Section 3 Ibuprofen (‘rufen’) in the treatment of catarrhal and respiratory viral diseases with rheumatismal manifestations

Summary

One hundred and eighteen patients were treated with 800 trig, to 1200?mg. ibuprofen daily for periods up to 6 weeks during influenza epidemics. Forty-one patients with rheumatoid arthritis and 47 with arthroses responded well both regarding joint symptoms and their general condition, and only 6 developed catarrhal and respiratory viral disease. Ten patients with catarrhal rheumatism and 20 with influenza were also treated with good control of their fever and general malaise.     

Efficacy and Safety of Paliperidone Extended Release 1.5 mg/day—A Double-blind,Placebo- and Active-Controlled,Study in the Treatment of Patients with Schizophrenia

Background

Paliperidone extended-release (paliperidone ER) is an approved oral antipsychotic medication (dosing range 3–12 mg/day) for treatment of schizophrenia and schizoaffective disorder in adults.

Methods

In this 3-arm, double-blind, placebo- and active-controlled, parallel-group study, paliperidone ER 1.5 mg was assessed to determine the lowest efficacious dose in patients (N = 201) with acute schizophrenia. Paliperidone ER 6 mg was included for assay sensitivity.

Results

Patients (intent-to-treat analysis set) had a mean age of 39.4 years; 74% were men, 43% Asian, and 40% black. The baseline mean (SD) Positive and Negative Syndrome Scale (PANSS) total score was 92.6 (13.02) and the mean (SD) change from baseline to endpoint was: placebo group, –11.4 (20.81); paliperidone ER 1.5 mg group, –8.9 (23.31); and paliperidone ER 6 mg group, –15.7 (26.25). Differences between paliperidone groups versus placebo were not significant (paliperidone ER 1.5 mg [p = 0.582], paliperidone ER 6 mg, [p = 0.308]). Safety results of paliperidone ER 1.5 mg and placebo were comparable. The most frequently reported treatment emergent adverse events (≥10%) were: placebo group—headache (15.6%) and psychotic disorder (14.1%); paliperidone ER 1.5 mg group—insomnia (13.6%); and paliperidone ER 6 mg group—headache (11.4%), insomnia (10%), and tremor (10%).

Conclusions

In this study, paliperidone ER 1.5 mg did not demonstrate efficacy in patients with acute schizophrenia. A markedly high placebo response was noted. Assay sensitivity with the 6 mg dose was not established. Paliperidone ER 1.5 mg was generally tolerable with a safety profile comparable to placebo.     

Efficacy and Safety of Cerivastatin, 0.2 mg and 0.4 mg,in Patients with Primary Hypercholesterolemia: a Multinational,Randomised, Double-blind Study

Summary

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4?mg.

This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin OAmglday with that of cerivastatin 0.2?mg/day in patients with primary hypercholesterolemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4mg (n = 332) or 0.2mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 ± 0.7% from baseline in the 0.4?mg group, compared with a decrease of 31.5 ± 0.9% in the 0.2mg group (p < 0.0001). There was a significant gender difference in the 0.4?mg group: LDL-C decreased by 44.4 ± 8.9% in women, compared with a decrease of 37.0 ± 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 ± 0.5% from baseline in the 0.4mg group, compared with a decrease of 21.6 ± 0.7% in the 0.2mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4 %) patients in the 0.4?mg group and five (3.1 %) patients in the 0.2?mg group withdrew owing to adverse events.

Cerivastatin 0.2?mg/day and 0.4?mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.     

The Effect of Benzyltetrahydropalmatine (BTHP) on Action Potentials and the Two Components of Delayed Rectifying Potassium Currents in Guinea Pig Ventricular Myocytes

苄基四氢巴马汀为四氢巴马汀的衍化物，本文采用标准膜片钳全细胞记录技术，研究了苄基四氢巴马汀对豚鼠心室肌单细胞动作电位及延迟整流钾通道（Ｉｋ）两种成分（Ｉｋｓ和Ｉｋｒ）的选择性作用。结果表明：（１）３０μｍｏｌ·Ｌ－１苄基四氢巴马汀可显著延长无钙细胞外液条件下动作电位的ＡＰＤ９０（从１４３±１６ｍｓ到１８４±２１ｍｓ，Ｐ＜００１，ｎ＝５），而对ＲＰ，ＡＰＡ无明显影响，其对ＡＰＤ９０的延长作用不依赖于胞外钙。（２）苄基四氢巴马汀对延迟整流钾通道两种成分均有不同程度的阻滞作用，其阻滞Ｉｋｒ的ＩＣ５０（半数抑制浓度）为７９μｍｏｌ·Ｌ－１，阻滞Ｉｋｓ的ＩＣ５０为２２４μｍｏｌ·Ｌ－１，可见苄基四氢巴马汀对Ｉｋ的阻滞作用无选择性     

The role of descending inhibition in the antinociceptive effects of the pyrazolone derivatives,metamizol (dipyrone) and aminophenazone (“Pyramidon”)

Summary The study was carried out to provide further evidence that the two pyrazolone derivatives, metamizol and aminophenazone, produce central antinociceptive effects by stimulating inhibition descending from the periaqueductal grey (PAG) to the spinal cord. Experiments were carried out on rats in which the tail-flick response to radiant heat, nociceptive activity in ascending axons of the spinal cord, and activity of neurones in the PAG and the substantia nigra were studied. Microinjection of procaine (10 g) into the PAG reduced the tail-flick latency and abolished the increase in latency caused by i.p. injection of metamizol (40 mg/kg) and aminophenazone (150 mg/kg); it did not significantly reduce the antinociceptive effect of i.p. injection of morphine (2 mg/kg). Threshold doses of morphine (1 and 2 g) administered by intrathecal (i.t.) injection potentiated the effect of threshold doses of metamizol injected i.p. (10 mg/ kg) or into the PAG (10 g) in the tail-flick test. Morphine (2 g) injected i.t. potentiated the effect of i.v. injection of metamizol (80 mg/kg) on nociceptive activity in ascending axons by eliminating the stimulant effect of metamizol on about one third of the axons. Threshold doses of morphine injected i.t. failed to potentiate the antinociceptive effect of aminophenazone (50 mg/kg) injected i.p. in the tail-flick test. The results support the view that metamizol and aminophenazone activate pathways descending from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level.Supported by the Schwerpunkt Nociception and Schmerz of the Deutsche Forschungsgemeinschaft Send offprint requests to I. Jurna at the above address     

The effect of (-) Δ 9-tetrahydrocannabinol,alone and in combination with ethanol,on human performance

Twenty five volunteers received (-) ⁹-tetrahydrocannabinol (THC) (320 g/kg) or placebo (both orally, T₀), and, 60 min later, they consumed an ethanolic beverage (0.54 g/kg) or placebo. The effects of this medication were measured at T₁ (100 min after THC ingestion), T₂ (160 min), T₃ (220 min) and T₄ (280 min) using a battery of cognitive, perceptual and motor function tests. Factorial analysis indicated that the test procedures could be adequately expressed by four rotated factors: a reaction speed factor (I), a cognitive factor (II), a standing steadiness factor (III) and a psychomotor coordination factor (IV), The first principal component (I) was used as a measure of general performance across the whole test battery.Both THC and ethanol produced significant decrements in the general performance factor. Ethanol produced significant decrements in standing steadiness and psychomotor coordination, while THC caused a significant deterioration in performance on all the four rotated factors. In all cases the peak effect of ethanol occurred at T₁ and by T₄ the effect had worn off. The performance decrements induced by THC were slower in onset and lasted longer than those induced by ethanol. In general, the peak effect of THC occurred at T₁ and T₂. There was no evidence of any interaction between THC and ethanol, and the effects of a combination of THC and ethanol were no more than additive. THC (but not ethanol) produced a significant rise in pulse rate. Prior administration of THC did not significantly affect the blood ethanol levels obtained. The subjects were able to identify correctly which of the treatments they had received.     

Efficacy of 5-Vinyl-l-β-D-arabinofuranosyluracil (VaraU) Against Herpes Simplex Virus Type 2 Strains in Cell Cultures and Against Experimental Herpes Encephalitis in Mice: Comparison with Acyclovir and Foscarnet

The sensitivity of different herpes simplex virus type 2 (HSV-2) strains to inhibition by 5-vinyl-l--D-arabinofuranosyluracil (VaraU) was evaluated in comparison to 9-(2-hydroxyethoxymethyl)guanine (ACV; acyclovir) and trisodiumphosphonoformate (Na₃PFA; foscarnet), using a plaque inhibition assay in primary rabbit testes (PRT) cells as well as in human embryonic lung fibroblast (HELF) cell cultures. The order of decreasing activity found was ACV VaraU > Na₃PFA in PRT cells and ACV > VaraU Na₃PFA in HELF cells, with 50% inhibition doses (ID₅₀) of 1.8, 8.8, and >110 µM for the three drugs in HELF cells, respectively. After 72hr of drug treatment, inhibition of HELF cell proliferation by VaraU (ID₅₀, >1000 µM) was less than that by ACV and Na₃PFA, resulting in high selectivity indexes of >100 against HSV-2 for VaraU and ACV. Their in vivo efficacy was assessed in a mouse encephalitis model. Using a treatment schedule of three daily intraperitoneal (ip) doses over a period of 5 days, only the survival times of mice were considerably prolonged by VaraU (150 or 300 mg/kg per day; P < 0.05 or P < 0.001, respectively). In contrast, ACV treatment (150 mg/kg per day) led to a nearly complete prevention of encephalitis and death (P < 0.001). Similar therapy results with VaraU application through the drinking water were obtained using only one-sixth of the high ip dose (50 mg/kg per day) but over a prolonged period of treatment. Under similar conditions no therapeutic effect of oral Na₃PFA was observed.     

The Role of Permeability in Drug ADME/PK,Interactions and Toxicity—Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans

Purpose The objective was to establish in vitro passive permeability (P _e) vs in vivo fraction absorbed (f _a)-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a P _e-based ADME/PK classification system (PCS). Materials and Methods P _e- and intestinal f _a-data were taken from an available data set. Hepatic f _a was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal f _a (reabsorption) was estimated using renal pharmacokinetic data, and brain f _a was predicted using animal in vitro and in vivo brain P _e-data. Hepatic and intestinal f _a-data were used to predict bile excretion potential. Results Relationships were established, including predicted curves for bile excretion potential and minimum oral bioavailability, and a 4-Class PCS was developed: I (very high P _e; elimination mainly by metabolism); II (high P _e) and III (intermediate P _e and incomplete f _a); IV (low P _e and f _a). The system enables assessment of potential drug–drug transport interactions, and drug and metabolite organ trapping. Conclusions The PCS and high quality P _e-data (with and without active transport) are believed to be useful for predictions and understanding of ADME/PK, elimination routes, and potential interactions and organ trapping/toxicity in humans. This paper includes personal opinions of the author, which do not necessarily represent the views or policies of AstraZeneca.     

The development and performance of a radioimmunoassay for the analysis of ZM 213,689, the major metabolite of meropenem—a carbapenem antibiotic—in plasma and urine

The development of a radioimmunoassay for the analysis of ZM 213, 689, the major metabolite of meropenem found in the plasma and urine of rat, dog and humans, is described. The assay is rapid in order to minimise the effect of degradation of meropenem to ZM 213,689 in biological samples and has a working range of 0.08–3.5 mg l⁻¹ (RSD ⩽ 15%). The antibody was specific for ZM 213,689 with cross-reactivity to meropenem of only 0.4%. The synthesis of the immunogen and radiotracer involved a novel approach due to the multifunctional nature of ZM 213,689.     

Efficacy and safety evaluation of once-daily OROS hydromorphone in patients with chronic low back pain: a pilot open-label study (DO‑127)

ABSTRACT

Objective: To evaluate the safety, tolerability, and efficacy of once-daily osmotic controlled-release oral delivery system (OROS) hydromorphone in patients with chronic low back pain of moderate-to-severe intensity.

Research design and methods: This was a 6-week, multicenter, nonrandomized, noncomparative, open-label, repeat-dose study of chronic (≥?6 weeks) low back pain. The study comprised three periods: prior opioid stabil­ization (2–7 days); OROS hydromorphone conversion, titration, and stabilization (3–14 days); and OROS hydro­morphone maintenance (28 days). Patients were evalu­ated weekly. Baseline pain assessment was performed at the end of prior opioid stabilization. For pain relief rating, endpoint was defined as the mean pain relief score from the last 2 nonmissing days before study termination. For other assessments, endpoint was defined as the last post-baseline evaluation.

Results: Of the 207 patients who received the study drug, 131 completed the trial. Scores (mean ± SD) for Brief Pain Inventory ‘worst pain in the last 24 hours’ decreased significantly from baseline to endpoint (–0.8 ± 2.06, p < 0.0001). The proportions of patients and investigators rating the global effectiveness as good, very good, or excellent increased from 31.6% at baseline while patients were on prior opioids to 63.2% at endpoint while patients received OROS hydromorphone, and from 29.8% at baseline while patients were on prior opioids to 65.8% at endpoint while patients received OROS hydromorphone, respectively. Daily pain relief ratings also increased significantly (+0.26 ± 1.084, p = 0.0008). Significant improvements in health-related quality of life and sleep problems were observed. Adverse events were mild to moderate in severity; the most common of these were constipation, nausea, headache, and somnolence. The limitations of this study include its pilot-type design and the lack of comparison of OROS hydromorphone with a placebo or another drug. Additional comparative and longer-term studies are needed to confirm these findings.

Conclusions: OROS hydromorphone may be an effective treatment for chronic low back pain of moderate-to-severe intensity. Adverse events were typical of those associated with opioid therapy.     

Comparison of Two Forms of Loperamide–Simeticone and a Probiotic Yeast (Saccharomyces boulardii) in the Treatment of Acute Diarrhoea in Adults: A Randomised Non-Inferiority Clinical Trial

Background

Acute diarrhoea is a frequent health problem in both travellers and residents that has a social and economic impact. This study compared the efficacy and tolerability of two loperamide–simeticone formulations and a Saccharomyces boulardii capsule as symptomatic treatment.

Methods

This was a prospective, randomised, single (investigator)-blind, three-arm, parallel group, non-inferiority clinical trial in adult subjects with acute diarrhoea at clinics in Mexico and India, with allocation to a loperamide–simeticone 2/125 mg caplet or chewable tablet (maximum eight in 48 h) or S. boulardii (250 mg twice daily for 5 days).

Outcome Measures

The primary outcome measure was the number of unformed stools between 0 and 24 h following the initial dose of study medication (NUS 0–24). The secondary outcome measures were time to last unformed stool (TLUS), time to complete relief of diarrhoea (TCRD), time to complete relief of abdominal discomfort (TCRAD) and the subject’s evaluation of treatment effectiveness. Follow-up endpoints at 7 days were feeling of complete wellness; stool passed since final study visit; and continued or recurrent diarrhoea.

Subjects

In this study, 415 subjects were randomised to either a loperamide–simeticone caplet (n = 139), loperamide–simeticone chewable tablet (n = 139) or S. boulardii capsule (n = 137) and were included in the intention-to-treat analysis.

Results

With regards to mean NUS 0–24, the loperamide–simeticone caplet was non-inferior to loperamide–simeticone tablets (3.4 vs. 3.3; one-sided 97.5 % confidence interval ≤0.5), with both significantly lower than S. boulardii (4.3; p < 0.001). The loperamide–simeticone groups had a shorter median TLUS [14.9 and 14.0 vs. 28.5 h (loperamide–simeticone caplet and chewable tablet groups, respectively, vs. S. boulardii); p < 0.001], TCRD (26.0 and 26.0 vs. 45.8 h; p < 0.001) and TCRAD (12.2 and 12.0 vs. 23.9 h; p < 0.005) than S. boulardii. Treatment effectiveness for overall illness, diarrhoea and abdominal discomfort relief was greater (p < 0.001) in the loperamide–simeticone groups than with S. boulardii. At 7-day follow-up most subjects reported passing stool at least once since the final study visit (loperamide–simeticone caplet 94.1 %, loperamide–simeticone chewable tablet 94.8 %, S. boulardii 97.0 %), did not experience continued or recurrent diarrhoea [loperamide–simeticone caplet 3.7 % (p < 0.03 vs. S. boulardii), loperamide–simeticone chewable tablet 3.7 %, S. boulardii 5.7 %] and felt completely well [loperamide–simeticone caplet 96.3 % (p < 0.02 vs. S. boulardii), loperamide–simeticone chewable tablet 96.3 % (p < 0.02 vs. S. boulardii), S. boulardii 88.6 %]. All treatments were well-tolerated with few adverse events.

Conclusions

The loperamide–simeticone caplet was non-inferior to the original loperamide–simeticone chewable tablet formulation; both formulations can be expected to demonstrate similar clinical efficacy in the relief of symptoms of acute diarrhoea. Both loperamide–simeticone formulations were superior to the S. boulardii capsule in the primary and secondary endpoints.

Clinical Trial Registration

ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00807326","term_id":"NCT00807326"}}NCT00807326.     

Antiallodynic effect and side effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer: Comparison with ω-conotoxin MVIIA and morphine

Phα1β is a potent toxin obtained from the spider Phoneutria nigriventer that blocks neuronal voltage-sensitive Ca²⁺ channels. This study compared the antiallodynic effects of Phα1β, ω-conotoxin MVIIA and morphine in mice and their side effects in rats. Mechanical allodynia was measured in mice receiving single intrathecal administration of Phα1β, ω-conotoxin MVIIA or morphine before or after the incisional plantar procedure. The effect of the treatments on cardiovascular profile and global neurological were evaluated in rats. The expression of pro or anti-inflammatory cytokines of human polymorph mononuclear cells was also evaluated. Preemptive use of ω-conotoxin MVIIA (1.0 or 10 pmol/site) or morphine (1000 pmol/site) induced shorter antiallodynic effect than Phα1β (100 pmol/site) in mice. Post-incision administration of Phα1β (200 pmol/site) induced longer mechanical antiallodynic effect than ω-conotoxin MVIIA (1.0 or 10 pmol/site) or morphine (1000 pmol/site). Intrathecal injection of Phα1β (200 pmol/site) and morphine (433 pmol/site) did not change while ω-conotoxin MVIIA (100 pmol/site) increased the heart rate in rats 3 h after its administration. Phα1β (200 pmol/site), ω-conotoxin MVIIA (100 pmol/site) and morphine (433 pmol/site) did not change mean arterial pressure 0.5 and 3 h after their administration. The treatments did not alter neurological performance assessed by global neurological evaluation and open-field test. The tested drugs did not induced expression of pro or anti-inflammatory cytokines in CD4 monocytes. In conclusion, preemptive administration Phα1β in mice induced longer antiallodynic effect than ω-conotoxin MVIIA and morphine. Phα1β also induced a longer mechanical antiallodynic effect than ω-conotoxin MVIIA and morphine when used after the surgical incision. The present results suggest that Phα1β has a potential application in the management of postoperative pain with low side effects.     

The effects of new sigma (σ) receptor ligands,PB190 and PB212, in the models predictive of antidepressant activity

BackgroundA number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms (e.g. forced swim test, tail suspension test, olfactory bulbectomy model, conditioned fear stress). The objective of the present study was to find out whether PB190 and PB212, new σ₁ receptor ligands, show the effects in some models predictive of antidepressant activity.MethodsThe impact of PB190 and PB212 on the immobility time in the forced swim test (FST) and tail suspension test (TST) was assessed in C57BL/6J male mice. Extracellular bradykinin triggers a transient increase in intracellular calcium concentration by activating the phospholipase C/IP₃ pathway. The intracellular calcium concentration was estimated with the dual wavelength ratiometric probe Fura-2.ResultsIn the FST model, PB190 showed a moderate antidepressant-like effect (only in the dose of 3 mg/kg) which was enhanced by joint treatment with amantadine (AMA), 10 mg/kg (inactive per se). The decrease in the immobility time induced by the combined treatment with PB190 and AMA was counteracted by PB212 and by BD1047, a σ₁-receptor antagonist. The in vitro studies indicated that Ca²⁺-response was increased by 1 μM PB190, like by the σ₁-agonist (+)-pentazocine, while 1 μM PB212 behaved line σ₁-antagonist, BD1063. On the other hand, 100 μM PB190 negatively affected the Ca²⁺-response after bradykinin.ConclusionsThe obtained results: 1/indicated that in the in vivo conditions PB190 behaved as a σ₁-receptor agonist while PB212 counteracted its effect, confirming the in vitro data; 2/gave support to the hypothesis that σ₁-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity; 3/revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA.