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1.  Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay) 
Background
Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population).
Methods
All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC.
Results
It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM).
Conclusion
A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy.
doi:10.1186/1472-6904-6-8
PMCID: PMC1630702  PMID: 17062149
2.  Finasteride induced depression: a prospective study 
Background
Finasteride is a competitive inhibitor of 5 alpha-reductase enzyme, and is used for treatment of benign prostatic hyperplasia and androgenetic alopecia. Animal studies have shown that finasteride might induce behavioral changes. Additionally, some cases of finasteride-induced depression have been reported in humans. The purpose of this study was to examine whether depressive symptoms or anxiety might be induced by finasteride administration.
Methods
One hundred and twenty eight men with androgenetic alopecia, who were prescribed finasteride (1 mg/day) were enrolled in this study. Information on depressed mood and anxiety was obtained by Beck Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS). Participants completed BDI and HADS questionnaires before beginning the treatment and also two months after it.
Results
Mean age of the subjects was 25.8(± 4.4) years. At baseline, mean BDI and HADS depression scores were 12.11(± 7.50) and 4.04(± 2.51), respectively. Finasteride treatment increased both BDI (p < 0.001) and HADS depression scores significantly (p = 0.005). HADS anxiety scores were increased, but the difference was not significant (p = 0.061).
Conclusion
This preliminary study suggests that finasteride might induce depressive symptoms; therefore this medication should be prescribed cautiously for patients with high risk of depression. It seems that further studies would be necessary to determine behavioral effects of this medication in higher doses and in more susceptible patients.
doi:10.1186/1472-6904-6-7
PMCID: PMC1622749  PMID: 17026771
3.  Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy 
Background
Voriconazole was introduced for the treatment of life-threatening fungal infections. The intravenous form includes the solvent vehicle sulphobutylether beta cyclodextrin sodium which shows an impaired clearance under intermittent dialysis therapy. This investigation aimed to determine first clinical data on sulphobutylether beta cyclodextrin sodium blood levels to verify the risk for accumulation.
Methods
In four patients suffering from renal insufficiency and intermittent dialysis therapy who needed a treatment with intravenous voriconazole as a reserve antifungal at the intensive care unit of the Mainz University Hospital the trough levels of voriconazole and sulphobutylether beta cyclodextrin sodium were measured.
Results
A 75-year-old woman showed a maximal sulphobutylether beta cyclodextrin sodium plasma level of 145 μg/ml in the initial phase. After a few days renal function recovered and the plasma levels came down to less than 20 μg/ml. In contrast to this patient with a recovery of renal function the remaining three patients showed renal failure during the complete period of intravenous treatment with voriconazole. In these patients an accumulation of sulphobutylether beta cyclodextrin sodium plasma levels was determined with a maximum of 523 μg/ml in a 18-year-old man, 409 μg/ml in a 57-year-old man, and 581 μg/ml in a 47-year-old man.
Conclusion
The present data indicate an accumulation of sulphobutylether beta cyclodextrin sodium in patients treated with intravenous voriconazole and dialysis therapy. Fortunately, no toxic effects were observed, although the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals.
doi:10.1186/1472-6904-6-6
PMCID: PMC1592308  PMID: 16981986
4.  Hemolytic uremic syndrome following the infusion of oxaliplatin: case report 
Background
Oxaliplatin is a platinum derivative, which is used in the treatment of colorectal cancer. A small number of oxaliplatin-related hemolytic and/or thrombocytopenic reactions have been reported. We present a case of hemolytic-uremic syndrome that developed during the 4th cycle of combination chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin.
Case presentation
A 52-year-old-male was administered chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin for a Duke's stage C colorectal carcinoma. Three cycles of chemotherapy had been administered without complications when, at the beginning of the fourth cycle, the patient developed clinical and laboratory abnormalities consistent with the development of the hemolytic-uremic syndrome. Treatment was discontinued; the patient was managed with monitored IV hydration and loop diuretics, high dose corticosteroids and fresh frozen plasma infusions and recovered completely.
Conclusion
The hemolytic-uremic syndrome may be a rare complication of oxaliplatin-based chemotherapy. Clinicians need to maintain a high index of suspicion to diagnose and treat this life-threatening adverse event.
doi:10.1186/1472-6904-6-5
PMCID: PMC1574347  PMID: 16968538
5.  Single and multiple dose pharmacokinetics of maritime pine bark extract (Pycnogenol) after oral administration to healthy volunteers 
Background
Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers.
Methods
Eleven volunteers received a single dose of 300 mg pine bark extract, five volunteers ingested 200 mg daily for five days to reach steady state concentrations. Plasma samples were obtained before and at defined time points after intake of the extract. Samples were analyzed by HPLC with ion-pair reagents and simultaneous UV and electrochemical detection.
Results
We quantified total plasma concentrations of catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (δ-(3,4-dihydroxy-phenyl)-γ-valerolactone). Additionally, we describe plasma time courses and steady state appearance of ten so far unknown compounds, U1 to U10. After single ingestion, compounds derived from the extract were rapidly absorbed and the majority of them were detectable over whole experimental period of 14 h. The analysis of steady state plasma samples revealed significant phase II metabolism.
Conclusion
We present the first systematic pharmacokinetic analysis of compounds derived from maritime pine bark extract. Beyond the known constituents and metabolites we uncovered the plasma time courses of ten unknown compounds. In concert with our previous detection of anti-inflammatory bioefficacy of these plasma samples ex vivo we suggest that constituents and metabolites of Pycnogenol bear potential for disclosure of novel active principles.
doi:10.1186/1472-6904-6-4
PMCID: PMC1559639  PMID: 16887024
6.  Serum sickness-like reaction associated with cefazolin 
Background
Although rare, serum sickness-like reactions have been documented to occur following the administration of many antibiotics. Cefazolin, a first generation cephalosporin, is a commonly prescribed antibiotic which is considered to be generally safe and well tolerated. There have been no prior reports linking this drug with sickness-like reactions. We report a probable case of serum sickness-like reaction following a single dose of cefazolin.
Case Presentation
A 23 year old man with no significant past medical history was admitted to undergo a laparoscopic donor nephrectomy as part of a living-related renal transplant. One gram of intravenous cefazolin was administered perioperatively. The surgery was completed without complication and the remainder of his hospital course was uneventful. Ten days following discharge the patient developed fevers, painful and swollen joints, and a cutaneous eruption overlying his trunk and extremities. There was no evidence of systemic vasculitis. These clinical findings were most consistent with a serum sickness-like reaction. A brief course of corticosteroids and antihistaminergic therapy was initiated, and complete resolution of the patient's symptoms followed. The Naranjo probability scale indicated that this adverse drug event was probable.
Conclusion
Serum sickness-like reaction may be associated with cefazolin therapy.
doi:10.1186/1472-6904-6-3
PMCID: PMC1397863  PMID: 16504095
7.  High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection 
Background
The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy.
Methods
Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel.
Results
The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within ± 15%, except at the limit of quantitation where values within ± 20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m2 of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion.
Conclusion
We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase.
doi:10.1186/1472-6904-6-2
PMCID: PMC1382254  PMID: 16412237
8.  Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat 
Background
The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class.
Methods
The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest.
Results
The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution.
Conclusion
If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained.
doi:10.1186/1472-6904-6-1
PMCID: PMC1373666  PMID: 16398929

Results 1-8 (8)