Long Duration Of Effect Research Articles

Botulinum Toxin Type a Treatment for Drooling in Taiwanese Children with Cerebral Palsy: Three casereports

Botulinum toxin is a promising treatment option for the management of drooling in patients with cerebral palsy. However, the effect of botulinum toxin type A in treating drooling of Taiwanese children with cerebral palsy has not been reported thus far. We injected single dose botulinum toxin into bilateral parotid glands of three children with cerebral palsy, and followed the results over a 9-month period. Drooling improved in all three patients without significant adverse effects during follow up. There were individual differences in terms of efficacy and duration of effect. Two patients had longer duration of effect than that reported in previous western studies. The findings for this series of patients suggest that botulinum toxin injection can be effective in reducing saliva secretion and drooling.

Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions

Injectable calcium hydroxylapatite is a soft-tissue augmentation material that is used off-label for facial augmentation, including repletion of depressed nasolabial folds. We sought to assess the safety of calcium hydroxylapatite injection for correction of nasolabial fold depressions. Specifically, we sought to obtain a quantitative assessment of injection-related adverse events using a reproducible placement technique with long-term follow-up. We conducted an open-label, single-center prospective study using reproducible technique with 1- to 1.5-year follow-up. All patients were treated with infraorbital nerve blocks. Then, parallel linear threading technique using 27-gauge/1.25-in needles was used to place 1 to 2 mL of injectant at the dermal subcutaneous junction into each pair of depressed folds. A triangular array of injectant was deposited under the melonasal junction. At follow-up at 2 to 3 weeks and at 1 to 1.5 years, respectively, patients were asked to report and characterize injection-related redness, swelling, bruising, nodule or granuloma formation, asymmetric correction, textural change, hypersensitivity reactions, degree of correction remaining, and overall satisfaction. In addition, patients who had received other injectable soft-tissue materials were asked to compare these with calcium hydroxylapatite in terms of risk profile and longevity of effect. In all, 22 patients were treated and complete follow-up data were obtained from 18. Of the 18 patients, all reported at least mild postinjection redness and swelling, which abated within 1 to 5 days. Bruising was reported by fewer than half, and resolved within 4 to 10 days. Palpable but not visible nodules were reported by 2 of 18 patients; these resolved within 3 months of injection. Asymmetric correction, textural change, granulomas, and hypersensitivity reactions were not reported. In all, 14 of 18 patients reported that cosmetically significant correction lasted longer than 1 year. Two thirds of injected patients who had received other fillers for nasolabial fold correction preferred calcium hydroxylapatite, with the primary reason being increased longevity of effect. There was a lack of objective outcomes measures. When a consistent, defined injection technique is used, injectable calcium hydroxylapatite appears to be a well-tolerated soft-tissue augmentation material for correction of nasolabial fold depressions. A long duration of effect may make this material particularly desirable for some patients.

The use of inhaled formoterol in the treatment of asthma

To discuss the clinical efficacy and safety of formoterol when used to relieve symptoms of asthma and prevent exercise-induced bronchoconstriction (EIB). A PubMed search was performed for articles published between 1997 and 2005 with the keywords formoterol, asthma, and long-acting beta2-adrenergic agonist, with cross-referencing to identify peer-reviewed journal articles. Published articles on the clinical use of formoterol for asthma or EIB were included as well as articles detailing the pharmacologic properties of the drug. To present a thorough review of the literature, published studies based on patient number, study design, or other measures of study quality were not excluded. Formoterol is the only long-acting beta2-adrenergic agonist that combines a rapid onset of action (within 3 minutes) with a long duration of effect (approximately 12 hours). Clinically, as recommended by asthma treatment guidelines, formoterol in conjunction with inhaled corticosteroids (ICSs) is a preferred treatment for moderate to severe persistent asthma. Significant clinical data support the use of formoterol in combination with ICSs for the treatment of asthma, with studies demonstrating improved pulmonary function and symptom scores and decreased need for maintenance ICSs and short-acting beta2-adrenergic agonists (SABAs) as relief medication. Recent studies also demonstrate that use of formoterol as needed as relief medication is associated with a prolonged time to exacerbation, improved pulmonary function, and decreased asthma symptoms. When used as monotherapy, formoterol provides protection against EIB. Clinical data also demonstrate that formoterol is safe and well tolerated even in high doses, with an adverse event profile similar to that of SABAs. Overall, formoterol is safe and effective as adjunct controller therapy for moderate and severe persistent asthma and as monotherapy for EIB.

Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers

SummaryBackground: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects.Objective: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers.Methods: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis.Results: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to ≥ 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels.Conclusions: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model

The effect of LMWH (tinzaparin) on coagulation and fibrinolytic activation in pregnant women at risk of thrombosis

0049-3848/$ see front matter D 2005 Elsevier Ltd. All rights reserv doi:10.1016/j.thromres.2005.03.016 Abbreviations: LMWH, low molecular weight heparin; TAT, thrombi * Corresponding author. Tel.: +353 1 453 1888; fax: +353 1 453 161 E-mail address: lnorris@tcd.ie (L.A. Norris). factors for venous thrombosis may lead to a disturbance of haemostatic balance culminating in enhanced thrombin and fibrin production predisposing to a thrombotic event. Heparin prophylaxis has been successfully used in the prevention of deep vein thrombosis in pregnancy for many years. Low molecular heparins (LMWHs), which have increased bioavailability and longer duration of effect than standard heparin, are becoming increasingly popular for use in prophylaxis of venous thromboembolism during pregnancy [3]. In the non-pregnant population, monitoring of LMWH therapy is not required; however, we and others have shown that the pharmacokinetics of LMWH are affected by pregnancy. [4,5] Compared with the non-pregnant population, higher doses are required to maintain adequate anti-Xa levels, particularly as pregnancy Thrombosis Research (2006) 117, 283—290

Safety, effectiveness, and duration of effect of BOTOX after switching from Dysport for blepharospasm, cervical dystonia, and hemifacial spasm

ABSTRACTBackground: Local injection of botulinum toxin type A is first-line treatment of blepharospasm, cervical dystonia, and hemifacial spasm; however, there is uncertainty about the optimal dose of toxin for each indication as well as dose-conversion ratios that should be used when switching products in clinical practice.Objective: The goal of this study was to compare the safety, effectiveness, and duration of clinical effect of BOTOX and Dysport after drug switching (Dysport to BOTOX) among patients with movement disorders.* BOTOX is a registered trade name of Allergan, Irvine, CA, USA† Dysport is a registered trade name of Ipsen Limited, Slough, UKMethods: A total of 48 patients diagnosed with blepharospasm (n = 27), cervical dystonia (n = 12), or hemifacial spasm (n = 9) were evaluated during a single-arm, crossover-design study in which each patient was his/her own historical control using a 5:1 or 4:1 conversion ratio of Dysport to BOTOX units. Patients were assessed (using Jankovic, Visual Analog Scale, general pain scale, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] scores) after the last injection of Dysport and the first injection of BOTOX. Moreover, each patient kept a diary during treatment to track onset and duration of therapeutic effect.Results: Although BOTOX and Dysport were both clinically effective, this effect was more significant with BOTOX compared to Dysport based on TWSTRS for cervical dystonia ( p = 0.012), and Jankovic scores for blepharospasm ( p = 0.006). Longer duration of effect also was noted with BOTOX than with Dysport (blepharospasm, 62.2 days vs 47.4 days ( p = 0.001); cervical dystonia, 64.3 days vs 44.6 days ( p = 0.014); hemifacial spasm, 65.1 days vs 41.8 days ( p < 0.014), respectively). Of the 48 patients, 19 experienced at least one adverse drug reaction (ADR) during Dysport treatment, with the most commonly reported ADRs being ptosis for blepharospasm and hemifacial spasm and neck weakness for cervical dystonia. No patient reported an ADR during BOTOX treatment.Conclusions: Results suggest therapeutic effectiveness is enhanced with BOTOX compared to Dysport at a dosing ratio between 5:1 and 4:1 (Dysport:BOTOX). Safety and duration of therapeutic effect also are enhanced with BOTOX. Further research is needed.

Tiotropium bromide, a new, once-daily inhaled anticholinergic bronchodilator for chronic-obstructive pulmonary disease

Tiotropium bromide is a quaternary ammonium compound structurally related to ipratropium and has recently been approved in the US for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic-obstructive pulmonary disease (COPD). It is available in a dry powder form, where 18 mg of the drug is inhaled once-daily through a device, the HandiHaler®. The potency and long duration of effect of this anticholinergic bronchodilator result primarily from a prolonged blockade of the M1 and M3 muscarinic receptors in the airways and a relatively more rapid dissociation from the M2 receptor (which provides inhibitory feedback). Multiple studies of up to a duration of 1 year have demonstrated its effectiveness as a bronchodilator for COPD, with a trough increase (measured ∼ 24 h after administration of the drug) in forced expiratory volume in 1 s of ∼ 0.12 l and a peak increase of ∼ 0.25 l. Tiotropium inhalation also leads to a significant reduction in static lung volumes in hyperinflated patients with COPD; this probably contributes to the reduction in dyspnoea that is associated with long-term use of this maintenance bronchodilator. Regular use of the drug was associated with clinically meaningful increases in the Transitional Dyspnoea Index, which indicate reductions in dyspnoea associated with daily activities. Improvement in the respiratory-specific health status questionnaire, the St George’s Respiratory Questionnaire component and total scores was also documented. Finally, pooled data from two 1-year studies and two 6-month studies documented 20 and 28% reductions in the number of exacerbations per patient per year. Side effects have been relatively minimal, with dry mouth the most common symptom, ranging 6 – 16% of patients and rarely leading to discontinuation of the study drug. Limited comparisons of efficacy with other bronchodilators are available. Once-daily tiotropium has been demonstrated to be clearly superior to ipratropium four times daily as a bronchodilator for COPD. Combined results from two studies comparing once-daily tiotropium to twice-daily inhalation of standard doses of salmeterol, indicate a magnitude of the bronchodilator response similar in the two drugs early in the study. However, by 6 months, the bronchodilator effect of tiotropium was somewhat greater than that of the long-acting β-agonist. Preliminary data suggest that combining tiotropium with long-acting β-agonists may produce additional bronchodilator action in COPD.

Efficacy of oral and intravenous dexamethasone in horses with recurrent airway obstruction.

Although the efficacy of dexamethasone for the treatment of recurrent airway obstruction (RAO) has been documented, the speed of onset of effect and duration of action are unknown, as is the efficacy of orally administered dexamethasone with or without fasting. To document the time of onset of effect and duration of action of a dexamethasone solution i.v. or orally with and without fasting. Protocol 1 used 8 RAO-affected horses with airway obstruction in a crossover design experiment that compared the effect of i.v. saline and dexamethasone (0.1 mg/kg bwt) on pulmonary function over 4 h. Protocol 2 used 6 similar horses to compare, in a crossover design, the effects of dexamethasone i.v. (0.1 mg/kg bwt), dexamethasone per os (0.164 mg/kg bwt) with and without prior fasting, and dexamethasone per os (0.082 mg/kg) with fasting. Dexamethasone i.v. caused significant improvement in lung function within 2 h with a peak effect at 4-6 h. Dexamethasone per os was effective within 6 h with peak effect at 24 h at a dose of 0.164 mg/kg bwt prior to feeding. The duration of effect was, for all dexamethasone treatments, statistically significant for 30 h when compared to saline and tended to have a longer duration of effect when used orally. Dexamethasone per os at a dose of 0.164 mg/kg bwt to fed horses had mean effects comparable to dexamethasone at a dose of 0.082 mg/kg bwt per os given to fasted horses, indicating that feeding decreases bioavailability. Dexamethasone administered i.v. has a rapid onset of action in RAO-affected horses. Oral administration of a bioequivalent dose of the same solution to fasted horses is as effective as i.v. administration and tends to have longer duration of action. Fasting horses before oral administration of dexamethasone improves the efficacy of treatment. Oral administration to fasted horses of a dexamethasone solution intended for i.v. use provides an effective treatment for RAO-affected animals.

A Prospective, Double-Blind, Randomized, Parallel- Group, Dose-Ranging Study of Botulinum Toxin Type A in Female Subjects With Horizontal Forehead Rhytides

BACKGROUND Botulinum toxin type A is used cosmetically to improve facial lines, but it has not been thoroughly investigated for the treatment of horizontal forehead rhytides. OBJECTIVE To compare the efficacy and safety of three doses of botulinum toxin type A in females with horizontal forehead rhytides and to establish whether the response rate and the duration of response are dose dependent. METHODS Fifty-nine female patients with horizontal forehead rhytides scoring 2 (moderate) or 3 (severe) on the facial wrinkle scale (FWS) were randomly assigned to receive 16, 32, or 48 U of botulinum toxin type A (Botox, Botox Cosmetic; Allergan, Irvine, CA), which was administered to eight injection sites. Half of the dose was administered to the brow depressors and the other half to the elevators. Wrinkle severity was assessed by the investigator and patient using the FWS at baseline, at Weeks 2 and 4, and then every 4 weeks for 48 weeks. RESULTS Improvements in horizontal rhytides were observed in all dosage groups. Significant dose–response trends were observed for rate of improvement at maximum brow elevation (53% in the 48-U group vs. 15% in the 16-U group at 16 weeks) and rate of relapse to baseline (35% in the 48-U group vs. 75% in the 16-U group at 16 weeks) by a trained observer. CONCLUSION Higher botulinum toxin type A doses resulted in greater efficacy and longer duration of effect in the reduction of horizontal rhytides.

High Affinity Hydroxypiperidine Analogues of 4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the Dopamine Transporter: Stereospecific Interactions in Vitro and in Vivo

In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)-ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC(50); 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC(50); 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic (+/-)-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and (+/-)-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses.

SYMBICORT® TURBUHALER®: A NEW CONCEPT IN ASTHMA MANAGEMENT

SUMMARYSymbicort® is a novel asthma product containing both budesonide and formoterol in a single inhaler, Turbuhaler®. Budesonide is a corticosteroid that treats underlying airway inflammation in asthma; formoterol is a rapid‐ and long‐acting β2‐agonist that prevents and reverses airway obstruction. Budesonide and formoterol therefore have complementary effects, treating two different components of asthma. Clinical studies have shown that Symbicort is more effective in the treatment of asthma than double‐dose corticosteroid, and clinical experience to date indicates that Symbicort is at least as effective and well tolerated as budesonide and formoterol given in separate inhalers. Symbicort has a fast onset of effect, which may help patients feel more in control of their condition and improve adherence to their medication, and a long duration of effect that allows twice‐daily or even once‐daily dosing during periods of good control. More convenient treatment represents another important benefit for patients with asthma, as ease of use can also result in improved adherence, leading to better disease control.

Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: A randomized, placebo-controlled clinical trial

Background: Rofexocib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. Objective: The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofexocib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. Methods: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of ≥2 third molars were randomized to receive a single dose of rofexocib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. Results: A total of 305 patients were randomized to treatment: 121 received rofexocib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group. Conclusions: A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.

Pharmacological similarities and differences between β2-agonists

Formoterol and salmeterol are both long-acting bronchodilators that are effective in the treatment of asthma. However, some differences exist in their pharmacology that are reflected in their clinical profiles. Formoterol has a rapid onset of action, whereas salmeterol causes bronchodilation in a somewhat slower manner. However, both of these drugs are long-acting. After single doses clear effects are maintained for 12 hafter, inhalation, and with high doses effects are observed even at 24 h. Differences between the maximal effects of both drugs are also a consequence of their pharmacological properties. Thus, formoterol has higher intrinsic activity than salmeterol, which means that it is a full agonist, whereas salmeterol is a partial agonist on the β 2-receptor. Physicochemical properties of the drugs may explain the differences in onset and duration of action. Adequate water solubility and moderate lipophilicity of formoterol ensures rapid diffusion to the β 2-receptor on the smooth muscle and rapid bronchodilating activity. Salmeterol, on the other hand, may diffuse more slowly to the β 2-receptor because of its high lipophilicity explaining the slower onset of action. Unlike salbutamol, which is hydrophilic and has a rapid onset and short duration of action, both formoterol and salmeterol possess adequate lipophilic properties to remain in the airway tissues as a depot in close vicinity to the β 2-receptor, explaining their long duration of effect. The long duration of salmeterol has also been suggested to depend on an anchored binding within the β 2-receptor (I). The pharmacological evidence for a rapid onset of action of formoterol, but long duration of effect, is supported by several clinical studies. The fast onset of bronchodilation and high intrinsic activity of formoterol therefore suggest that it can be used for relief treatment in patients with asthma if they are concomitantly treated with inhaled glucorticoids.

Pharmacokinetic actions of exendin‐4 in the rat: Comparison with glucagon‐like peptide‐1

AbstractExendin‐4, originally isolated from saliva of the lizard Heloderma suspectum, shares 53% sequence homology and several potentially antidiabetic actions with the mammalian hormone glucagon‐like peptide‐1(7‐36)amide (GLP‐1). It shows a higher potency and longer duration of effect in vivo, which may be partly attributed to pharmacokinetic properties. The present study compares the pharmacokinetics of GLP‐1 and exendin‐4 in rats after intravenous (iv), subcutaneous (sc), or intraperitoneal (ip) administration. Samples were assayed for active GLP‐1 (7‐36) amide using an enzyme‐linked immunosorbent assay that does not detect GLP‐1 (1‐36‐amide), (1‐37), (9‐36‐amide) or (9‐37). In parallel experiments, samples were assayed for exendin‐4 using a two‐site immunoradiometric assay that reacts specifically with full‐length exendin‐4. The estimated half‐life for GLP‐1 and exendin‐4 were 0.8–4.7 min and 18–41 min for iv bolus, and 4.6–7.1 min and 90–216 min for SC administration, respectively. Half‐lives after ip injection were 0.6–13.5 min for GLP‐1 and 125–174 min for exendin‐4. Bioavailability for GLP‐1 and exendin‐4 was 44–71% and 65–75%, respectively, for sc injection. For ip injection, bioavailability for GLP‐1 and exendin‐4 was 36–67% and 74–76%, respectively. Plasma clearance, as determined from iv infusion data, was 35–38 ml/min for GLP‐1 and 4‐8 ml/min for exendin‐4. Both Co/Cmax and AUC values were proportional to dose with each route of administration. Plasma clearance of exendin‐4 was reduced by 4.4‐fold in nephrectomized animals. In conclusion, exendin‐4 exhibited a much longer plasma half‐life than GLP‐1 in rats after iv, sc, or ip injection, which may contribute in some part to reported differences in duration of biological action of the two peptides. Drug Dev. Res. 53:260–267, 2001. © 2001 Wiley‐Liss, Inc.

Therapeutic equivalence of alendronate 70 mg onceweekly and alendronate 10 mg daily in the treatment of osteoporosis

Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double- blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.

In vivo evaluation of arteether liposomes

Arteether is a potent antimalarial agent that is available as oily solution intended for intramuscular injection. Liposomal formulation composed of dipalmitoylphosphatidylcholine (DPPC), dibehynoyl-phosphatidylcholine (DBPC), cholesterol and arteether in the molar ratio of 1:1:2:1 was chosen for in vivo evaluation. This composition was found to give stable liposomes compared with other formulations and it gave 67.56% trapping efficiency and particle size of 3.21±0.76 μm. The liposomes were administered orally and intravenously to New Zealand rabbits at a dose of 50 mg/kg. The pharmacokinetic parameters following drug administration were determined in each case. Pharmacokinetic parameters after oral administration of liposomes were compared with those of oral aqueous suspension of micronized arteether. High bioavailability of arteether was evident in case of oral liposomes where faster rate and better absorption of arteether were observed compared with aqueous suspension. Oral liposomes gave higher C max and shorter T max as well as a higher value for AUC. Almost complete arteether absorption was observed for oral liposomes where relative bioavailability was 97.91% compared with 31.83% for the oral suspension. Intersubject variations were found to be relatively high in oral liposomes. The obtained values for mean residence time (MRT) and mean absorption time (MAT) indicated that arteether remains longer in gastrointestinal tract (GIT) with longer time period for absorption in case of suspension compared with liposomal formulation. In addition, arteether was successfully administered intravenously in liposomal formulations and showed longer elimination half-life with respect to other artemisinin derivatives. Thus an optimum oral liposomal formulation for arteether can be developed for fast and complete absorption of the drug from GIT. Furthermore, liposomal formulation of arteether could allow for intravenous administration of the drug in high-risk malaria patients with long duration of effect.

Blepharospasm and Hemifacial Spasm: Randomized Trial to Determine the Most Appropriate Location for Botulinum Toxin Injections

Purpose: The purpose of the study is to analyze the effectiveness and side effects of botulinum toxin using four different treatment site applications to determine the most successful treatment regime with the least side effects.Methods: In a prospective trial, 92 patients (50 blepharospasm and 42 hemifacial spasm) were assigned randomly to 1 of 4 different treatment groups (standard [S], brow [B], inner orbital [10], or outer orbital [00]). Each treatment group had a different pattern of injection sites in the orbicularis. A total of 285 treatments were given, and the mean follow-up time was 16.4 months.Results: In the blepharospasm group, patients assigned to the standard group had a significantly longer duration of effect than for those in the brow, inner orbital, and outer orbital groups (8.1 weeks compared with 4.5, 4.2, and 3.1 weeks, respectively;P <0.001). In the hemifacial spasm group, patients in the outer orbital group had significantly shorter duration of effect than those in standard, brow, or inner orbital group (7.2 weeks compared with 12.6, 12.8, and 10.4 weeks, respectively;P <0.001). The four major complications of botulinum toxin treatment were epiphora, ocular irritation, ptosis, and diplopia. The inner orbital treatment produced significantly more episodes of ptosis (13% of treatments). However, the standard treatment produced the most epiphora and ocular irritation (18% of treatments).Conclusions: The position of the injection sites around the orbicularis influences the effectiveness and side effects of botulinum toxin treatment for patients with blepharospasm and hemifacial spasm. The further the treatment is away from the eyelid margin, the lower the risk of ocular side effects. The standard treatment produces the longest duration of effect in the blepharospasm group but with the most transient ocular irritation and epiphora. In the hemifacial spasm group, the brow treatment has an equally long duration of effect as that of the standard treatment with fewer side effects.

Does intramuscular vitamin K1 act as an unintended depot preparation?

To propose a hypothesis that the long duration of effect of intramuscular (i.m.) vitamin K1 in preventing late onset haemorrhagic disease results from a depot effect after i.m. injection. Review of scientific literature relating to the pharmacology of vitamin K, and the aetiology of late onset haemorrhagic disease. A single i.m. dose of vitamin K1 is effective for at least 2 months, whereas the duration of effect of a single oral dose is about 3-4 weeks. The known pharmacological properties of vitamin K1 are seemingly at variance with the long duration of effect of an i.m. dose. Menaquinones (vitamins K2) are absent in the newborn liver, but gradually accumulate after birth. This, together with the low concentrations of vitamin K1 in human breast milk, may explain the peak frequency of late onset haemorrhagic disease at 4-8 weeks. We hypothesize that after i.m. injection, vitamin K1 acts as a depot preparation by forming a viscous mass in muscle tissue which is slowly absorbed over many weeks. This hypothesis is supported by reports indicating significantly higher plasma vitamin K1 levels several weeks after i.m., as compared to oral vitamin K1. The prolonged efficacy of i.m. vitamin K1, compared to oral preparations may be due to a depot effect. New oral preparations of vitamin K1, despite greatly improved bioavailability, may have a shorter duration of effect than i.m. vitamin K1, and therefore be less effective for long-term prophylaxis.

Quinoxaline N-oxide containing potent angiotensin II receptor antagonists: synthesis, biological properties, and structure-activity relationships.

A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.

Salmeterol Xinafoate

Salmeterol xinafoate, like salbutamol (albuterol), is a saligenin derivative, and a selective beta 2-adrenoceptor agonist. It produces bronchodilation for at least 12 hours following inhalation of a single 50 micrograms dose. Salmeterol is intended for regular twice-daily treatment of reversible airways obstruction and not for immediate symptomatic relief, and when used in this manner, 50 micrograms twice daily is more effective than salbutamol 200 micrograms or terbutaline 500 micrograms administered 4 times daily, or individually titrated oral doses of theophylline in improving objective and subjective criteria of efficacy in patients with mild to moderate asthma. Salmeterol 100 micrograms inhaled twice daily may provide better control than the lower dose in patients with severe asthma. The long duration of effect of salmeterol makes it particularly suitable for treating patients with nocturnal asthma in whom it improves sleep quality. The place of salmeterol, like that of other beta 2-adrenoceptor agonists used regularly in the treatment of asthma, is being debated. Patients in need of regular beta 2-agonist therapy should also be regarded as candidates for inhaled corticosteroids to counteract underlying inflammation. Thus, salmeterol may be particularly useful in patients requiring regular treatment with beta 2-agonists for nocturnal asthma and results of trials in progress involving large numbers of patients are awaited with interest.