Oral administration of a low dose of midazolam (75μg) as an in vivo probe for CYP3A activity

Objective: We investigated whether the oral administration of a low dose (75µg) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. Methods: Plasma concentrations of midazolam, 1′OH-midazolam and 4′OH-midazolam were measured after the oral administration of 7.5mg and 75µg midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2days with ketoconazole (200mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4days with rifampicin (450mg q.d.), a CYP3A inducer. Results: After oral administration of 75µg midazolam, the 30-min total (unconjugated + conjugated) 1′OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean±SD): 6.23±2.61, 0.79±0.39 and 56.1±12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1′OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r2=0.64, P<0.001) and in the three groups taken together (r2=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5h and 4h. Conclusion: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1′OH-midazolam/midazolam ratios at 30min or by the determination of midazolam plasma levels between 1.5h and 4h after its administratio

Premedication with midazolam in intellectually disabled dental patients: intramuscular or oral administration? A retrospective study

Background: The use of midazolam for dental care in patients with intellectual disability is poorly documented. The purpose of this study was to determine which method of premedication is more effective for these patients, 0.15 mg/kg of intramuscular midazolam or 0.3 mg/kg of oral midazolam. Material and Methods: This study was designed and implemented as a non-randomized retrospective study. The study population was composed of patients with intellectual disability who required dental treatment under ambulatory general anesthesia from August 2009 through April 2013. Patients were administered 0.15 mg/kg of midazolam intramuscularly (Group IM) or 0.3 mg/kg orally (Group PO). The predictor variable was the method of midazolam administration. The outcome variables measured were Observer’s Assessment of Alertness/ Sedation (OAA/S) Scale scores, the level of cooperation when entering the operation room and for venous cannulation, post-anesthetic agitation and recovery time. Results: Midazolam was administered intramuscularly in 23 patients and orally in 21 patients. More patients were successfully sedated with no resistance behavior during venous cannulation in Group PO than in Group IM ( p =0.034). There were no differences in demographic data and other variables between the groups. Conclusions: The results of this study suggest that oral premedication with 0.3 mg/kg of midazolam is more effective than 0.15 mg/kg of midazolam administered intramuscularly, in terms of patient resistance to venous cannulation. If both oral and intramuscular routes of midazolam are acceptable in intellectually disabled patients, the oral route is recommended

A Comparison of Moderate Oral Sedation Drug Regimens for Pediatric Dental Treatment: A Pilot Study

Purpose: Compare moderate oral sedation of pediatric patients using Hydroxyzine and Meperidine with either Diazepam or Midazolam in management of pediatric dental patients. Methods: Randomized, double-blind, crossover pilot study of patients 3 to 7 years of age requiring two sedation visits. Frankl and Houpt behavior scores recorded at injection time, initiation of treatment and 100% oxygen at end of treatment. Postoperative phone call surveys conducted within eight hours and within 24 hours of discharge. Wilcoxon Signed-Rank tests, Fisher’s Exact Chi-squared test and 0.10 significance level. Results: 25 subjects completed 35 sedations. Eight participants completed both treatments and demonstrated significantly higher total Houpt Scores with Diazepam at all treatment stages. Frankl scores favored Diazepam at injection time. More abnormal behavior was found with Midazolam, less memory of the visit with Diazepam, but longer sleep time with Diazepam. Conclusions: Sedation with the Hydroxyzine, Meperidine and Diazepam regimen may allow for a better overall sedation experience. Postoperative monitoring is essential. The results are promising and demonstrate the value of a larger study on sedation with Diazepam

The effects of Andrographis paniculata (Burm.f.) Nees on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers

Andrographis paniculata (Burm.f.) Nees has been widely used for centuries in Asia for the treatment of common coldand diarrhea. Although it was previously reported to inhibit cytochrome P450 in vitro, the potential to cause herb-druginteraction has been questioned. The purpose of this study was to evaluate the effects of A. paniculata on the pharmacokineticsand pharmacodynamics of midazolam, a CYP3A4 probe drug, in normal healthy volunteers. The study was anopen-label, randomized, 2-phase crossover design with a 2-weeks washout period. Twelve healthy male volunteers received4 capsules of 250 mg A. paniculata 3 times a day orally for 7 days. Midazolam plasma concentration time profiles werecharacterized after a single oral dose of 7.5 mg midazolam on the day before and after A. paniculata medication. Pharmacodynamicsof midazolam were also evaluated. The results demonstrated that pretreatment with A. paniculata did not changemean pharmacokinetic parameters (Cmax, Tmax, AUC0-12, AUC0-”, T1/2, Cl/F) of oral midazolam. Since midazolam is the mostsensitive substrate for CYP3A4, thus, herb-drug interaction caused by CYP3A4 inhibition after A. paniculata in healthyvolunteers was considered not clinically relevant. However, A. paniculata potentiated the effect of midazolam in loweringblood pressure and pulse rate. Therefore, co-administration of A. paniculata with midazolam should be warranted

Comparison of Triple Combination Oral Sedation Regimens for Pediatric Dental Treatment

Purpose: Compare the efficacy of two benzodiazepines (diazepam or midazolam) in combination with meperidine and hydroxyzine for pediatric dental sedation. Methods: A randomized, double blind observation study of behaviors and outcomes related to two sedation groups. Frankl and Houpt behavior scores were recorded at three time points: injection time, initiation of treatment and at the end of treatment. Postoperative phone call surveys were conducted within eight hours of discharge to assess sleep, activity, and behavior. Results: A total of 40 sedation subjects were included in the study, of which 20 were treated with diazepam triple Combination (Di+M+H) and 20 with midazolam triple regime (Mi+M+H). Treatment was successful for 45% of cases with midazolam and 70% with diazepam (P value=.20). Houpt sleep scores were significantly higher for diazepam than midazolam at injection (P-value=.0043) and during treatment (P-value=.0152). Although Frankl scores, Houpt move and Houpt cry scores tended to favor diazepam, none were statistically significantly different. More abnormal behavior was reported with midazolam, though not statistically significant (35% vs 6%, P-value=.0854). Postoperative sleep time was longer for midazolam, but not significantly different (median sleep time: 61 vs 45 minutes, P-value=.2071). Conclusion: The diazepam, meperidine, hydroxyzine triple combination sedation regimen shows promising results as a successful alternative to midazolam triple combination. Longer postoperative monitoring may be required with diazepam, but this study has shown postoperative sleep times to be less than previously reported. Larger sample size is needed to determine if the current trend will be maintained

Oral sedation with midazolam in blepharoplasty

OBJETIVO: Avaliar a eficácia e a segurança do emprego oral de midazolam (15 mg) como medicação pré-anestésica em pacientes submetidos a blefaroplastias. MÉTODOS: Foi desenvolvido um ensaio clínico prospectivo, duplo cego, randomizado, controlado com 42 pacientes, risco ASA I e II, divididos em três grupos de 14 pacientes: grupo M (midazolam 15 mg), grupo P (placebo) e grupo SM (sem medicação). Os pacientes foram avaliados quanto ao grau de sedação e dor intraoperatórias e variação entre os períodos pré e transoperatórios da ansiedade, pressão arterial sistólica e diastólica, frequência respiratória e pulso. RESULTADOS: A análise de variância unifatorial com teste de Tukey mostrou que a administração de midazolam ocasionou uma redução significativa da pressão arterial sistólica e da frequência respiratória no período transoperatório em relação aos pacientes que utilizaram placebo ou não fizeram uso de medicamento. Esses efeitos foram discretos e acompanhados de diminuição na percepção da dor, discreta sedação e redução da ansiedade. CONCLUSÃO: A sedação via oral com midazolam em pacientes submetidos a cirurgias palpebrais demonstrou ser eficiente de fácil aplicação e com mínimos efeitos sistêmicos.PURPOSE: To evaluate the safety and usefulness of the use of oral sedation with midazolam (15 mg) in patients submitted to blepharoplasty. METHODS: Randomized double-blind prospective study of 42 patients (surgical risk ASA I and II) divided into three groups of 14 patients each: Group M (midazolam 15 mg), group P (placebo) and group SM (no medication). All patients were evaluated according to the degree of sedation and pain during surgery and the variation of anxiety between the preoperative and intraoperative period, arterial pressure (systolic-SAP and diastolic-DAP), respiratory frequency (RF) and pulsation. RESULTS: Unifatorial variance analysis with Tukey test demonstrated that the use of midazolam provoked a significant SAP and RF reduction during the intraoperative period. These effects were not pronounced and were accompanied by a reduction of pain perception and anxiety and mild sedation. CONCLUSIONS: Oral sedation with midazolam in patients that had undergone eyelid surgical procedures is safe and easy to perform with minimal systemic effects

Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences

Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs. These interactions are particularly of clinically relevance when metabolizing enzymes and xenobiotic transporters, which are responsible for the fate of many drugs, are induced or inhibited, sometimes resulting in unexpected outcomes. This article discusses the general use of herbal medicines in the management of several ailments, their concurrent use with conventional therapy, mechanisms underlying herb-drug interactions (HDIs) as well as the drawbacks of herbal remedy use. The authors also suggest means of surveillance and safety monitoring of herbal medicines. Contrary to popular belief that "herbal medicines are totally safe," we are of the view that they are capable of causing significant toxic effects and altered pharmaceutical outcomes when coadministered with conventional medicines. Due to the paucity of information as well as sometimes conflicting reports on HDIs, much more research in this field is needed. The authors further suggest the need to standardize and better regulate herbal medicines in order to ensure their safety and efficacy when used alone or in combination with conventional drugs

Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study.

Determining factors that contribute to interindividual and intra-individual variability in pharmacokinetics (PKs) and drug metabolism is essential for the optimal use of drugs in humans. Intestinal microbes are important contributors to variability; however, such gut microbe-drug interactions and the clinical significance of these interactions are still being elucidated. Traditional PKs can be complemented by untargeted mass spectrometry coupled with molecular networking to study the intricacies of drug metabolism. To show the utility of molecular networking on metabolism we investigated the impact of a 7-day course of cefprozil on cytochrome P450 (CYP) activity using a modified Cooperstown cocktail and assessed plasma, urine, and fecal data by targeted and untargeted metabolomics and molecular networking in healthy volunteers. This prospective study revealed that cefprozil decreased the activities of CYP1A2, CYP2C19, and CYP3A, decreased alpha diversity and increased interindividual microbiome variability. We further demonstrate a relationship between the loss of microbiome alpha diversity caused by cefprozil and increased drug and metabolite formation in fecal samples. Untargeted metabolomics/molecular networking revealed several omeprazole metabolites that we hypothesize may be metabolized by both CYP2C19 and bacteria from the gut microbiome. Our observations are consistent with the hypothesis that factors that perturb the gut microbiome, such as antibiotics, alter drug metabolism and ultimately drug efficacy and toxicity but that these effects are most strongly revealed on a per individual basis

Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency

Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency(ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drugmetabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design:We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. Results: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. Conclusions: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered

Alcohol Withdrawal – Therapeutical Management in Surgical Patients with Upper Intestinal Bleeding

Psychological dependence involves a desire to use a drug to avoid the unpleasant withdrawal syndrome that results from cessation of exposure to it. Alcohol withdrawal syndrome is one of the most feared complications of alcohol addiction and sometimes can be fatal if not treated properly. Withdrawal syndrome is characterized by neurological hyperexcitability, which can lead to severe psychological and neurological symptoms. A survey was conceived in order to monitor the efficiency of several drug associations (Clonidine, Midazolam, IV ethanol), which were administered at the beginning of intensive therapy admission of achohol addicts. By comparing the postoperative evolution parameters and complications incidences for these patients (such as the hospitalization duration in AIT department, the tracheobronchitis incidence, complications as sepsis, pneumonia and cardiac complications), we managed to determine which treatment is the most beneficial for these cases. Benzodiazepines are frequently used for pharmacological therapy of alcohol addicted patients. In our study Midazolam was very efficient, compared to other therapies. When administered for a maximum of 7 days, the inccidence of side effects remains minimal