vmax = 2882 ± 457 μg min−1 kg−1 vs 2205 ± 315 μg min−1 kg−1, P<0.01). In contrast to controls, GBL pre‐treated rats did not lose righting reflex. In the third series, a slow infusion of 480 mg kg−1 h−1 was given after 7 days pre‐treatment, which allowed fitting a sigmoid Emax model to the EEG amplitude versus GHB plasma concentration curve. This showed reduced end‐organ sensitivity to GHB in the GBL pre‐treated rats (EC50 (concentration required to obtain 50% depression of the baseline effect) = 653 ± 183 μg mL−1 vs 323 ± 68 μg mL−1, P < 0.001). In conclusion, chronic pre‐treatment with gamma‐butyrolactone in the rat results in a reduced sleeping time and this tolerance is reflected by the EEG. This can mainly be explained by reduced end‐organ sensitivity.

Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4

OBJECTIVE This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS Three complementary studies were performed: 1) a dose-finding study in CKD stages 1–5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. RESULTS First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. CONCLUSIONS Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.

Physiological Aspects Determining the Pharmacokinetic Properties of Drugs

Publisher Summary Each drug molecule that reaches the target site can add to the intended pharmacological effect of the drug. Pharmacokinetics is the study of the drug concentrations in the different parts of the organism as a function of time. These concentrations depend on the dose administered and upon the rate and extent of absorption, distribution, and elimination. This chapter provides an overview of some of these physiological aspects. It briefly focuses on some pharmacokinetic parameters and terminology and on variability in pharmacokinetics. Drugs need to cross different biological barriers. These barriers can be a single layer of cells (e.g., the intestinal epithelium), several layers of cells (e.g., in the skin), or the cell membrane itself. Absorption can be defined as the passage of a drug from its site of administration into the systemic circulation. After absorption into the systemic circulation, drugs are distributed to the various organs and tissues in the body. The fact that molecules can also be excreted through the loss of hair, nails, and skin is of toxicological and forensic significance. The major routes of drug elimination discussed are renal excretion and hepatic biotransformation. When a plasma-concentration curve is constructed for different patients that have been given an identical dose of an identical drug, interindividual differences are noted. Besides some very obvious causes, such as body weight and body composition, some other factors involved in the interindividual variability in pharmacokinetics are concisely explained.

Chapter 23 – Physiological Aspects Determining the Pharmacokinetic Properties of Drugs

Each drug molecule that reaches the target site can add to the intended pharmacological effect of the drug. Pharmacokinetics is the study of the drug concentrations in the different parts of the organism as a function of time. These concentrations depend on the dose administered and upon the rate and extent of absorption, distribution, and elimination. This chapter provides an overview of some of these physiological aspects. It briefly focuses on some pharmacokinetic parameters and terminology and on variability in pharmacokinetics. Drugs need to cross different biological barriers. These barriers can be a single layer of cells (e.g., the intestinal epithelium), several layers of cells (e.g., in the skin), or the cell membrane itself. Absorption can be defined as the passage of a drug from its site of administration into the systemic circulation. After absorption into the systemic circulation, drugs are distributed to the various organs and tissues in the body. The fact that molecules can also be excreted through the loss of hair, nails, and skin is of toxicological and forensic significance. The major routes of drug elimination discussed are renal excretion and hepatic biotransformation. When a plasma-concentration curve is constructed for different patients that have been given an identical dose of an identical drug, interindividual differences are noted. Besides some very obvious causes, such as body weight and body composition, some other factors involved in the interindividual variability in pharmacokinetics are concisely explained.