Effects of Danshen tablets on pharmacokinetics of amlodipine in rats.

CONTEXT: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with amlodipine (ALDP) for treating coronary heart disease. OBJECTIVE: This study investigated the effects of DST on the pharmacokinetics of ALDP and the potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of ALDP (1 mg/kg) in male Sprague-Dawley rats (n = 6), with or without pretreatment of DST (100 mg/kg for 7 d), were investigated using LC-MS/MS. The effects of DST on the metabolic stability of ALDP were also investigated using rat liver microsomes (RLM). RESULTS: The results indicated that Cmax (16.25 ± 2.65 vs. 22.79 ± 2.35 ng/ml), AUC(0-t) (222.87 ± 59.95 vs. 468.32 ± 69.87 n gh/ml), and t1/2 (10.60 ± 1.05 vs. 14.15 ± 1.59 h) decreased significantly when DST and ALDP were co-administered, which suggested that DST might influence the pharmacokinetic behaviour of ALDP when they are co-administered. The metabolic stability of ALDP was also decreased (23.6 ± 4.7 vs. 38.9 ± 5.2) with the pretreatment of DST. DISCUSSION AND CONCLUSIONS: This study indicated that DST could accelerate the metabolism of ALDP in RLM and change the pharmacokinetic behaviours of ALDP. Accordingly, these results showed that the herb-drug interaction between DST and ALDP might occur when they were co-administered. Therefore, the clinical dose of ALDP should be increased when DST and ALDP are co-administered.

Lack of Antiparkinsonian Effects of Systemic Injections of the Specific T-Type Calcium Channel Blocker ML218 in MPTP-Treated Monkeys.

Dopaminergic medications ameliorate many of the motor impairments of Parkinson's disease (PD). However, parkinsonism is often only partially reversed by these drugs, and they can have significant side effects. Therefore, a need remains for novel treatments of parkinsonism. Studies in rodents and preliminary clinical evidence have shown that T-type calcium channel (TTCC) antagonists have antiparkinsonian effects. However, most of the available studies utilized nonselective agents. We now evaluated whether systemic injections of the specific TTCC blocker ML218 have antiparkinsonian effects in MPTP-treated parkinsonian Rhesus monkeys. The animals were treated chronically with MPTP until they reached stable parkinsonism. In pharmacokinetic studies, we found that ML218 reaches a peak CSF concentration 1-2 h after s.c. administration. In electrocardiographic studies, we found no effects of ML218 on cardiac rhythmicity. As expected, systemic injections of the dopamine precursor L-DOPA dose-dependently increased the movements in our parkinsonian animals. We then tested the behavioral effects of systemic injections of ML218 (1, 10, or 30 mg/kg) or its vehicle, but did not detect specific antiparkinsonian effects. ML218 (3 or 10 mg/kg) was also not synergistic with L-DOPA. Using recordings of electrocorticogram signals (in one animal), we found that ML218 increased sleep. We conclude that ML218 does not have antiparkinsonian effects in MPTP-treated parkinsonian monkeys, due at least in part, to the agent's sedative effects.

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.

Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats.

BACKGROUND AND OBJECTIVE: Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine for treating senile hypertension in clinic. The aim of this study was to study the pharmacokinetics of amlodipine after oral administration of amlodipine and GLT and to investigate the potential for pharmacokinetic herb-drug interactions between GLT and amlodipine in rats. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method was developed for quantification of amlodipine in rat plasma. The accuracy, precision, linearity, selectivity and recovery were all within an acceptable range. Male Sprague-Dawley rats were randomly assigned to two groups: amlodipine group and amlodipine + GLT group. Plasma concentrations of amlodipine were determined at the designated time points after oral administration by using the developed LC-MS/MS method, and the main pharmacokinetic parameters were calculated and compared. As ginkgolides A, ginkgolides B, bilobalide, quercetin and kaempferol were the main components of GLT, the effects of these ingredients in GLT on metabolism of amlodipine were further investigated in rat liver microsomes. RESULTS: The pharmacokinetic parameters, maximum plasma concentration (C max), time to reach C max (T max), area under the concentration-time curve (AUC), area under the first moment plasma concentration-time curve (AUMC) and elimination half-life (t 1/2), of amlodipine were significantly increased in amlodipine + GLT group, which suggested that GLT may influence the pharmacokinetic behavior after oral co-administration with amlodipine. Amlodipine is metabolized by cytochrome P450 (CYP) 3A4, so it was speculated that GLT may change the pharmacokinetic parameters of amlodipine through modulating the metabolism of CYP3A4 enzymes. When ginkgolides B, bilobalide, or quercetin and amlodipine were co-incubated in the rat liver microsomes, the metabolic rate of amlodipine was prolonged to 533.1, 216.1 and 407.6 min, respectively, from 73.7 min. CONCLUSIONS: These results suggested that these components in GLT inhibit the metabolism of amlodipine. So it can be speculated that the herb-drug interactions between GLT and amlodipine resulted from inhibiting the metabolism of amlodipine by GLT when they were co-administered.

Continuous venovenous hemodiafiltration along with charcoal hemoperfusion for the management of life-threatening lercanidipine and amlodipine overdose.

Overdose with calcium channel blockers is uncommon, but is associated with high mortality. The management includes fluid resuscitation, calcium gluconate, glucagon, vasopressors, and high-dose insulin-euglycemia therapy. We describe a rare case of massive overdose of lercanidipine with shock, refractory to conventional therapies and multi-organ failure. Charcoal hemoperfusion with continuous venovenous hemodiafiltration was then used successfully and the patient showed remarkable recovery.

Treatment for calcium channel blocker poisoning: a systematic review.

CONTEXT: Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. OBJECTIVE: To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. METHODS: Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types. RESULTS: The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue. CONCLUSIONS: The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.

Matrix effect and optimization of LC-MSn determination of trachylobane-360 in mice blood.

Xylopia langsdorffiana A. St.-Hil. & Tul. (Annonaceae) is popularly known as "pimenteira-da-terra". Various constituents have been isolated from this species, including diterpenes, such as 8(17), 12E, 14-labdatrien-18-oic acid, ent-atisan-7α, 16α-diol (xylodiol), ent-7α-hydroxytrachyloban-18-oic acid (trachylobane-318) and ent-7α-acetoxytrachyloban-18-oic acid, a crystalline solid with a molecular weight of 360 and molecular formula of C22H32O4 (trachylobane-360). When administered intraperitoneally to mice, trachylobane-360 (T-360) significantly inhibits growth of the solid tumor sarcoma 180 transplanted in mice, without causing alterations in biochemical, hematological and histopathological parameters that are frequently associated with the clinical use of antineoplastic. Furthermore, this diterpene blocks voltage-dependent calcium channels (Cav), showing spasmolytic activity. The present study shows that variables such as extraction solvent (methanol, acetonitrile and chloroform), centrifugation force (1000, 7000 and 14,000×g), and centrifugation time (5, 15 and 25min), are important in the liquid-liquid extraction of T-360 from male Swiss mice blood in HPLC-MSn studies. The study confirms matrix influence on recovery and detection of T-360. The recovery for T-360 was 37.02% using chloroform as better extractor solvent, while centrifuged at 14,000×g for 15min demonstrated the importance of the parameters chosen for the extraction/recovery process of analyte. The effect of mice blood matrix for T-360 was -51.23%. This method was optimized by repeating the extraction procedure and acidification of samples. These conditions were essential in increasing recovery (49.47%) by decreasing the matrix effect (-37.60%). The efficiency of the process, after optimization with two extractions and acidification, increased by 14.19% when compared to the initial method, from 18.05% to 32.24%. According to Marchi et al. (2010), the matrix effect does not necessarily need to be reduced or eliminated, but it does need to be identified and quantified. Therefore, these findings are essential for the subsequent evaluation of the pharmacokinetic parameters of this promising natural product.

Effect of diallyl trisulfide on the pharmacokinetics of nifedipine in rats.

This study aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic, on the pharmacokinetics of nifedipine. Pharmacokinetic parameters of nifedipine were determined in rats following an oral gavage (3 mg/kg) or intravenous administration (0.75 mg/kg) of nifedipine with co-administration of DATS (20 mg/kg) and long-term pretreatment of DATS (20 mg/kg/d for 15 consecutive days). Compared to the control groups, higher C(max) and AUC(0-24 h) were observed for oral gavage of nifedipine after short-term and long-term pretreatment of DATS, whereas those for intravenous nifedipine were little changed. The oral bioavailabilities of nifedipine were remarkably enhanced via the concomitant use of DATS. In conclusion, DATS increased the oral exposure of nifedipine in rats likely by the modification of intestinal metabolism of nifedipine, indicating that combined use of DATS or DATS-containing supplement with nifedipine may require caution because high plasma concentrations may lead to an undesired toxicity of this agent. Practical Application: Patients suffering from cardiovascular disease should take caution in combined use of DATS or DATS-rich garlic supplement with nifedipine because long-term treatment of DATS could lead high plasma concentrations of nifedipine.

A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain.

Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.

The effect of licorice drink on the systemic exposure of verapamil in rabbits.

The effect of licorice root drink (aqueous extract of Glycyrrhiza glabra Fabaceae) on plasma concentration of verapamil, using rabbits as animal model, was investigated. Two groups of locally inbred New Zealand male rabbits were used. The first group was given a single dose of licorice drink (4 ml/kg body weight) concomitantly with 30 mg/kg verapamil, and the second group was given a daily dose of licorice drink (4 ml/kg body weight) for two weeks, with single doses of verapamil on days, 7 and 14. Single dose treatment resulted in a nonsignificant decrease in mean C(max) by 33.2% (P = 0.41), but in a significant decrease of AUC(0-24) and AUC(0-infinity) by 60.5% and 63.6%, respectively (P = 0.01). First period of multiple dose treatment study (7 days), resulted in a significant reduction in mean C(max), AUC(0-24) and AUC(0-infinity) by 55.0%, 47.0% and 45.7%, respectively (P = 0.02, 0.03 and 0.03, respectively). A more pronounced effect was seen at second period of multiple dose treatment study (14 days), where the corresponding decrease was, 85.4%, 76.8% and 73.3%, respectively (P < 0.01). Mean T(max) was significantly increased 4.2-fold over control period at day 14 of multiple dose study (P = 0.02). In conclusion, licorice root drink decreased verapamil systemic exposure both after single dose and after daily doses for 14 days.

Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats.

This study investigated the effects of orally administered morin, an inhibitor of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), on the pharmacokinetics of orally and intravenously administered nicardipine in rats. Nicardipine is reportedly a substrate for CYP3A4 and P-gp. Nicardipine was administered orally (12 mgkg(-1)) with or without orally administered morin (1.5, 7.5 and 15 mgkg(-1)), and intravenously (4 mgkg(-1)) with or without orally administered morin (7.5 and 15 mgkg(-1)). In the presence of morin, the pharmacokinetic parameters of nicardipine were significantly altered in the oral group but not in the intravenous group, suggesting that CYP3A-mediated metabolism of nicardipine in the liver is not significantly inhibited by morin. The presence of 7.5 and 15 mgkg(-1) of morin significantly increased (P < 0.01, 67.8-112%) the area under the plasma concentration-time curve and the peak plasma concentration (P < 0.01, 53.5-93.1%) of orally administered nicardipine. The presence of 7.5 and 15 mgkg(-1) of morin significantly decreased (P < 0.01, 40.4-52.8%) the total body clearance of orally administered nicardipine compared with the control group. The enhanced oral bioavailability of nicardipine suggests that intestinal-mediated CYP3A4 metabolism and P-gp-mediated efflux of nicardipine are inhibited by morin. Based on these results, concomitant use of morin or morin-containing dietary supplements with nicardipine may require close monitoring for potential drug interactions.

The effect of silymarin on oral nifedipine pharmacokinetics.

Silibinin, the main component of silymarin (a milk thistle extract used for treatment of liver injury), has been shown to inhibit CYP3A4 in human liver microsomes. The present study was conducted to examine whether inhibition of CYP3A4 by silymarin is also present IN VIVO. Immediate release nifedipine (10 mg) was administered as a CYP3A4 test drug either alone or with co-administration of silymarin (280 mg administered 10 hours and 1.5 hours prior to the administration of nifedipine) to 16 healthy male volunteers (mean age 27 years, mean body weight 77 kg). Nifedipine and silibinin concentrations were quantified by HPLC, heart rate and blood pressure were monitored for safety reasons. Pharmacokinetic parameters were calculated by non-compartmental methods, and the potential interaction by silymarin was handled as an equivalence problem. We found that nifedipine AUC was 1.13-fold higher (90 % CI, 0.97- to 1.32-fold) in the silymarin period, C (max) values were 0.70-fold (90 % CI, 0.39- to 1.27-fold) of those of the reference period, with a trend to delayed absorption in the silymarin period. Intraindividual variability especially for C (max) (intrasubject CV 120 %) was unexpectedly high. There was no meaningful effect on hemodynamic parameters. In conclusion, our data suggest that co-administration of silymarin does not considerably change the extent of absorption or metabolism of nifedipine but may decrease the absorption rate. Silymarin thus is not a potent CYP3A4 inhibitor IN VIVO.

Rapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical herb-drug interaction study.

Nifedipine (NIF), a calcium channel antagonist, is metabolized primarily by cytochrome P450 (CYP3A4) to dehydronifedipine (DNIF). As such, NIF is often used as a probe drug for determining CYP3A4 activity in human studies. A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated to simultaneously determine NIF and DNIF in human plasma using nitrendipine as the internal standard (IS). After extraction of the plasma samples by ether-n-hexane (3:1, v/v), NIF, DNIF and the IS were subjected to LC/MS/MS analysis using electro-spray ionization (ESI). Chromatographic separation was performed on a Hypersil BDS C(18) column (50 mm x 2.1 mm, i.d., 3 microm). The method had a chromatographic running time of approximately 2.5 min and linear calibration curves over the concentrations of 0.5-100 ng/mL for NIF and DNIF. The recoveries of the one-step liquid extraction method were 81.3-89.1% for NIF and 71.6-80.4% for DNIF. The lower limit of quantification (LLOQ) of the analytical method was 0.5 ng/mL for both analytes. The intra- and inter-day precision was less than 15% for all quality control samples at concentrations of 2, 10, and 50 ng/mL. The validated LC/MS/MS method has been successfully used to study pharmacokinetic interactions of NIF with the herbal antidepressant St. John's wort in healthy volunteers. These results indicated that the developed LC/MS/MS method was efficient with a significantly shorter running time (2.5 min) for NIF and DNIF compared to those methods previously reported in the literature. The presented LC/MS/MS method had acceptable accuracy, precision and sensitivity and was used in a clinical pharmacokinetic interaction study of NIF with St. John's wort, a known herbal inducer of CYP3A4. St. John's wort was shown to induce NIF metabolism with increased plasma concentrations of DNIF.

Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage - a pilot study.

OBJECTIVE: The pharmacokinetics of nimodipine following enteral administration in the early phase after subarachnoid haemorrhage (SAH) has not been described. If a sufficient absorption could be achieved with enterally administered nimodipine, this would be more feasible dosage form and result in a significant reduction in pharmaceutical costs given that the parenteral formulation of nimodipine currently used is tenfold more expensive than the enteral formulation. METHODS: This was a pilot study in which 17 patients with aneurysmal SAH were randomly assigned to receive nimodipine within 24 h after initial bleeding either as an 60 mg tablet/suspension at 4-h intervals, or as a continuous intravenous infusion of 2 mg/h. Serum nimodipine concentrations were measured during the 4 h following the first dose, and at 24 and 72 h on a validated gas chromatography mass spectrometer (GC-MS). RESULTS: Nimodipine AUC values (expressed in mug min/ml) were lower in the eight SAH patients receiving enteral nimodipine [AUC(0-4) range: 0.13-5.4 (median: 0.32); AUC(24-28) range: 0.16-6.1 (0.71); AUC(72-76) range: 0.47-20.6 (1.9)] than in the nine patients receiving a continuous intravenous infusion of nimodipine [AUC(0-4) range: 2.4-4.9 (3.4), p=0.059; AUC(24-28) range: 4.7-10.3 (7.3), p=0.001; AUC(72-76) range: 3.4-8.6 (6.9), p=0.001]. In three of five good-grade SAH patients receiving nimodipine tablets the AUC values were comparable to those of the intravenous administration, but in two good-grade patients with tablets and in all three poor-grade (Hunt&Hess, grade IV) SAH patients receiving the suspension, the rate and extent of nimodipine absorption was negligible. CONCLUSION: This pilot study indicates that the rate and extent of nimodipine absorption following enteral administration in some acute SAH patients could be negligible, and this may particularly be the case in patients with a decreased level of consciousness.

The use of heat treatment to eliminate drug interactions due to grapefruit juice.

Grapefruit juice (GJ) contains components that may increase the bioavailability of drugs; however, approaches to the removal of these components have been little investigated. It is known that furanocoumarin derivatives (FCs), such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB) in GJ, induce such drug interactions. In the present study, it was found that the heat treatment of grapefruit juice decreases concentrations of BG and DHB as well as their interactions both in vitro and in vivo. We incubated GJ for 10, 20, 30, 40, 50, and 60 min at 37, 62, 72, and 95 degrees C; FCs in each sample were then measured, using high-performance liquid chromatography (HPLC). The concentrations of BG and DHB were decreased in a time- and temperature-dependent manner, by 82.5 and 97.9% respectively, after incubation for 1 h at 95 degrees C. In contrast, the concentration of bergaptrol (BT) increased in a time- and temperature-dependent manner (27.7% after 60 min at 95 degrees C). In addition, the effect of each GJ sample on testosterone 6beta-oxidation in human liver microsomes was observed. The inhibitory effects of GJ heated to 95 degrees C were decreased in a time-dependent manner, as in the case of BG and DHB concentrations. Furthermore, 2 ml of GJ treated for 60 min at 95 degrees C was administered into the rat duodenum. After 30 min, nifedipine (NFP) was administered intraduodenally at a dose of 3 mg/kg body weight. The concentrations of NFP in the plasma samples were determined by HPLC. No significant increase in the AUC of NFP was observed in the rats given heat-treated GJ. These results suggest that the heat treatment of GJ reduces the concentrations of FCs, thus eliminating the potential for drug interactions.

[Pharmacokinetics of osthole in rabbits].

AIM: To investigate the pharmacokinetics of osthole in rabbits and obtain the main pharmacokinetic parameters. METHODS: A simple high-performance liquid chromatography (HPLC) method was developed to study the pharmacokinetics of osthole in rabbits by joining an internal standard (paeonal). Methanol-water (80:20) was used as the mobile phase. According to the 3P87 pharmacokinetic program, the main parameters were calculated. RESULTS: The osthole pharmacokinetics conforms to a two compartment open model after i.v. administration, T1/2 alpha = 5.81 min, T1/2 beta = 42.2 min, K21 = 0.036 0.min-1, K12 = 0.045 0.min-1, K10 = 0.054 0.min-1, AUC = 235 mg.min.L-1, CLs = 0.043 0 L.min-1.kg-1, Vc = 0.780 L.kg-1. CONCLUSION: The pharmacokinetics of osthole after i.v. administration showed a rapid distribution and elimination process in rabbits.

Administration of nifedipine CR immediately after awakening prevents a morning surge in hypertensive patients. Case report of three cases.

Although the blood pressure-lowering action of some long-acting calcium antagonists may last more than 24 h, some patients taking this drug still experience a morning surge, i.e. an early morning increase in blood pressure. We evaluated this morning surge in three hypertensive patients with morning surge after administration of antihypertensive drugs including nifedipine CR. Nifedipine CR is one of the once-a-day formulations of nifedipine, which after administration, results in two peaks in the plasma concentration of nifedipine. The first concentration peak of occurs 3 h after administration and the second around 12 h after intake. When the time of intake of nifedipine CR was changed from after breakfast to immediately after awakening, the morning surge was suppressed in these patients without the use of other drugs such as alpha- or beta-blockers. Administration of nifedipine CR immediately after awakening is one option that can be used to prevent morning surge as well as to control blood pressure throughout the day.

Formulation and in vivo evaluation of membrane-moderated transdermal therapeutic systems of nicardipine hydrochloride using carvone as a penetration enhancer.

A membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride was developed using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 8%w/w of carvone as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38, or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28%w/w vinyl acetate) or EVA 2825 membrane/skin composite also was studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED and 2%w/w HPC gel as reservoir containing 8%w/w of carvone as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 23 hr with improved bioavailability in comparison with the immediate-release capsule dosage form.

A double masked placebo controlled study on the effect of nifedipine on optic nerve blood flow and visual field function in patients with open angle glaucoma.

AIMS: To investigate whether nifedipine affects ocular perfusion or visual fields in open angle glaucoma patients. METHODS: In a parallel group study nifedipine or placebo was administered for 3 months (n = 30). Ocular fundus pulsation amplitude (FPA), cup blood flow (Flowcup) and visual field mean deviation (MD) were measured. RESULTS: Five patients receiving nifedipine discontinued due to adverse events. Nifedipine did not affect FPA [difference: 0.3 microm (95% CI -0.3,0.9); P = 0.70], Flowcup: [difference: -9 rel.units (95% CI -133,114); P = 0.99], or MD [difference: 0.2dB (95% CI -2.2,2.7); P = 0.51] vs placebo. CONCLUSIONS: Systemic nifedipine is not well tolerated in glaucoma patients and exerts no effect on visual fields or ocular perfusion.

A double-blind trial of perindopril and nitrendipine in incipient diabetic nephropathy.

UNLABELLED: We conducted a randomised, double-blind multicentre trial to compare the efficacy of the inhibitor of the angiotensin-converting enzyme (ACE) perindopril (P) with nitrendipine (N) in incipient diabetic nephropathy. METHODS: Forty-six patients with insulin-treated diabetes mellitus and mild-to-moderate hypertension and stable microalbuminuria were examined. P 4 or 8 mg once daily was compared to N 20 or 40 mg once daily; an optional open combination treatment with indapamide 2.5 mg once daily was given when needed. Main outcome measures were urinary albumin excretion rate, creatinine clearance and isotopic clearance measurements after 12 months. RESULTS: Baseline characteristics (blood pressure, HbA1, renal function) were highly comparable between groups. No serious adverse events occurred during the study period. Blood pressure was controlled (<140/90 mmHg) in all patients except for one in each group who dropped out. At the end of the study, albumin excretion rate was stabilized in both groups (P: 72% of baseline, N: 108%, NS). There were no significant differences found in radiometric clearance measurements. Creatinine clearance rose in patients treated with P by 10.0 ml/min on average, while it decreased by 9.8 m/min under N treatment (group effect: p<0.05). CONCLUSIONS: In this head-to-head comparison, P and N were effective in stabilising most parameters of renal function in incipient diabetic nephropathy.