Herbal modulation of P-glycoprotein

P-glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp-expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity. Many of these herbal constituents, in particular flavonoids, were reported to modulate Pgp by directly interacting with the vicinal ATP-binding site, the steroid-binding site, or the substrate-binding site. Some herbal constituents (e.g., hyperforin and kava) were shown to activate pregnane X receptor, an orphan nuclear receptor acting as a key regulator of MDR1 and many other genes. The inhibition of Pgp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells, whereas the stimulation of Pgp expression or activity has implication for chemoprotective enhancement by herbal medicines. Certain natural flavonols (e.g., kaempferol, quercetin, and galangin) are potent stimulators of the Pgp-mediated efflux of 7,12-dimethylbenz(a)-anthracene (a carcinogen). The modulation of Pgp activity and expression by these herb constituents may result in altered absorption and bioavailability of drugs that are Pgp substrates. This is exemplified by increased oral bioavailability of phenytoin and rifampin by piperine and decreased bioavailability of indinavir, tacrolimus, cyclosporine, digoxin, and fexofenadine by coadministered St. John's wort. However, many of these drugs are also substrates of CYP3A4. Thus, the modulation of intestinal Pgp and CYP3A4 represents an important mechanism for many clinically important herb-drug interactions. Further studies are needed to explore the relative role of Pgp and CYP3A4 modulation by herbs and the mechanism for the interplay of these two important proteins in herb-drug interactions.     

Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma

BACKGROUND: This Phase II study was designed to evaluate the efficacy and safety of irinotecan in patients with advanced nasopharyngeal carcinoma (NPC). METHODS: Patients with disseminated, undifferentiated NPC that progressed during or within 3 months of platinum-based and/or taxane-based regimen were eligible. Irinotecan at a dose of 100 mg/m(2) was administered on Days 1, 8, and 15 every 28 days, up to a maximum of 6 cycles, until disease progression or the appearance of intolerable toxicity. RESULTS: Twenty-eight patients were evaluable for toxicity and response. Patient characteristics were as follows: The median age was 46.5 years (range, 40.3-71.6 years), the median number of prior lines of chemotherapy was 2 (range, 1-9), the majority of patients (89%) had good Eastern Cooperative Oncology Group performance status (0-1), and the majority of patients (82.1%) had >/= 2 sites of distant metastases. A total of 79 cycles of irinotecan with a median of 3 cycles per patient were administered. Toxicity > Grade 3 included neutropenia in 5 patients (17%), anemia in 5 patients (17%), and diarrhea in 4 patients (14%). The best response outcomes were 4 patients (14%) who achieved partial responses and 1 patient (4%) who achieved stable disease. Global quality-of-life scores were stable during treatment. Using the Kaplan-Meier method, the median progression-free survival was 3.9 months, and the median overall survival was 11.4 months. The partial responders had a durable response (range, 5.7-12.2 months). CONCLUSIONS: Results from this trial suggest that irinotecan is an active salvage agent with modest toxicity in patients with advanced NPC who are refractory to platinum/taxane-based chemotherapy. Studies combining irinotecan with other active agents in the first-line setting are warranted.     

The modulation of irinotecan-induced diarrhoea and pharmacokinetics by three different classes of pharmacologic agents

Diarrhoea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11) in the clinical setting. This study was designed to evaluate the effects of different pharmacological agents in the modulation of CPT-11 induced diarrhoea in Sprague-Dawley rats. We studied the effects of intravenous valproic acid (VPA), ceftriaxone (CTX) and oral charcoal in the modulation of CPT-11 induced diarrhoea. Male Sprague-Dawley rats (n=7 per group) were given CPT-11 60 mg/kg as intravenous injection from day 1 to 5 (total dose 300 mg/kg) in all treatment groups. Group 1 (G1) rats only received CPT-11, group 2 to 6 (G2 to G6) rats received in addition to IV CPT-11 60 mg/kg, IV valproic acid (VPA) 200 mg/kg (G2), IV VPA 200 mg/kg + IV ceftriaxone (CTX) 100 mg/kg (G3), IV VPA 200 mg/kg + oral activated charcoal 250 mg administered twice daily (G4), IV CTX 100 mg/kg (G5) and oral charcoal 250 mg every 12 hourly (G6). We compared the pharmacokinetics of total CPT-11 and its metabolites and the frequency and grade of diarrhoea in each group of rats. There were no significant differences in the pharmacokinetic parameters of total CPT-11 between treatment groups (p>0.05). Cotreatment with CTX and charcoal resulted in a lower total SN-38G AUC0- infinity (p<0.05 and p<0.01, respectively). Cotreatment with CTX also resulted in a lower Cmax for total SN-38G compared to other groups (p<0.01). A higher frequency of grade 3 diarrhoea was observed in G1 rats compared to other groups. Co-treatment with VPA (log OR: -1.13; 95% CI: -1.85, -0.41) or CTX (log OR: -1.66; 95% CI: -2.43, -0.88) were found to be associated with a lower odds of grade 3 diarrhoea compared to control or charcoal treated groups. Our findings indicate that CPT-11 treated rats given VPA and CTX, either alone or in combination has similar effects in preventing high grade diarrhoea. Activated charcoal was not found to be effective in the prevention of high grade diarrhoea.     

Effect of coenzyme Q10 on the disposition of doxorubicin in rats.

The effect of exogenous coenzyme Q10 (CoQ10) on the pharmacokinetic profiles and biliary excretion of doxorubicin and its main metabolites, doxorubicinol and doxorubicinolone, was investigated in rats. No statistically significant changes in the pharmacokinetic parameters of doxorubicin was observed following the intravenous bolus administration of 10 mg/kg doxorubicin to rats during a 6-day oral regimen of CoQ10 (20 mg/kg daily). Treatment with CoQ10 did not affect the formation of the doxorubicinol, but produced a 75% increase (P < 0.05) in the AUC of doxorubicinolone. Correspondingly, CoQ10 had no apparent effect on the biliary excretion of doxorubicin and formation clearance of doxorubicinol, whereas the formation clearance of doxorubicinolone was significantly increased by 69% in CoQ10-pretreated rats (P < 0.05). Overall, the results suggest that CoQ10 treatment has no significant effect on the pharmacokinetics of doxorubicin and the formation of the cytotoxic metabolite, doxorubicinol.     

An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore

Much of the interindividual variability in drug response is attributable to the presence of single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes and drug transporters. In recent years, we have investigated the polymorphisms in a number of genes encoding phase I and II drug-metabolizing enzymes including CYPIA1, CYP3A4, CYP3A5, GSTM1, NAT2, UGT1A1, and TPMT and drug transporter (MDR1) in three distinct Asian populations in Singapore, namely the Chinese, Malays, and Indians. Significant differences in the frequencies of common alleles encoding these proteins have been observed among these three ethnic groups. For example, the frequency of the variant A2455G polymorphism of CYP1A1 was 28% in Chinese and 31% in Malays, but only 18% in Indians. CYP3A4*4 was detected in two of 110 Chinese subjects, but absent in Indians and Malays. Many Chinese and Malays (61-63%) were homozygous for the GSTM1*0 null genotype compared with 33% of Indians. The frequency of the UGTIA1*28 allele was highest in the Indian population (35%) compared to similar frequencies that were found in the Chinese (16%) and Malay (19%) populations. More importantly, our experience over the years has shown that the pharmacogenetics of these drug-metabolizing enzymes and MDR1 in the Asian populations are different from these in the Caucasian and African populations. For example, the CYP3A4*1B allele, which contains an A-290G substitution in the promoter region of CYP3A4, is absent in all three Asian populations of Singapore studied, but occurs in more than 54% of Africans and 5% of Caucasians. There were no difference in genotype and allelic variant frequencies in exon 12 of MDR1 between the Chinese, Malay, and Indian populations. When compared with other ethnic groups, the distribution of the wild-type C allele in exon 12 in the Malays (34.2%) and Indians (32.8%) was relatively high and similar to the Japanese (38.55%) and Caucasians (41%) but different from African-Americans (15%). The frequency of wild-type TT genotype in Asians (43.5% to 52.1%) and Japanese (61.5%) was much higher than those found in Caucasians (13.3%). All the proteins we studied represent the primary hepatic or extrahepatic enzymes, and their polymorphic expression may be implicated in disease risk and the disposition of drugs or endogenous substances. As such, dose requirements of certain drugs may not be optimal for Asian populations, and a second look at the factors responsible for this difference is necessary.     

Special delivery: when the pills "absolutely, positively" can't be delivered at home

The practice of storing and dispensing medications by providers at an inner city neighborhood health center that serves predominantly ethnic minority clients was terminated due to accreditation regulations. This practice promoted adherence since many clients did not want to receive medications by mail at home due to confidentiality concerns or were unwilling to present to their local pharmacy due to fear of discrimination related to HIV status. The purpose of this paper is to describe an alternative means to access HIV medications in a safe and supportive environment for clients confronted with cultural and social barriers through a unique collaboration between an HIV specialty care program and HIV specialty pharmacy.     

Transatrial permanent pacing lead implantation in a patient of Ebstein's anomaly after one and half repair

Several innovative approaches have been described to achieve endocardial pacing in patients with operated complex congenital heart diseases. We report herein a case of Ebstein's anomaly who underwent a Hardy's repair with a bidirectional Glenn shunt, tricuspid valve annuloplasty and atrial septal defect closure following which she developed complete heart block. The chest was reopened through the previous midsternotomy and a screw-in lead implanted transatrially that resulted in optimal pacing thresholds. This technique offers a viable alternative for endocardial pacing in peri-operative patients requiring permanent pacing.     

Open mitral commissurotomy in the current era: indications,technique, and results

BACKGROUND: The present retrospective study is focused on indications, techniques, and results of open mitral commisurotomy in the current era. METHODS: Of the 1,280 patients undergoing open-heart surgical procedures for rheumatic mitral stenosis between January 1990 and July 2000, 276 (21.6%) patients underwent open mitral commissurotomy. Major indications included presence of left atrial thrombus/clot (n = 82, 29.7%), severe subvalvular disease (n = 110, 39.8%), mitral valve calcification (n = 42, 15.2%), mild mitral regurgitation (n = 28, 10.0%), associated aortic valve disease (n = 55, 19.9%), organic tricuspid valve disease (n = 20, 7.2%), and failure or restenosis after closed or balloon mitral valvuloplasty (n = 55, 19.9%). Age of patients ranged from 7 to 67 years (mean, 30.2 +/- 12 years). The majority (76%) were in New York Heart Association class III or IV, and 6.9% were in congestive heart failure. Atrial fibrillation was present in 134 (48.6%) patients. Mitral valve area ranged from 0.3 to 0.7 cm2 (mean, 0.52 +/- 0.12 cm2). Mid-diastolic gradients across the mitral valve ranged from 8 to 34 mm Hg (mean, 14.5 +/- 6.2 mm Hg), and end-diastolic gradients ranged from 8 to 42 mm Hg (mean, 15.2 +/- 5.7 mm Hg). Open mitral commissurotomy was performed using standard cardiopulmonary bypass. Associated aortic valve procedure was performed in 55 patients, and either tricuspid valvotomy or repair was performed in 28 patients. RESULTS: There were four early deaths. All these patients had associated aortic valve procedure (Ross procedure in 2 and homograft aortic valve replacement in 2). Three patients developed severe mitral regurgitation in early postoperative period (< or = 30 days) and required reoperation. Predischarge echocardiography showed mitral valve area from 1.4 to 3.5 cm2 (mean, 2.6 +/- 0.6cm2) and moderate mitral regurgitation in 4 patients. Follow-up ranged from 1 to 130 months (mean, 64.5 +/- 28.6 months). There was no late death. There were three reoperations for mitral valve failure, and an additional 2 patients developed severe mitral stenosis (mitral valve area < 1.0 cm2). In operative survivors, freedom from mitral valve failure at 10 years was 87.0% +/- 3.5%. In patients with isolated open mitral commissurotomy, the incidence of thromboembolism was 0.5%/patient-year. CONCLUSIONS: Open mitral commissurotomy provides excellent early and long-term results in a selected group of patients.