Oral bioavailability of phenobarbital: a comparison of a solution in myvacet 9‐08, a suspension, and a tablet

Purpose: A threeway crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 908, and as a suspension, compared with a 100 mg phenobarbital tablet. Materials and methods: At 4week intervals each subject received the solution in Myvacet 908, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentrationversustime curves C _maxand T _max were determined and AUC₀₄₈ was calculated. Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant diffences in T _maxwere observed. Conclusion: The oral solution in Myvacet 908, and the suspension of phenobarbital proved to be bioequivalent to a tablet.     

Evaluation of the durability of pain relief throughout a 12 hour dosing interval of a novel,extended-release,abuse-deterrent formulation of oxycodone

Background: Abuse deterrent formulations (ADF) are designed to prevent the misuse of opioids by tampering (e.g. physical and chemical manipulation) in order to ingest the opioid in a manner other than intended. Extended-release (ER) formulations are formulated with a larger drug load than immediate-release (IR) formulations, which makes ER opioids more desirable to drug abusers than I.R. formulations. ADFs, therefore, are particularly useful with ER opioid agents, which are designed to produce consistent analgesia over prolonged dosing intervals. However, the drug release properties of these formulations vary and sometimes may not provide adequate pain relief throughout the intended dosing interval, requiring patients to take additional medication for pain relief. Oxycodone DETERx* (Xtampza ER** Xtampza^? ER is a registered trademark of Collegium Pharmaceutical Inc. that uses DETERx^®, an abuse deterrent technology also a registered trademark of the owner, Collegium Pharmaceutical Inc., Canton, MA, USA) is a novel, microsphere-in-capsule opioid formulation, which allows for twice daily dosing (i.e. every 12?hours) and mitigates the ability to tamper with the formulation.

Objective: To evaluate the durability of pain relief of a novel formulation of oxycodone throughout the 12?hour dosing interval.

Research design and methods: This study is a post-hoc analysis of 193 subjects in a Phase 3 randomized withdrawal, double-blind, placebo-controlled, enriched-enrollment, parallel-group, multicenter, 12-week clinical study.

Main outcome measures: The analysis evaluated the frequency and distribution of use of oxycodone ER and rescue medication during the Double-blind Maintenance Phase of the study.

Results: Usage patterns captured by an electronic diary indicated limited overall and limited per-day use of rescue medication with no increase in rescue medication consumption 8 to 12?hours post-dose, suggesting that subjects did not experience end-of-dose failure during this time period.

Limitations: This study is limited in that it is a post-hoc analysis based on data gathered electronically from a large, prospective, double-blind, randomized, placebo-controlled, Phase 3 clinical study.

Conclusion: The evaluation of dosing patterns indicates that this ER oxycodone capsule formulation has durability of effect over the entire 12-hour dosing interval. These data support the use of abuse-deterrent oxycodone ER as a 12-hour dosing formulation.     

Comparison of the Rates of Disintegration,Gastric Emptying,and Drug Absorption Following Administration of a New and a Conventional Paracetamol Formulation,Using γ Scintigraphy

Purpose. To investigate the hypothesis that faster drug absorption from a new paracetamol formulation containing sodium bicarbonate compared to that from a conventional formulation results from a combination of enhanced gastric emptying and disintegration/dissolution. Methods. Each formulation was administered in both fasted and fed states to 12 healthy volunteers. Gastric emptying and disintegration times were assessed by scintigraphy, and serum paracetamol concentrations were determined by HPLC. Results. The mean time to complete disintegration of the new tablets was faster than that for conventional tablets in both fasted (10.2 min vs. 22.5 min) and fed (14.3 min vs. 46.4 min) states, although this difference was statistically significant in the fed state only (p = 0.0053). Mean gastric emptying times for the new tablets, as measured by t₅₀ and t₉₀, were also faster than those for conventional tablets in both fasted (t₅₀ = 22.4 min vs. 47.5 min, t₉₀ = 30.9 min vs. 64.1 min) and fed (t₅₀ = 76.9 min vs. 106.4 min, t₉₀ = 152.7 min vs. 155.5 min) states, although these differences were not statistically significant. Two subjects showed dramatically retarded gastric emptying of the new tablets in the fasted state: if these atypical data are excluded, the differences in both t₅₀ and t₉₀ in the fasted state are significant (p = 0.0110 and 0.0035, respectively). Rate of paracetamol absorption reflected the gastric emptying profiles as shown by significant correlation of emptying times with partial AUC. Conclusions. It would seem that a combination of faster disintegration and gastric emptying of the new tablets is responsible for the faster rate of absorption of paracetamol from PA compared to P observed in both this study and in previous studies. The differences in gastric emptying are more pronounced in the fasted state, and the differences in disintegration are more pronounced in the fed state.     

Zaltoprofen,a noninferior alternative to diclofenac for the treatment of primary knee osteoarthritis – a comparative evaluation of efficacy and safety in a 4-week,multicentric, randomized,double-blind,double-dummy trial

Objective: To demonstrate the clinical noninferiority of the analgesic effect of zaltoprofen (80 mg t.i.d.) compared with diclofenac (50 mg t.i.d.) in active knee osteoarthritis patients.

Method: In this multicentric, double-blind, double-dummy, randomized, parallel-group, comparative study, 213 patients of either sex, aged 40 – 65 years having radiological and clinically confirmed primary knee osteoarthritis were randomized either to zaltoprofen (n = 105) or diclofenac (n = 108) and were followed-up at weeks 1, 2, 3 and 4. The treatment period was preceded by a washout period of 1 week.

Results: Patients in both the zaltoprofen and diclofenac groups exhibited significant improvement (p < 0.001) in pain intensity, functional status and pain relief at each visit from baseline with no statistically significant difference between the two treatment groups. There was no statistically significant difference between the treatment groups for global assessment rating done by the patient and investigator at the end of therapy (p > 0.05) and the proportion of patients who consumed ranitidine (p = 0.135) and paracetamol (p = 0.086) tablets during the treatment period on both the treatment arms. Both the study medications were well tolerated with no incidence of serious adverse events.

Conclusions: This study demonstrated that efficacy and safety of zaltoprofen is clinically noninferior to that of diclofenac.     

Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, α- and β-amyrin,in a mouse model of colitis

Background and purpose:

α- and β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α- and β-amyrin (α,β-amyrin) on an experimental model of colitis in mice.

Experimental approach:

Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with α,β-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-κB (NF-κB) and phospho-cyclic AMP response element-binding protein (CREB)

Key results:

TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,β-amyrin (3 mg·kg⁻¹, i.p.) or dexamethasone (1 mg·kg⁻¹, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. α,β-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1β levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-κB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,β-amyrin and dexamethasone.

Conclusions and implications:

Systemic administration of α,β-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-κB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,β-amyrin to control inflammatory responses in bowel disease.     

A case of accidental ingestion of a salbutamol sulfate inhalant, Venetlin®

Pediatricians examine increasing numbers of children with bronchial asthma every year. In Japan, medical institutions can provide standardized therapies according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2005. Inhalation therapy is highly beneficial, and a substantial proportion of patients choose to purchase inhalators and practice inhalation therapy at home. Recently, we experienced a case of accidental ingestion of a salbutamol sulfate inhalant by a non-asthmatic child, which reminded us anew of the importance of managing the medicines for asthma. We also recognized the need to educate patients and their families on the knowledge of these medicines. In this report, we analyze the case and discuss measures that pediatricians can implement to avoid accidental inhalant ingestion by children.     

Is self-efficacy for smoking abstinence a cause of, or a reflection on, smoking behavior change?

Social learning theory considers self-efficacy as a causal factor in behavior change. However, in line with behavioral theory, recent clinical research suggests self-efficacy ratings may reflect, rather than cause, behavior change. To test these two disparate views, self-efficacy was related to actual smoking abstinence on the next day (i.e., self-efficacy causes change), and abstinence status over 1 day was tested as a predictor of rated self-efficacy for quitting the next day (i.e., reflects change). All data were from two similar crossover studies evaluating the short-term effects of both placebo versus medication, nicotine patch (n = 209) or varenicline (n = 123), on smoking abstinence during week-long practice quit attempts. Placebo and active medication periods were separated by an ad lib smoking washout, and analyses were controlled for prior-day's abstinence or self-efficacy values. Results were very consistent between studies in showing essentially bidirectional associations: daily self-efficacy predicted next-day's abstinence, and current-day's abstinence status predicted self-efficacy for abstinence the next day. However, secondary factors differentially predicted abstinence and, to a lesser extent, self-efficacy, between these two medication studies. These data provide some support for both social learning and behavioral theories of smoking behavior change, although self-efficacy may only briefly predict subsequent short periods of abstinence as assessed in these studies. Nonetheless, because self-efficacy has long been assumed to cause behavior change, including smoking cessation, the notion of self-efficacy as a reflection of recent smoking behavior change in these studies warrants greater attention in clinical research on smoking cessation treatment.     

“Detoxication,a most Stimulating Concept of Toxicology”

1. Large, independent variations occur among New Zealand White rabbits in the 21-and 6β-hydroxylation of progesterone as catalysed by liver microsomes.

2. These reactions are catalysed respectively by two electrophoretically distinct types of rabbit-liver microsomal cytochrome P-450, 1 and 3b, as judged by their catalytic efficiency and the capacity of specific monoclonal antibodies to extensively inhibit the respective microsomal hydroxylases.

3. The relatively large variations in progesterone 6β-hydroxylase activity do not appear to be associated with differences in microsomal content of cytochrome P-450 3b, whereas differences in the microsomal concentration of cytochrome P-450 1 may underlie variations in 21-hydroxylase activity.

4. Preparations of cytochrome P-450 3b contain at least two catalytically distinct subforms, one of which catalyses both 6β- and 16α-hydroxylation of progesterone with a low K_m while the other subform catalyses predominantly 16α-hydroxylation with a significantly greater K_m.

5. The two catalytic subforms of cytochrome P-450 3b can be independently modulated in vitro by positive and negative effectors that can arise in vivo from the metabolism of progesterone.

6. The 6β-hydroxylase subform of cytochrome P-450 3b is not expressed in a genetically defined strain of rabbits, IIIVO/J, indicating a heritable basis for the differential expression of the two subforms of cytochrome P-450 3b.

7. These results indicate that the extent of cytochrome P-450 multiplicity may be greater than is evident from the isolation of electrophoretically distinct forms of cytochrome P-450, and that small differences in structure may underlie large differences in catalytic properties.

8. It is not known whether the differences among outbred New Zealand White rabbits in the expression of either cytochrome P-450 1 or the subforms of cytochrome P-450 3b reflect regulatory phenomena or genetic polymorphism.     

XW630, a conjugate of tetracycline and estrone, in treatment of osteoporosis in overiectomized rats

AIM: To study the effects of XW630 on the bone formation inoveriectomized (OVX ) rats and in human osteoblast--likeosteosarcoma cell line TE85. METHODS: The OVX rats wereobtained by abdominal oopholectomy. The static and dynamichistomorphometric studies were performed by bi-labeledtetracycline methods.The iNOS activity was determined by     

SSRIs,bone mineral density,and risk of fractures — a review

A possibility for selective serotonin reuptake inhibitors (SSRIs) to increase the risk of bone fracture has been debated during recent years. Proposed causes include an ability for the drugs to reduce bone mineral density (BMD). Experimental data have identified a functional 5-HT system in bone, although its role is unclear. Results from numerous epidemiological studies are heterogeneous and several different associations have been suggested; between depression and low BMD, SSRIs and low BMD, depression and falls, SSRIs and falls, depression and fractures, and SSRIs and fractures. In this paper, we review the available data and discuss the various study results. Based on the current available data, we conclude that it is not possible to determine whether SSRIs may negatively influence bone regulation or are innocent bystanders. It is likely that only a large, prospective, long-term study designed to investigate changes in BMD will be able to answer the question.     

Pharmacodynamic Modeling of Finasteride,a 5α-Reductase Inhibitor

Finasteride is a 4-azasteroid inhibitor of one isoenzyme of 5α-reductases that converts testosterone to dihydrotestosterone (DHT). We characterized the time course of DHT concentrations. The following model was used to assess DHT pharmacodynamics: where joint fitting of three dose levels yielded k^oin = 28% change/hour, k_out = 0.28 hour¹, IC₅₀ = 0.012 ng/ml, and E_max = 0.7. The modification of a previous model with the maximum partial effect factor, E_max, may be useful in characterizing the pharmacodynamics of drugs with similar indirect mechanisms.     

Molecular cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Malassezia globosa, a potential antidandruff target

A β-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Malassezia globosa has been cloned, characterized, and studied for its inhibition with sulfonamides. This enzyme, designated MG-CA, has significant catalytic activity in the CO(2) hydration reaction and was inhibited by sulfonamides, sulfamates, and sulfamides with K(I) in the nanomolar to micromolar range. Several sulfonamides have also been investigated for the inhibition of growth of M. globosa, M. dermatis, M. pachydermatic, and M. furfur in cultures, whereas a mouse model of dandruff showed that treatment with sulfonamides led to fragmented fungal hyphae, as for the treatment with ketoconazole, a clinically used antifungal agent. These data prompt us to propose MG-CA as a new antidandruff drug target.     

AVE 0991, a non-peptide mimic of angiotensin-(1–7) effects,attenuates pulmonary remodelling in a model of chronic asthma

BACKGROUND AND PURPOSE

AVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1–7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation.

EXPERIMENTAL APPROACH

We used BALB/c mice (6–8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse⁻¹, i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg⁻¹·per day, s.c.) or saline (100 μL·kg⁻¹·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates.

KEY RESULTS

Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs.

CONCLUSIONS AND IMPLICATIONS

AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1–7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.     

Follow-Up Assessment of Health Consequences after a Chlorine Release from a Train Derailment—Graniteville, SC, 2005

Introduction

After a train derailment released chlorine gas in Graniteville, South Carolina, in 2005, a multiagency team performed an epidemiologic assessment of chlorine exposure and resulting health effects. Five months later, participants were resurveyed to determine their health status and needs and to assist in planning additional interventions in the community.

Methods

Questionnaires were mailed to 279 patients interviewed in the initial assessment; follow-up telephone calls were made to nonresponders. The questionnaire included questions regarding duration of symptoms experienced after exposure and a posttraumatic stress disorder (PTSD) assessment tool.

Results

Ninety-four questionnaires were returned. Seventy-six persons reported chronic symptoms related to the chlorine exposure, 47 were still under a doctor’s care, and 49 were still taking medication for chlorine-related problems. Agreement was poor between the first and second questionnaires regarding symptoms experienced after exposure to the chlorine (κ = 0.30). Forty-four respondents screened positive for PTSD. PTSD was associated with post-exposure hospitalization for three or more nights [relative risk (RR) = 1.7; 95% confidence interval (CI) = 1.1–2.6] and chronic symptoms (RR = 9.1; 95% CI = 1.3–61.2), but not with a moderate-to-extreme level of chlorine exposure (RR = 1.2; 95% CI = 0.8–1.8).

Conclusions

Some victims of this chlorine exposure event continued to experience physical symptoms and continued to require medical care 5 months later. Chronic mental health symptoms were prevalent, especially among persons experiencing the most severe or persistent physical health effects. Patients should be interviewed as soon as possible after an incident because recall of acute symptoms experienced can diminish within months.     

Effects of a hydroxylated metabolite of the β-adrenoreceptor antagonist,carvedilol, on post-ischaemic splanchnic tissue injury

1. Reactive oxygen species have been demonstrated to play a critical role in post-ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new β-adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)-induced shock and tissue injury.
2. Administration of SB 211475 two min before R attenuated SI/R injury in a dose-dependent manner. At doses of 0.5 mg kg⁻¹ and 1.0 mg kg⁻¹, SB 211475 exerted significant anti-shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium-dependent vasorelaxation.
3. Administration of 1 mg kg⁻¹ carvedilol attenuated shock-induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg⁻¹ carvedilol had no protective effects on post-ischaemic tissue injury.
4. Previous studies have shown that SB 211475 has virtually no β-blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post-ischaemia tissue injury.

     

Synthesis,Physicochemical Properties,and Cytotoxicity of a Series of 5′-Ester Prodrugs of 5-Iodo-2′-deoxyuridine

Five aliphatic 5-esters of 5-iodo-2deoxyuridine (IDU) were synthesized via an acid chloride alcoholysis reaction. The solubility in pH 7.4 phosphate buffer, lipophilicity as determined by partition experiments in octanol/pH 7.4 buffer, and cytotoxicity of these potential prodrugs were evaluated. The esters showed a 43- to 250-fold increase in lipophilicity and a 1.6- to 14-fold decrease in aqueous solubility relative to IDU. At a concentration of 50 µM, all esters showed reduced cytotoxicity toward uninfected Vero cells relative to IDU.     

Levels and circadian rhythmicity of plasma ACTH,cortisol, and β-endorphin as a function of family history of alcoholism

Rationale Individuals with a family history of alcoholism may present a dysfunction in the activity of the hypothalamic–pituitary–adrenal (HPA) axis that predates the development of alcoholism. Objective The present study investigated the hypothesis that this HPA-axis dysfunction is associated with alterations in the pattern of the circadian (24 h) secretions of adrenal corticotropic hormone (ACTH), cortisol, and β-endorphin. Methods Men with [high risk (HR)] or without [low risk (LR)] family history of alcoholism participated in the study. Blood samples were drawn every 30 min for 24 h for estimation of the plasma hormone levels. Participants ingested meals at predetermined intervals and filled out mood questionnaires prior to the placement of the catheter and 1 h after each meal. Results The circadian peaks for β-endorphin, ACTH, and cortisol occurred between 0800 and 0830 hours in both LR and HR participants. The plasma ACTH and β-endorphin concentrations were lower in HR than LR participants, while the plasma cortisol concentrations were similar between HR and LR participants. For each hormone, the total 24-h secretion was estimated from the area under the 24-h time–concentration curve (AUC). For ACTH and β-endorphin, but not the cortisol, AUC were lower in HR than LR participants. LR participants reported being more nervous than HR participants. For the LR participants, but not HR participants, the initial mood ratings of “nervous” were positively correlated with the initial plasma cortisol and β-endorphin concentrations as well as with the cortisol and β-endorphin AUC. Conclusions HR participants presented lower plasma concentrations as well as lower AUC for β-endorphin and ACTH but not for cortisol. This suggests a dysfunction of the HPA-axis in HR participants that predates the development of alcoholism and a dissociation between plasma ACTH and cortisol levels as a function of family history of alcoholism.     

Discovery of BIIB042, a Potent,Selective, and Orally Bioavailable γ-Secretase Modulator

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