Urinary Excretion: Does It Accurately Reflect Relative Differences in Bioavailability/Systemic Exposure When Renal Clearance Is Nonlinear?

PURPOSE: The purpose of this study was to assess the influence of nonlinear renal clearance on the ability of urinary excretion data to accurately determine relative differences in systemic exposure and bioavailability. METHODS: Serum concentration and urinary excretion-time profiles were simulated assuming an open one-compartmental model with first-order absorption, linear nonrenal clearance, and either linear or nonlinear renal clearance (saturable secretion). Renal clearance comprised 5% or 95% of total clearance. Doses were varied over a 100-fold range (10-fold decrease/increase from the reference dose). Relative systemic exposures were based on the ratios of AUC and C(max) and the corresponding ratios of cumulative amount excreted in urine (A(e)) and the maximum urinary excretion rate. Relative bioavailability was based on the ratios of A(e) and the test to reference dose (D(ratio)). RESULTS: When renal clearance was linear and urinary excretion data were used to assess relative systemic exposure and relative bioavailability, no significant errors in accuracy were observed. However, when renal clearance was nonlinear, errors in the accuracy of estimation of relative bioavailability (Clr =5% only) and relative systemic exposure ranged from -53% to +125%; minimal error in accuracy existed in the estimation of relative bioavailability when Clr = 95% (-3% to +6%). CONCLUSIONS: Prior to the use of urinary excretion data to assess relative systemic exposure or bioavailability, the relationship between serum concentration and renal clearance should be established.     

Effect of dihydroergosine (DHESN) on the serotoninergic system and behaviour: Is DHESN a new antidepressive agent?

Acute (50.0 mg/kg) and repeated (0.1–10.0 mg/kg) administration of dihydroergosine (DHESN) to rats over 5 days lowered the concentration of 5-HIAA in the brain. DHESN given acutely increased the brain 5-HT in p-CPA-treated animals and diminished the probenecid-induced increase in brain 5-HIAA. In pargyline-treated rats DHESN enhanced the 5-HT/5-HIAA ratio. DHESN administered to rats repeatedly over 5 days decreased the level of 5-HT in blood platelets, and in vitro at concentrations of 10^-4 M and 10^-3 M inhibited the uptake of [¹⁴C]-5-HT in platelets. DHESN (10.0–100.0 mg/kg) potentiated the 5-HT syndrome produced in rats by pargyline and 5-HTP. This potentiation was blocked with cyproheptadine but not with haloperidol. DHESN (1.0 and 10.0 mg/kg) lowered the locomotor activity of rats and 10.0 mg/kg DHESN also reduced the duration of immobility in rats forced to swim in a restricted space. The results indicate that DHESN, like antidepressants, decreases the turnover of serotonin in the brain and potentiates the 5-HT-mediated behaviour. This might suggest that the drug should be further investigated for its potential antidepressive properties.     

Is the effect of smoking on rosacea still somewhat of a mystery?

Context: Rosacea is an inflammatory skin disease with a chronic course. In the past, the association between rosacea and smoking was examined only in a few studies.

Objective: The objective of this study is to investigate the prevalence and the influence of smoking in rosacea patients.

Materials and methods: This prospective cross-sectional study includes 200 rosacea patients and 200 age- and gender-matched rosacea-free controls. Using National Rosacea Society Expert Committee classification, we divided patients into three subgroups as having erythematotelangiectatic (ETR), papulopustular (PPR), and phymatous rosacea (PhR). Demographic data, risk factors, and smoking habits were recorded.

Results: In multivariate analysis, the prevalence of smoking was significantly higher (66%) among patients compared with controls. ETR subtype (43.5%) was found to be significantly higher among active smokers (p?<?0.001). Considering the risk factors, caffeine intake and alcohol consumption could not be evaluated because of their never or rarely intake. Whereas rates of photosensitive skin type and positive family history were significantly prominent in ETR patients (p?<?0.001). While PhR was mostly detected in men who are very old, a significant tendency was found to develop ETR in women.

Conclusion: While a significantly increased risk of developing rosacea among smokers was observed in this study, ETR seems to be the disease of active smokers. Further studies are required for better understanding of the association between rosacea and smoking.     

Dependence of Dissolution Rate on Surface Area: Is a Simple Linear Relationship Valid for Co-Compressed Drug Mixtures?

A quantitative analysis of the dependence of dissolution rate on the relative surface area occupied by two non-interacting drug mixtures from co-compressed slabs is described. The results from the experimental dissolution rates of each component from naproxen/ phenytoin co-compressed slabs under laminar flow conditions, when corrected for the area occupied by that component in the slab, contradict the stagnant layer model predictions, where dissolution rates are assumed to be directly proportional to the occupied surface area. Simulations from non-mixed co-compressates of naproxen and phenytoin indicated that dissolution rates are proportional to bL^2/3, as reported for pure compounds in the laminar dissolution apparatus by Shah and Nelson. However, for a well mixed co-compressate, which differs with the non-mixed case only in the distribution of particles, this proportionality did not hold. The deviation was explained by carryover of material from one section of the component to the next due to fluid flow, resulting in an increase in apparent effective length of the component in the slab (L_eff).     

Can the Enhanced Renal Clearance of Antibiotics in Cystic Fibrosis Patients Be Explained by P-Glycoprotein Transport?

Purpose. To investigate in vitro if P-glycoprotein (P-gp) transport can differentiate between antibiotic drugs exhibiting increased active renal clearance (CL_r) in cystic fibrosis (CF) patients (i.e., dicloxacillin, trimethoprim) and drugs that do not exhibit this phenomenon (i.e., cefsulodin, sulfamethoxazole). Methods. Transport studies were carried out in MDCK (wild type) and MDR1-MDCK (P-gp overexpressing) cells that were grown to confluence on Transwell inserts. [¹⁴C]-mannitol transport and transepithelial electrical resistance (TEER) were measured to validate the integrity of the cells. Drug concentrations were analyzed using HPLC. Results. Dicloxacillin and trimethoprim are substrates of P-gp (BA/AB ratios in MDR1-MDCK cells are 32 and 50, respectively). P-gp inhibitors (i.e., GG918, cyclosporine, ketoconazole, vinblastine) decreased the BA transport of dicloxacillin and trimethoprim and increased the AB transport of trimethoprim while non-P-gp inhibitors (e.g., PAH) had no effect. In contrast, cefsulodin and sulfamethoxazole are not substrates of P-gp (BA/AB values in MDCK and MDR1-MDCK cells are 1). Conclusions. Our in vitro studies suggest that P-glycoprotein may play a role in increasing renal clearance of drug substrates in CF patients. Dicloxacillin and trimethoprim, which are both substrates of P-gp, show increased active renal clearance in CF patients while cefsulodin and sulfamethoxazole, which are not P-gp substrates, do not show increased active renal clearance in CF patients.     

Effect of IMOD? on the inflammatory process after acute ischemic stroke: a randomized clinical trial

Background and purpose of the study

Considering the role of inflammation in acute cerebrovascular accidents, anti-inflammatory treatment has been considered as an option in cerebrovascular diseases. Regarding the properties of Setarud (IMOD™) in immune regulation, the aim of the present study was to evaluate the role of this medication in treating patients with acute ischemic stroke.

Methods

In this randomized clinical trial, 99 patients with their first ever acute ischemic stroke were divided into two groups of IMOD™ (n = 49) and control (n = 50). The control group underwent routine treatment and the intervention group underwent routine treatment plus daily intermittent infusion of IMOD™ (250mg on the first day and then 375mg into DW5% serum during a 30-minute period for 7 days). The serum levels of inflammatory markers were evaluated on the first day (baseline) and on 4th and 7th days. Data were analyzed and the results were compared.

Results and major conclusion

58 males (58.6%) and 41 females (41.4%) with a mean age of 67.00 ± 8.82 years, who had their first ever stroke attack, were enrolled in this trial. Treatment with IMOD™ showed a decreasing trend in IL-6 levels compared to the control group (p = 0.04). In addition, the treatment resulted in the control of increasing serum levels of hsCRP after 7 days compared to the control group (p = 0.02). There was an insignificant decrease in TNF-α and IL-1 levels in the IMOD™ group. Considering the prominent role of inflammation after an ischemic cerebral damage, it appears that treatment with IMOD™ improves the inflammatory profile. Therefore, IMOD™ (Setarud) might be considered as a therapeutic option in the acute ischemic stroke. However, future studies are necessary on its long-term results and clinical efficacy.     

Predictive Evidence Threshold Scaling: Does the Evidence Meet a Confirmatory Standard?

Making better use of evidence is one of the tenets of modern drug development. This calls for an understanding of the evidential strength of nonconfirmatory evidence relative to a confirmatory standard. Such inferential comparisons can be done via predictive evidence threshold scaling (PETS). Under PETS, the evidence meets a confirmatory standard if the predictive probability of a positive effect reaches the predictive evidence threshold from hypothetical confirmatory data. These probabilities require plausible assumptions about between-trial heterogeneity and potential biases. Two examples are discussed. The first is breakthrough designation, illustrated by a recent Food and Drug Administration approval of crizotinib for the treatment of non-small-cell lung cancer based on phase I and II data. The second is childhood Guillain–Barré syndrome, with sparse children data enriched with adult data. The examples suggest that the evidential strength of nonconfirmatory data can meet a confirmatory standard. This is reassuring for modern drug development, which exploits various types of evidence to inform adaptive licensing decisions. Supplementary materials for this article are available online.     

Vitamins for the Management of Cardiovascular Disease: A Simple Solution to a Complex Problem?

Attention is focusing on the relationship between homocysteine and cardiovascular disease and the role of vitamins in the management of this prevalent ailment. Epidemiologic studies have shown that a relationship between elevated homocysteine concentrations and cardiovascular disease may exist; however, a cause-and-effect relationship has not been proven. The B vitamins are key components of homocysteine metabolism, and the trend is toward their being increasingly prescribed for cardiovascular disease. Prescribing of antioxidant vitamins, vitamin E in particular, has increased as well. Vitamin E may decrease the risk of nonfatal myocardial infarction in patients with coronary artery disease, but its benefit in preventing fatal myocardial infarction has not been shown. Vitamin supplements are not warranted in all patients with cardiovascular disease but may have a place in therapy for selected patients.     

The impact of pharmacoeconomics on the practitioner and the patient: a conflict of interests?

It is very easy to polarise the debate between clinicians and economists by asserting that clinicians regard the needs of individual patients as paramount, whereas economists are more interested in the priorities of society as a whole. Economists have criticised clinicians for failing to recognise the scarcity of resources relative to wants and also for being unable to appreciate the diversity of individual preferences. Furthermore, economists will assert that the wants of patients are not the same as their needs. A clinician may use degree of illness as a guide to relative need for treatment, whereas an economist would ask for information about response to treatment, explicitly acknowledging that the most severely ill patient may not derive the greatest benefit from treatment. We believe that the key to this problem lies in the differences in the definition of terms by the 2 sides, and in fact that there is some confusion over the primacy of the individual versus society. Both clinicians and economists are liable to assert that healthcare resources should be distributed equitably. However, clinicians have a somewhat imprecise appreciation of the concept of equity, whereas economists have developed a set of explicit definitions of equity, which clearly show the consequences of shifting the balance of resources to achieve equitable distribution. Inevitably, this leads to diversion of resources from one segment of society to another. At present, any transfer of resources is liable to be viewed as a sacrifice of an individual patient's needs in the interests of society as a whole. This paper shows that clinicians already accept that there is a conflict of interests between the wants of individuals and the needs of society. We believe that progress can only be made by increasingly explicit debate about the merits of different treatments. Economists have developed the theoretical framework; it is up to clinicians to turn theory into practice.     

Impact of Study Design on the Evaluation of Inhaled and Intranasal Corticosteroids' Effect on Hypothalamic–Pituitary–Adrenal Axis Function

In part I of this review, an overview of the designs of hypothalamic–pituitary–adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2963–2979, 2014     

Modification of a cyclo-olefin surface by radio-sterilization: Is there any effect on the interaction with drug solutions?

A cyclo-olefin copolymer was subjected to an e-beam ionizing treatment. Two doses were studied: one corresponding to the recommended dose for the sterilization of pharmaceutical packaging (25 kGy), and a greater one to enhance the modifications caused by the treatment (150 kGy). The surface modifications were studied by X-ray photoelectron spectroscopy (XPS), contact angle measurements and atomic force microscopy (AFM). The roughness and the wettability of the surface were enhanced by the treatment. The consequences of the surface modifications on the drug interaction with the polymer were studied.     

The Damaging Effect of Systemic Injection of Monosodium Glutamate (MSG) on the Development of Normal and Form‐Deprived Eyes of the Chick

Glutamate has been implicated in ocular development. The present study aims to characterize the physical changes that occur as a result of systemic intake of monosodium glutamate (MSG). As MSG has also been suggested to play a part in myopia, its effect on form‐deprived eyes was also investigated. Form‐deprivation myopia (FDM) was induced by placing a black goggle over one eye of each chick. Neonatal chicks were injected with daily MSG (0.1, 1 and 10 mg/day) or saline control for 14 days intraperitoncally (n = 6–7 in all cases). The results show that MSG significantly reduced the eye weight (EW), ocular length (OL), and equatorial diameter (ED) of the normal (i.e. with MSG treatment but not form‐deprived) ocular growth (mean ± s.e.m, MSG dose in parenthesis): EW, 0.90 ± 0.02 vs. 0.81 ± 0.05 (0.1), 0.78 ± 0.04 (1), 0.83 ± 0.04 (10); OL, 1.02 ± 0.03 vs. 0.94 ± 0.03 (0.1), 0.95 ± 0.01 (1), 0.97 ± 0.02 (10); ED, 1.36 ± 0.01 vs. 1.30 ± 0.02 (0.1), 1.28 ± 0.02 (1), 1.33 ± 0.03 (10). As a result of FDM, these measurements of the eye tend to increase as well as result in thinning of the retina and thickening of the sclera. However, under MSG treatment, no significant increase in these parameters with form‐deprived chicks occurred. In fact, a gradual downward trend was observed. Histological measurements show that both the normal and myopic retinal and scleral layers were thinner than the controls (i.e. no MSG or FDM) at MSG‐1 and 10 mg/day (thickness ± s.e.m, MSG dose in parenthesis): control retina: 97 ± 12 vs. 77 ± 3 (1) and 78 ± 2 (10); FDM retina: 83 ± 16 vs. 74 ± 4 (1) and 75 ± 3 (10); control sclera: 44 ± 7 vs. 29 ± 2 (1) and 36 ± 3 (10); FDM sclera; 41 ± 5 vs. 31 ± 2 (1) and 32 ± 2 (10). However, MSG # injections of 0.1 mg/day caused a significant increase in both normal and myopic retinal and scleral thickness compared to the controls stated above: MSG retina, 140 ± 14 and FDM retina, 157 ± 15; MSG sclera, 55 ± 7 and FDM sclera, 63 ± 8. The results suggest that MSG at high concentrations can cause a reduction in ocular growth probably due to its related cytotoxicity and the subsequent cellular destruction with or without inherent FDM. The increase in retinal and scleral thickness at low dose of MSG may be due to intracellular swelling as has been reported in other studies. The damaging effect of MSG to the retina of both goggled and open eyes may be sufficient to cause the eye to become myopic as images will thus be projected in front of the retina. Despite the low dosage used, it still caused significant ocular damages, which suggests that the amount of MSG intake must be viewed with caution.     

Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review

Background

The authors carried out a systematic and critical review of the scientific literature regarding the possible development of neutralising antibodies developed in patients treated with growth hormone biosimilars (defined as a drug expected to be similar to the originator or original pharmaceutical -European Medicines Agency) as compared to the reference drug. As a consequence, we discovered two major issues, namely, the poor quality of the comparative clinical trials and the poor quality of the antibody assays used during the trials.

Methods

The literature review was performed according to the principle of the Cochrane Collaboration and SBU. The electronic literature search included the databases PubMed, EMBASE and The Cochrane Library up to December 2012. Two independent reviewers assessed abstracts and full-text articles.

Results

The search identified 1,553 abstracts related to the subject. Only six articles contained data on biosimilar growth hormone or antibody results obtained with appropriate methods. None of the studies fulfilled the criteria for high quality randomised controlled trials. Qualitative rather than quantitative assays were used for monitoring antibody formation.

Conclusions

It is our firm opinion , that since biosimilars are not identical, emphasis must be placed on the quality of the comparative clinical trials performed and the quality of the analytical studies in order to guarantee patient safety. Clinical trials should follow established quality rules for controlled comparative randomised clinical trials. A whole set of new guidelines is required.     

Effect of K+ and Rb+ on the action of verapamil on a voltage-gated K+ channel,hKv1.3: implications for a second open state?

Background and purpose:

Verapamil blocks current through the voltage-gated K⁺ channel K_v1.3 in the open and inactivated state of the channel but not the closed state. The binding site for verapamil was proposed to be close to the selectivity filter and the occupancy of the selectivity filter might therefore influence verapamil affinity.

Experimental“ approach:

We investigated the influence of intra- and extracellular K⁺ and Rb⁺ on the effect of verapamil by patch-clamp studies, in COS-7 cells transfected with hK_v1.3 channels.

Key results:

Verapamil affinity was highest in high intracellular K⁺ concentrations ([K⁺]_i) and lowest in low [Rb⁺]_i, indicating an influence of intracellular cations on verapamil affinity. Experiments with a mutant channel (H399T), exhibiting a strongly reduced C-type inactivated state, demonstrated that part of this changed verapamil affinity in wild-type channels could be caused by altered C-type inactivation. External K⁺ and Rb⁺ could influence verapamil affinity by a voltage-dependent entry into the channel thereby modifying the verapamil off-rate and in addition causing a voltage-dependent verapamil off-rate.

Conclusions and implications:

Recovery from verapamil block was mainly due to the voltage-dependent closing of channels (state-dependent block), implying a second open state of the channel. This hypothesis was confirmed by the dependency of the tail current time course on duration of the prepulse. We conclude that the wild-type hK_v1.3 channel undergoes at least two different conformational changes before finally closing with a low verapamil affinity in one open state and a high verapamil affinity in the other open state.     

Effect of Kollidon? SR on the release of Albuterol Sulphate from matrix tablets

The objective of this study was to evaluate Kollidon SR for the development of extended release Albuterol Sulphate matrix tablets in comparison with other polymers as Hydroxypropylmethylcellulose K15M, Carbopol 71G NF, and Eudragit L100-55. The mechanical properties of the tablets were improved as concentration of Kollidon SR or other polymers increased. It was found that Kollidon SR 30% (w/w) and HPMC 30% (w/w) tablets have f₂ similarity factor of 83.5 in their Albuterol Sulphate dissolution profile. The marketed product was found to release 99.7% of drug content within 8 h, while Kollidon SR and HPMC tablets with 30% (w/w) polymer concentration level released 92.7% and 92.9% respectively of drug content within 8 h. Kollidon SR has a unique character of maintaining tablets geometric shape until the end of dissolution test, this is mainly due to the water insoluble content, polyvinyl acetate, forming 80% (w/w) of Kollidon SR, while the remaining content 20% (w/w) is the water soluble, polyvinylpyrrolidone, responsible for pore formation causing a diffusion controlled release. Drug release from all previous formulations is best described to be controlled by more than one kinetic mechanism of release.In conclusion, Kollidon SR and HPMC and Carbopol were found to be potential candidates for the development of extended release of Albuterol Sulphate tablets.