In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and t_d of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and t_d between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t_1/2 (7.12 h), while apparent t_1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for C_max and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.     

D—氨基葡萄糖盐酸盐的制备研究

从龙虾壳制备的甲壳素，经盐酸水解得Ｄ－氨基葡萄糖盐酸盐，收率＞５０％，纯度＞９８．７％。水解条件考察表明，以１２ｍｏｌ／ＬＨＣｌ水解２．５～３ｈ效果最佳。     

Effects of fexofenadine and desloratadine on subjective and objective measures of nasal congestion in seasonal allergic rhinitis

BACKGROUND: In vitro studies have shown much higher H1-receptor antagonist potency with desloratadine (DL) compared to fexofenadine (FEX), although it is unclear whether this has any clinical relevance on disease control parameters in seasonal allergic rhinitis (SAR), especially for nasal congestion. OBJECTIVE: To compare the relative efficacy between presently recommended doses of DL and FEX on daily measurements of peak nasal inspiratory flow (PNIF) and nasal symptoms in SAR. METHODS: Forty-nine patients with SAR were randomized into a double-blind, placebo-controlled cross-over study during the grass pollen season, comparing 2 weeks of once daily treatment with (a) 180 mg FEX or (b) 5 mg DL, taken in the morning. There was a 7-10 day placebo run-in and washout prior to each randomized treatment. Measurements were made in the morning (AM) and in the evening (PM) for PNIF (the primary outcome variable), nasal and eye symptoms. The average of AM/PM values were used for analysis. RESULTS: There were significant (P < 0.05) improvements, compared to placebo, with FEX and DL, for PNIF, nasal blockage, nasal irritation, and total nasal symptoms, but not nasal discharge or eye symptoms. There were no significant differences between active treatments. Values for PNIF (L/min) for mean placebo baseline, mean difference from baseline (95% CI for difference) were 126, 10 (4-16) for FEX; and 122, 11 (4-17) for DL. The mean difference (95% CI) between FEX vs. DL was 1 L/min (-7-8). Values for total nasal symptoms (out of 12) were: 3.2, 0.7 (0.2-1.2) for FEX; and 3.4, 0.9 (0.3-1.5) for DL, and for nasal blockage (out of 3) were: 1.1, 0.2 (0.1-0.4) for FEX; and 1.2, 0.3 (0.1-0.5) for DL. The mean difference (95% CI) in total nasal symptoms and nasal blockage between FEX vs. DL was 0.1 (-0.6-0.8) and 0.1 (-0.2-0.3), respectively. CONCLUSIONS: Recommended once daily doses of fexofenadine and desloratadine were equally effective in improving nasal peak flow and nasal symptoms in SAR.     

Clinical and antimicrobial effects of a single episode of subgingival irrigation with tetracycline HCI or chlorhexidine in deep periodontal pockets

Abstract. 15 adults, each providing 4 non-adjacent untreated periodontal pockets with a probing depth (PD) exceeding 6 mm. volunteered for a randomized, split-mouth, double-blind, clinical study evaluating subgingival irrigation with chlorhexidine (CHX) or tetracycline HCl (TTC). The study protocol included oral hygiene instructions followed by scaling and root planing. Experimental and immediately adjacent teeth did not receive instrumentation. The 4 deep periodontal pockets in each patient were assigned to be irrigated with 150 ml CHX (0.12%). TTC (10 or 50 mg/ml; TTC10, TTC50), or sterile saline (control) in a single episode. Post-irrigation mechanical plaque control was supported by 2× daily CHX rinses throughout the 12-week observation interval. Recordings of oral hygiene (PlI), gingival health (GI). bleeding on probing (BoP). probing depth (PD), clinical attachment level (CAL), and microbial morphotypes from subgingival paper point samples were performed pre-irrigation. and at 1, 2, 4, 6, 8, 10, and 12 weeks post-irrigation. Mean post-irrigation PlI was low, fluctuating between 0.0 and 0.4, without significant differences between experimental groups. Mean pre-irrigation GI approximated 1.4 and reached 0.8 at the exit of study without significant differences between experimental groups. All experimental sites exhibited BoP pre-irrigation. BoP was significantly reduced in TTC50 compared to TTC10, CHX and control sites from week 8 post-irrigation. PDs were reduced for the experimental groups with TTC50 exhibiting the strongest reduction. CALs remained unaltered from pre-irrigation for TTC10. CHX and control sites over the 12-week observation interval, whereas TTC50 sites consistently improved to significantly differ from all other groups at week 10 and 12 post-irrigation. The distribution of bacterial morphotypes was significantly altered towards one of periodontal health for all experimental groups with a profound effect for TTC50 sites. Our results suggest that subgingival irrigation with TTC solutions at high concentrations may have a rôle in the management of adult periodontitis.     

Reduction of side-effects from ultrarush immunotherapy with honeybee venom by pretreatment with fexofenadine: a double-blind, placebo-controlled trial

BACKGROUND: Immunotherapy with Hymenoptera venoms is highly effective but causes allergic side-effects frequently, especially when honeybee venom is used. Therefore, our objective was to investigate the effect of pretreatment with the antihistamine fexofenadine on the incidence of allergic side-effects during ultrarush immunotherapy with bee venom. METHODS: In a double-blind, placebo-controlled trial, 57 patients with a history of systemic allergic reactions to honeybee stings and positive diagnostic tests (skin tests, serum specific IgE to honeybee venom) were investigated. Bee venom immunotherapy was started with an ultrarush protocol and patients were randomized to pretreatment with either fexofenadine 180 mg or placebo on days 1, 8, 22, and 50 of the protocol. Local and systemic allergic side-effects were registered. RESULTS: Fifty-four patients completed the study, 28 on fexofenadine and 26 on placebo pretreatment. On day 1, large local reactions were significantly reduced in both extension and duration by fexofenadine pretreatment (P<0.025). Systemic allergic side-effects on the whole were not reduced. However, the symptoms pruritus, urticaria, and angioedema occurred less frequently with fexofenadine (P<0.05). CONCLUSIONS: Pretreatment with fexofenadine during venom immunotherapy reduces local allergic reactions and generalized symptoms of the urticaria and angioedema type.     

Is there a non-dopaminergic nigrostriatal pathway?

Sixteen per cent of the substantia nigra cell bodies normally labeled from the injection of a fluorescent retrograde tracer in the caudate-putamen complex could still be labeled by the same procedure after multiple intracisternal 6-hydroxydopamine treatments that depleted dopamine levels in the caudate-putamen complex to 1.0% of control. However, the demonstration of glyoxylic-acid-induced catecholamine histofluorescence in tissue from these lesioned rats revealed that many of the surviving retrogradely-labeled substantia nigra cell bodies still contained dopamine. The persistence of some dopamine in the substantia nigra of the lesioned animals was confirmed biochemically. Therefore, retrograde tracing in 6-hydroxydopamine lesioned rats overestimated the extent of the non-dopaminergic nigrostriatal tract.The simultaneous combination of retrograde fluorescent tracing and catecholamine histofluorescence in unlesioned animals revealed that only 5% or less of the substantia nigra cell bodies retrogradelylabeled from the caudate-putamen complex were without catecholamine fluorescence. These apparently non-dopaminergic nigrostriatal cells were located primarily in the ventral tegmental area, substantia nigra pars reticulata and extreme medial edge of the substantia nigra pars compacta.     

Exposure to nicotine enhances acquisition of ethanol drinking by laboratory rats in a limited access paradigm

 Observations in humans suggest that the initial use of tobacco occurs in close temporal proximity to experimentation with alcohol. There have been relatively few research reports, however, examining possible interactions between these two agents. The present experiments examined the effect of nicotine exposure on the acquisition of ethanol drinking behavior in a limited access procedure. In experiment 1, rats were presented with 1-h access to ethanol solutions of increasing concentration for a period of 20 days. Subcutaneous injections of nicotine (0.6 or 1.2 mg/kg salt) or vehicle were administered 30 min prior to each ethanol presentation. Experiment 2 used a similar method, but rats were presented with water along with ethanol during the 1-h test session. Mecamylamine, a nicotinic receptor antagonist, was administered 30 min prior to the nicotine treatment. Nicotine was seen to produce a dose-dependent increase in ethanol drinking behavior which commenced at the 5% ethanol concentration and continued at 8% and again at 10%. In the second experiment, mecamylamine was observed to block completely the nicotine-induced increase in ethanol drinking behavior. The findings suggest that exposure to nicotine can facilitate the acquisition of ethanol drinking behavior in naive rats and that this effect is mediated by nicotine’s interaction at the nicotinic-cholinergic receptor. Received: 11 June 1998 / Final version: 1 October 1998     

Efficacy,duration, and absorption of a paediatric oral liquid preparation of ranitidine hydrochloride

The objectives of this study were to assess the clinical efficacy of a new oral ranitidine liquid preparation in reducing gastric acidity and volume, to determine the degree of absorption of the drug, and to determine the duration of drug effect. Eighty preoperative children between the ages of one and six years were enrolled in each of three centres. Each subject was allocated to one of the following groups: Group A - apple juice, 5 ml.kg-1 plus placebo liquid; Group B - apple juice, 5 ml.kg-1 plus ranitidine hydrochloride 2 mg.kg-1; Group C - water, 5 ml and placebo liquid; or Group D - water, 5 ml and ranitidine liquid 2 mg.kg-1. All study agents were administered at least two hours before surgery along with a dye marker, sulfobromophthalein 1 ml (50 mg.ml-1). Following induction of anaesthesia, gastric fluid was aspirated, and analyzed for pH, volume, and sulfobromophthalein content (as an index of the ingested fluids). A serum sample was also drawn and analyzed for ranitidine content by high performance liquid chromatography. Groups B and D had fewer subjects with pH below 2.5 and gastric volume > 0.4 ml.kg-1. The duration of reduced volume and acidity was shown to be greatest from two to four hours after drug administration. Thirty-three percent of subjects receiving oral ranitidine, 2 mg.kg-1 hydrochloride as a single dose demonstrated no measurable effect on gastric pH and volume; 28 of those subjects had adequate ranitidine serum levels.