Trends in oral drug bioavailability following bariatric surgery: examining the variable extent of impact on exposure of different drug classes

AIMS

To identify the most commonly prescribed drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral drug bioavailability post bariatric surgery.

METHODS

A retrospective audit was undertaken to document commonly prescribed drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for drug administration following bariatric surgery. The available literature was examined for trends relating to drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination.

RESULTS

No significant difference in the ‘post/pre surgery oral drug exposure ratio’ (ppR) was apparent between BCS class I to IV drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as ‘solubility limited’ displayed an overall reduction as compared with ‘freely soluble’ compounds, as well as an unaltered and increased ppR.

CONCLUSION

Clinical studies establishing guidelines for commonly prescribed drugs, and the monitoring of drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral drug exposure and in developing practical clinical guidance.     

High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139

Aim:

To discover antagonists of the orphan G-protein coupled receptor GPR139 through high-throughput screening of a collection of diverse small molecules.

Methods:

Calcium mobilization assays were used to identify initial hits and for subsequent confirmation studies.

Results:

Five small molecule antagonists, representing 4 different scaffolds, were identified following high-throughput screening of 16 000 synthetic compounds.

Conclusion:

The findings provide important tools for further study of this orphan G-protein coupled receptor.     

The ��apparent clearance�� of free phenytoin in elderly vs. younger adults

AIMS

To test the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in elderly patients.

METHODS

Two separate studies were conducted comparing free phenytoin ‘apparent clearance’ in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly.

RESULTS

In the retrospective study (n = 29), free phenytoin ‘apparent clearance’ was 0.27 ± 0.04 l kg⁻¹ day⁻¹ (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg⁻¹ day⁻¹ (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ‘apparent clearance’ showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg⁻¹ day⁻¹, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg⁻¹ day⁻¹, 95% CI 0.09, 0.26) in those not taking interacting drugs (n = 21).

CONCLUSIONS

This research does not prove the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect.     

Assessing the bioequivalence of analogues of endogenous substances (��endogenous drugs��): considerations to optimize study design

BACKGROUND

Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed.

AIMS

To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs.

METHODS

A literature search of the EMBASE and PubMed databases was performed.

RESULTS

The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance-deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses.

CONCLUSIONS

On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed.     

The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene

AIMS

To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors.

METHODS

A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n = 460) were hospitalized with acute coronary syndrome (ACS). Controls (n = 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real-time polymerase chain reaction using allele-specific probes

RESULTS

Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the ‘low risk’ haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the ‘high risk’ haplotype (one or two copies of GT).

CONCLUSIONS

We found little evidence of a gene/drug interaction. We found a statistically non-significant trend toward a lower risk of coronary events with NSAIDs in the presence of the ‘low risk’ haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.     

Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants

AIMS

To investigate time-dependent inhibition (TDI) of human drug metabolizing CYP enzymes by tricyclic antidepressants (TCAs).

METHODS

CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A/CYP3A4 activities were investigated following co- and preincubation with TCAs using human liver microsomes (HLM) and human recombinant CYP proteins (expressed in Escherichia coli) as the enzyme sources. A two-step incubation method was employed to examine the in vitro mechanism-based inactivation (MBI) criteria. Potential metabolite–intermediate complex (MIC) formation was studied by spectral analysis.

RESULTS

TCAs generally exhibited significant TDI of recombinant CYP1A2, CYP2C19 and CYP2D6 (>10% positive inhibition differences between co- and preincubation conditions). TDI of recombinant CYP2C9 was minor (<10%), and was minor or absent in experiments utilizing recombinant CYP3A4 or HLM as the enzyme sources. Where observed, TDI of recombinant CYP occurred via alkylamine MIC formation, but evidence to support similar behaviour in HLM was limited. Indeed, only secondary amine TCAs reduced the apparent P450 content of HLM (3–6%) consistent with complexation. As a representative TCA, nortriptyline fulfilled the in vitro MBI criteria using recombinant CYP2C19 and CYP3A4 (K_I and k_inact values of 4 µm and 0.19 min⁻¹, and 70 µm and 0.06 min⁻¹), but not with the human liver microsomal enzymes.

CONCLUSIONS

TCAs appear to have minimal potential for MBI of human liver microsomal CYP enzymes involved in drug metabolism. HLM and recombinant CYP (expressed in E. coli) are not equivalent enzyme sources for evaluating the TDI associated with some drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Much of the literature evidence for mechanism-based inactivation (MBI) of CYP by tricyclic antidepressants is limited to studies in rat liver microsomes.
• One report from this laboratory characterized MBI of human recombinant CYP2C8 by nortriptyline.

WHAT THIS STUDY ADDS

• Tricyclic antidepressants form alkylamine metabolite-intermediate complexes with human recombinant CYP enzymes (expressed in Escherichia coli) relatively easily, resulting in time-dependent inhibition.
• Evidence to support similar irreversible inhibition using human liver microsomal (HLM) fractions is limited.
• HLM and recombinant CYP (expressed in E. coli) are not equivalent enzyme sources for evaluating the time-dependent inhibition of human drug metabolizing CYP that is associated with some drugs.

     

Interpreting adverse drug reaction (ADR) reports as hospital patient safety incidents

AIM

In the UK, the National Patient Safety Agency (NPSA) includes adverse drug reactions as a reporting category, while the MHRA Yellow Card Scheme also collects data regarding adverse drug reactions (ADRs). In this study, we aimed to assess ADRs using NPSA criteria and discuss the resulting implications.

METHODS

ADRs identified in a 6-month prospective study of 3695 inpatient episodes were assessed according to their impact on the patient and on the organization, using tools developed by the NPSA.

RESULTS

Seven hundred and thirty-three (100%) ADRs were assessed. In terms of impact on the patient, 537 (73.3%) were categorized as ‘low’ (minor treatment), 181 (24.7%) as ‘moderate’ (moderate increase in treatment, no permanent harm), 14 (1.91%) as ‘severe’ (permanent harm) and 1 (0.14%) was categorized as ‘catastrophic’ (direct cause of death). In terms of impact on the organization, none was categorized as ‘no harm/ no risk’, 508 (69.3%) as ‘insignificant’, 188 (25.6%) as ‘minor’, 25 (3.4%) as ‘moderate’, 12 (1.6%) as ‘major’ and none was classed as ‘catastrophic’. Less than 2% of ADRs would be eligible for detailed analysis according to the NPSA guidance. The ADRs that cause incidents of greater significance relate to bleeding, renal impairment and Clostridium difficile infection.

CONCLUSIONS

Classification of ADRs according to NPSA guidance offers limited additional value over and above that offered by the Yellow Card System. A consistent message needs to be sent to prospective reporters of ADRs; the availability of more than one system is likely to confuse reporters and does not aid patient safety.     

Reimbursement for supportive cancer medications through private insurance in Saskatchewan

Background:

As demand for cancer treatment grows, and newer, more expensive drugs become available, public payers in Canada are finding it increasingly difficult to fund the full range of available cancer drugs.

Objective:

To determine the extent of private drug coverage for supportive cancer treatments in Saskatchewan, preparatory to exploring the potential for cost-sharing.

Methods:

Patients who presented for chemotherapy and who provided informed consent for participation were surveyed regarding their access to private insurance. Insurers were contacted to verify patients'' level of coverage for supportive cancer medications. Groups with specified types of insurance were compared statistically in terms of age, income bracket, time required to assess insurance status, and amount of deductible. Logistic regression was used to determine the effect of patients'' age and income on the probability of having insurance.

Results:

Of 169 patients approached to participate, 156 provided consent and completed the survey. Their mean age was 58.5 years. About two-fifths of all patients (64 or 41%) were in the lowest income bracket (up to $30 000). Sixty-three (40%) of the patients had private insurance for drugs, and 36 (57%) of these plans included reimbursement for supportive cancer medications. A deductible was in effect in 31 (49%) of the plans, a copayment in 28 (44%), and a maximum payment in 8 (13%). Income over $50 000 was a significant predictor of access to drug insurance (p = 0.003), but age was not significantly related to insurance status.

Conclusions:

A substantial proportion of cancer patients in this study had access to private insurance for supportive cancer drugs for which reimbursement is currently provided by the Saskatchewan Cancer Agency. Cost-sharing and optimal utilization of the multipayer environment might offer a greater opportunity for public payers to cover future innovative and supportive therapies for cancer, but further study is required to determine whether a cost-sharing program would be cost-effective and in the best interest of patients.     

Amoxicillin/clavulanic acid-warfarin drug interaction: a randomized controlled trial

AIMS

To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy.

METHODS

In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo.

RESULTS

The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P= 0.94). The day 7–day 1 factor II, R(–) and S(–) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P= 0.81, P= 0.45, P= 0.75, respectively).

CONCLUSION

Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.     

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject

• In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

• Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods

The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results

A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h⁻¹. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h⁻¹. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg⁻¹) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions

The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.     

Effectiveness of a medication reconciliation project conducted by PharmD students

Objectives

This study evaluated the effectiveness of a medication reconciliation program conducted by doctor of pharmacy (PharmD) students during an advanced pharmacy practice experience.

Methods

Patients admitted to medicine or surgery units at 3 hospitals were included. Students were instructed to interview each patient to obtain a medication history, reconcile this list with the medical chart, and identify and solve drug-related problems.

Results

Eleven students reconciled medications for 330 patients over 10 months and identified 922 discrepancies. The median number of discrepancies found per patient was 2, and no discrepancies were found in 25% of the cases. In cases in which discrepancies were identified, a greater number of medications had been prescribed for the patient (7.9 ± 4.0 medications compared to 5.4 ± 3.9 medications; p < 0.05). The students completed 59 interventions. Differences were found in the numbers of discrepancies and drug-related problems that different students at different sites identified (p < 0.05).

Conclusions

Pharmacy students provided a valuable service to 3 community hospitals. The students improved the quality of patient care by identifying and solving significant drug-related problems, identifying drug allergy information, and resolving home and admission medication discrepancies.     

Incidence of fatal adverse drug reactions: a population based study

Aims

To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

Methods

Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

Results

Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

Conclusions

The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

What is already known about this subject

• Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.
• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.
• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

What this study adds

• Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.
• Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.
• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

     

Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2

BACKGROUND AND PURPOSE

Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.

EXPERIMENTAL APPROACH

Itraconazole (20 mg·kg⁻¹) and metformin (100 mg·kg⁻¹) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V_max), Michaelis–Menten constant (K_m) and intrinsic clearance (CL_int) for the disappearance of each drug, apparent inhibition constant (K_i) and [I]/K_i ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro.

KEY RESULTS

After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration–time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes.

CONCLUSIONS AND IMPLICATIONS

The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.     

Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex

Aim:

To prepare a bergenin-phospholipid complex (BPC) to increase oral bioavailability of the drug.

Methods:

In order to obtain the acceptable BPC, a spherical symmetric design-response surface methodology was used for process optimization. The influence of reaction medium, temperature, drug concentration and drug-to-phospholipid ratio on the combination percentage and content of bergenin in BPC were evaluated. BPC was then characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray powder diffraction. The physicochemical properties such as microscopic shape, particle size, zeta-potential, solubility, crystalline form, and hygroscopicity were tested. The pharmacokinetic characteristics and bioavailability of BPC were investigated after oral administration in rats in comparison to bergenin and the physical mixture (bergenin and phospholipids).

Results:

BPC was successfully prepared under the optimum conditions [temperature=60 °C, drug concentration=80 g/L and drug-to-phospholipids ratio=0.9 (w/w)]. The combination percentage was 100.00%±0.20%, and the content of bergenin in the complex was 45.98%±1.12%. Scanning electron microscopy and transmission electron microscopy of BPC showed spherical particles. The average particle size was 169.2±20.11 nm and the zeta-potential was -21.6±2.4 mV. The solubility of BPC in water and in n-octanol was effectively enhanced. The C_max and AUC_0→∞ of BPC were increased, and the relative bioavailability was significantly increased to 439% of bergenin.

Conclusion:

The BPC is a valuable delivery system to enhance the oral absorption of bergenin.     

Drug packaging and delivery using perfluorocarbon nanoparticles for targeted inhibition of vascular smooth muscle cells

Aim:

To investigate the in vitro release profile of drugs encapsulated within perfluorocarbon (PFC) nanoparticles (NPs) and their ability to inhibit the activity of vascular smooth muscle cells (SMCs).

Methods:

Dexamethasone phosphate (DxP) or dexamethasone acetate (DxA) was encapsulated into PFC nanoparticles using a high-pressure homogenous method. The morphology and size of the NPs were examined using scanning electron microscopy (SEM) and a laser particle size analyzer. Drug loading and in vitro release were assessed by high-performance liquid chromatography (HPLC). The impact of NP capsules on SMC proliferation, migration and apoptosis in vitro was assessed using cell counting kit-8, transwell cell migration and flow cytometry assays.

Results:

The sizes of DxP-NPs and DxA-NPs were 224±6 nm and 236±9 nm, respectively. The encapsulation efficiency (EE) of DxP-NPs was 66.4%±1.0%, with an initial release rate of 77.2%, whereas the EE of DxA-NPs was 95.3%±1.3%, with an initial release rate of 23.6%. Both of the NP-coated drugs could be released over 7 d. Human umbilical artery SMCs were harvested and cultured for four to six passages. Compared to free DxP, SMCs treated with tissue factor (TF)-directed DxP-NPs showed significant differences in the inhibition of proliferation, migration and apoptosis (P<0.05).

Conclusion:

The results collectively suggest that PFC nanoparticles will be beneficial for targeted drug delivery because of the sustained drug release and effective inhibition of SMC proliferation and migration.     

Degarelix, a novel GnRH antagonist, causes minimal histamine release compared with cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples

AIMS

Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug candidates. In this study we have compared the histamine-releasing potential of four approved and marketed antagonists, degarelix, cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples.

METHODS

Human skin samples were obtained during cosmetic plastic surgery and kept in oxygenated saline solution. The samples were incubated either without or at different concentrations of the antagonists (3, 30 or 300 µg ml⁻¹ for all, except for ganirelix 1, 10 or 100 µg ml⁻¹). The drug-induced effect was expressed as the increase relative to basal release. The histamine-releasing capacity of the skin was verified by a universal histamine releaser, compound 40/80.

RESULTS

Degarelix had no significant effect on basal histamine release in the 3 to 300 µg ml⁻¹ concentration range. The effect of ganirelix was moderate causing a nonsignificant increase of 81 ± 27% at the 100 µg ml⁻¹ concentration. At 30 and 300 µg ml⁻¹ concentrations abarelix (143 ± 29% and 362 ± 58%, respectively, P < 0.05) and cetrorelix (228 ± 111% and 279 ± 46%, respectively, P < 0.05) caused significantly increased histamine release.

CONCLUSIONS

In this ex vivo human skin model, degarelix displayed the lowest capacity to release histamine followed by ganirelix, abarelix and cetrorelix. These findings may provide indirect hints as to the relative likelihood of systemic anaphylactic reactions in clinical settings.     

Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

Aim:

To prepare a novel formulation of phosphatidylcholine (PC)-bile salts (BS)-mixed micelles (MMs) loaded with silybin (SLB)-PC complex for parenteral applications.

Methods:

SLB-PC-BS-MMs were prepared using the co-precipitation method. Differential scanning calorimetry (DSC) analysis was used to confirm the formation of the complex and several parameters were optimized to obtain a high quality formulation. The water-solubility, drug loading, particle size, zeta potential, morphology and in vivo properties of the SLB-PC-BS-MMs were determined.

Results:

The solubility of SLB in water was increased from 40.83±1.18 μg/mL to 10.14±0.36 mg/mL with a high drug loading (DL) of 14.43%±0.44% under optimized conditions. The SLB-PC-BS-MMs were observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed spherical shapes. The particle size and zeta potential, as measured by photon correlation spectroscopy (PCS), were about 30±4.8 nm and −39±5.0 mV, respectively. In vivo studies showed that incorporation of the SLB-PC complex into PC-BS-MMs led to a prolonged circulation time of the drug.

Conclusion:

This novel formulation appears to be a good candidate for drug substances that exhibit poor solubility for parenteral administration.     

Trends of reporting of 'serious'vs. 'non-serious' adverse drug reactions over time: a study in the French PharmacoVigilance Database

AIM

To investigate trends in spontaneous reporting to the French Pharmacovigilance system of ‘serious’ (SADRs) and ‘non-serious’ (NSADRs) adverse drug reactions over time.

METHODS

Annual SADR : NSADR ratios were calculated for each drug and their evolution tested with linear trend tests.

RESULTS

Among the 39 new active substances commercialized in France in 2000, 16 had sufficient data to perform linear trend tests. An increasing linear relation was found for five widely prescribed drugs, a non-significant increasing trend for eight others, i.e. drugs mostly used in hospitals.

CONCLUSION

ADR reports mainly concern NSADRs during first years of marketing. Reports of SADRs are proportionally more frequent later.