Bioavailability of a new generic formulation of mycophenolate mofetil MMF 500 versus CellCept in healthy adult volunteers

Several studies have revealed a decreased incidence of early graft rejection with the use of mycophenate mofetil (MMF). The cost of the drug is, however, prohibitive especially in developing countries with limited resources. We compared the pharmacokinetic profile of a new MMF generic formulation (MMF 500 batch number: 06T3001; Medis Tunis) with those of Cellcept, (batch number: M1427; Hoffmann La Roche, Switzerland) in healthy volunteers. The study was double-blinded to investigator and volunteers. It had a balanced randomized, two-treatment, two-period, two-sequence, single-dose, crossover, comparative oral bioavailability design in adult healthy human volunteers. The study was designed, performed, and monitored by CRO Transmedical s.a.l International (Beirut, Lebanon) in accordance with the Basic Principals defined in the US 21 CFR Part 312.20, and the principals enunciated in the World Medical Association Declaration of Helsinki. We included nonsmoking healthy volunteers between the ages of 22 and 45 years. The subjects were admitted to the hospital one night prior to blood sampling. After volunteers received the same dinner, they were fasted overnight and for 2 hours postdosing. At 8 am each person received a single oral dose of 500 mg of either formulation. Blood samples were collected to construct the pharmacokinetic profiles as follows: 0, 0.15, 0.30, 0.45 minutes and 1, 1.15, 1.30, 2, 4, 6, 10, 12, and 24 hours. Water and food intake were the same for all volunteers during the whole study period. Following an 8-day washout period, the subjects were crossed over. Plasma mycophenolic acid concentrations were determined using a high-performance liquid chromatography validated enzyme-linked immunosorbent assay-based method (TransMedical, Beirut Lebanon). Physical examinations, hematology, urinanalysis, serum chemistry tests, and liver enzymes were performed at screening and at the end of each period. Subjects were monitored for safety and adverse events throughout the study by two physicians (one from the hospital and one from TransMedical). The Cmax, Tmax, and AUC for MMF 500 were 10.14 ng/mL, 51.82 minutes, and 18.33 ng/mL/h vs 10.94 ng/mL, 49.09 minutes, and 17.46 ng/mL/h for CellCept, respectively. The 90% confidence intervals (LSM) of Cmax, Tmax, and AUC for MMF 500 were 92.7%, 105.6%, and 105%, respectively, which is within the Food and Drug Administration (FDA)-assigned range for immunosuppressive drugs (90% to 111%). These results indicated that the products are equivalent and switchable according to FDA rulings.     

Safety and efficacy of a novel salmon calcitonin (sCT) technology-based oral formulation in healthy postmenopausal women: acute and 3-month effects on biomarkers of bone turnover.

Oral administration of calcitonin could improve compliance to long-term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months. INTRODUCTION: We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1,000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays. RESULTS: After the first dose, sCT evoked dose-dependent decreases in serum CTx (-60.8% to -81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r = 0.78, p < 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (-18.9% and -20.5%, respectively, p < 0.05). The placebo-corrected change in OC was -8.6 (p = 0.09), whereas the change in BSALP was -7.3 (p = 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups. CONCLUSION: The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.     

Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers

We evaluated the pharmacokinetics and pharmacodynamics of single 5-mg doses of midazolam after administration of a novel intranasal (IN) formula, IM, and IV midazolam in an open-label, randomized, 3-way cross-over study in 12 healthy volunteers. IN doses were delivered as 0.1-mL unit-dose sprays of a novel formulation into both naris. Blood samples were taken serially from 0 to 12 h after each dose. Plasma midazolam concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic parameters. The mean midazolam bioavailabilities and % coefficient of variation were 72.5 (12) and 93.4 (12) after the IN and IM doses, respectively. Median time to maximum concentration was 10 min for IN doses. Adverse events were minimal with all routes of administration, but nasopharyngeal irritation, eyes watering, and a bad taste were reported after IN doses. Our results support further development of this novel midazolam nasal spray.     

Effect of salmon calcitonin on deoxypyridinoline (Dpyr) urinary excretion in healthy volunteers

To evaluate the influence of synthetic salmon calcitonin (SMC) on bone resorption we investigated the modifications in urinary cross-links excretion [pyridinoline (Pyr) and deoxypyridinoline (Dpyr)] induced by a single dose of the drug. The study was carried out in 16 healthy volunteers given a single dose of either 50 IU SMC I.M. or placebo, according to a double-blind, cross-over design. Urine was collected every 24 hours during the 72 hours after each treatment and Pyr and Dpyr were measured by an automated HPLC method. Pyr showed no significant difference after the two treatments, whereas in the first 24-hour urine collection Dpyr (nmol/24 hours±SD) was considerably lower after SMC than after placebo (118.9±26.0 against 147.2±45.0, P<0.05). The amount of saved Dpyr was 19.2%. The selective effect of SMC on Dpyr excretion was more evident comparing the Pyr/Dpyr ratios for placebo and SMC during the first day of the study (4.1±0.6 against 4.8±0.7, respectively, P<0.01). Using Eyre's formula (10 nmol Dpyr =0.17 g bone) and assuming that no Dpyr is metabolized, the mean daily amount of bone resorbed was calculated (2.5 g for placebo and 2.0 g for SMC). The difference is the index of the bone-saving effect of SMC (0.48 g/day, or 19.2%). In conclusion, assuming that in healthy volunteers bone turnover is balanced with equal rates of formation and resorption, a dose of 50 IU I.M. of SMC reduces resorption, with a bone gain in the first 24 hours calculated as 9.4 mg/IU.     

Comparison of the acute biological action of injectable salmon calcitonin and an injectable and oral calcitonin analogue

Summary In most countries, calcitonin is available in the form of injections, and less frequently as an intranasal spray. An oral route of administration should improve compliance. In a preliminary feasibility study, we have compared the acute biological action of injectable salmon calcitonin (50 IU), with the injectable calcitonin analogue ASC 710 (0.2 mg) and oral ASC 710 (20 mg) in 6 patients suffering from active Paget's disease of bone. The intensity and duration of the biological response were not significantly different in the 3 modes of therapy. In conclusion, the oral calcitonin analogue ASC 710 possesses an antiresorbing activity in Paget's disease comparable to that of an injection of salmon calcitonin which demonstrates that it can cross the intestinal barrier.     

Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers

BACKGROUND: To compare the pharmacokinetics of intravenous, oral immediate-release (IR), and oral extended-release (OROS ) formulations of hydromorphone. METHODS: In this randomized, six-session, crossover-design study, 12 subjects received hydromorphone 8-mg intravenous, 8-mg IR oral, and 8-, 16-, and 32-mg OROS formulations or placebo orally followed by plasma sampling for hydromorphone determination. Pharmacokinetic analysis was performed using NONMEM. Using the disposition of hydromorphone from the intravenous administration, deconvolution was used to estimate the input rate function (release rate from the gut to the blood) for the IR and OROS formulations. A linear spline was used to describe the drug input rate function. RESULTS: The deconvolution using linear splines described the release characteristics of both the IR and OROS formulations. The mean absolute bioavailability for the 8-mg OROS formulation was significantly larger ( = 0.025) than for the 8-mg IR formulation: 0.24 (SD 0.059) versus 0.19 (SD 0.054), respectively. The bioavailability was the same for the three doses of the OROS formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS 8-mg doses, respectively. CONCLUSIONS: The OROS formulation of hydromorphone produced continued release of medication over 24 h, which should allow for once-daily oral dosing. The extended release of hydromorphone will produce less fluctuation of plasma concentrations compared with IR formulations, which should provide for more constant pain control. The in vivo release of hydromorphone from both IR and OROS formulations were adequately described using a linear spline deconvolution approach. The increased bioavailability from the OROS formulation may be related to decreased metabolism by a first-pass effect or enterohepatic recycling of hydromorphone.     

Clinical efficacy of salmon calcitonin in Paget's disease of bone

Clinical interest in salmon calcitonin began in 1972 when this peptide was shown to be effective in the treatment of Paget's disease. Salmon calcitonin is more potent than porcine calcitonin, with human calcitonin intermediate in potency. Salmon calcitonin is a highly effective therapeutic agent in the treatment of Paget's disease. During chronic treatment with salmon calcitonin, alkaline phosphatase activity and urinary hydroxyproline excretion decrease on an average of 50% in patients with Paget's disease. Patients may experience a variety of clinical benefits during chronic treatment, including relief of bone pain, a reversal of neurological deficits, stabilization or improvement of hearing loss, and improvement of vascularity of bone. Radiologic healing of osteolytic lesions is particularly striking with calcitonin treatment. Paget's disease patients prefer treatment with salmon calcitonin administered by means of a nasal spray. Salmon calcitonin has an excellent safety profile and produces mild side effects in a small percentage of patients. The most common side effects associated with salmon calcitonin administration are nausea and facial flushing. It is unusual to observe severe side effects. In about 20% of patients, production of antibodies may neutralize the effects of the exogenously administered calcitonin; these patients respond to human calcitonin. At this time salmon calcitonin should still be considered a valuable therapeutic agent in the treatment of Paget's disease, particularly in patients with osteolytic lesions.     

鲑鱼降钙素对维持性血液透析患者并发高钙血症的疗效观察

目的观察鲑鱼降钙素治疗维持性血液透析（MHD）患者并发高钙血症的疗效。方法对28例MHD患者合并高钙血症者给予鲑鱼降钙素肌肉注射,开始每天1次,连续6d,以后每周2次,透析后使用。疗程12周。以用药前和用药后第2、4、8、12周检测血钙、血磷、钙磷乘积和血全段甲状旁腺素（iPTH）为指标,应用视觉模拟疼痛评分法对骨关节疼痛程度进行定量,并进行统计学分析。结果25例完成观察。治疗后第4周血钙、钙磷乘积均有不同程度降低,与治疗前比较有统计学意义（P〈0．05）;血磷和iPTH也有降低,但与治疗前比较差异无显著性。治疗后第4周,所有患者骨关节疼痛、活动障碍等症状均有不同程度缓解;疗程结束后23例症状基本消失,但治疗前已发生的转移性钙化等现象无变化。结论鲑鱼降钙素治疗MHD患者并发高钙血症,可以有效降低高血钙、钙磷乘积,并能够有效缓解骨关节疼痛症状,近期疗效显著。     

The metabolic effects of oral tizanidine in healthy volunteers

This pilot study compared the metabolic effects of placebo and 6 mg and 12 mg of oral tizanidine in random double-blind cross-over fashion in five healthy volunteers.
The metabolic measurements were made with a portable metabolic chart (Deltatrac, Datex/Instrumentarium, Helsinki, Finland). Heart rate (HR), systolic (BPS), mean (BPM) and diastolic (BPD) blood pressure were measured noninvasively. Subjective assessment of tiredness and dryness of mouth were measured by using visual analogue scales (VAS).
There were no statistically significant differences in tiredness or dryness of mouth between the groups. BPD decreased significantly after both doses of tizanidine when compared to placebo (by an average of 12% after 6 mg of tizanidine and 15% after 12 mg of tizanidine from the baseline). Oxygen consumption and energy expenditure decreased significantly after 6 and 12 mg of tizanidine when compared to placebo. The average decrease in oxygen consumption was 3% after 6 mg of tizanidine and 8% after 12 mg of tizanidine, when compared to the baseline. Energy expenditure decreased by an average of 5% after 6 mg of tizanidine and 9% after 12 mg of tizanidine, when compared to the baseline. There were no other statistically significant differences between the groups.
This study indicates that 6 and 12 mg of oral tizanidine can be useful for reducing energy expenditure and oxygen comsumption without prominent cardiovascular effects.     

Biological properties of salmon calcitonin IV.

In this study we characterized the biological activity of the recently identified salmon calcitonin (sCT) IV, in order to evaluate its potential therapeutic value. In the rat bioassay, sCT IV exhibited a 30% higher hypocalcemic activity than sCT I. The capacity of the molecule to inhibit bone resorption was assessed in vitro by the bone resorbing assay and the pit assay. An inhibitory effect, similar to that of sCT I, was observed in both assays. The interaction of sCT IV with the rabbit CT receptor was also studied. The affinity of sCT IV for the receptor was similar to that of sCT I, as was the potency for stimulating cAMP production. The antigenicity of the two molecules was not identical. Thus, this new CT could represent a useful novel therapeutic agent for the treatment of bone disorders.     

Treatment of Paget's disease of bone with a combination of intranasal salmon calcitonin and oral calcium and thiazide

Summary The purpose of this study was to establish the smallest dose of nasally administered salmon calcitonin (SCT) which, if given in conjunction with a previously published calcium/thiazide treatment, would be as effective as parenteral SCT in the treatment of Paget's disease of bone. Forty patients suffering from symptomatic Paget's disease were treated with 0.5 g calcium three times daily, 10 mg/day clopamide, and 400 IU nasally administered salmon calcitonin given once or twice weekly. This regimen was given for 5 months, after which all treatment was ceased for 4 months. Parenteral SCT (100 IU) was then given three times weekly for 5 months to 25 of the patients. With the oral/nasal treatment, the plasma alkaline phosphatase level (AP) decreased by 30±15 (SD) % when the SCT was given once weekly and by 39±11% (P<0.05) when the SCT was given twice weekly. There were similar decreases in the fasting urinary hydroxyproline: creatinine ratios. The parenteral SCT reduced the AP by 33±23%. Though reduction in bone pain was similar with both treatments, most patients preferred the oral/nasal treatment. It is concluded that the oral/nasal treatment, when the SCT is given twice weekly, has similar efficacy to parenteral SCT, and is a well tolerated, effective initial treatment for Paget's disease of bone.     

Blind oral intubation: the development and efficacy of a new approach.

STUDY OBJECTIVE: To develop an approach to blind oral intubation. With the aid of a fiberoptic laryngoscope and stylet within an endotracheal tube, a video camera, a monitor, and a recorder to correlate the effects of various manipulations of the airway on access to the trachea, a suitable approach was devised. We then evaluated its efficacy. DESIGN: Randomized, prospective comparison of regimens. SETTING: Inpatient surgery at a university-affiliated teaching hospital. PATIENTS: One hundred adult patients with no known abnormalities of the upper airway by history or on physical examination, scheduled to undergo elective surgery, and without evidence of major cardiac disease or need for a rapid-sequence induction of anesthesia. INTERVENTIONS: Fifty patients in each of two groups were given fentanyl 5 micrograms/kg intravenously (IV), followed 2 minutes later by thiopental sodium 5 mg/kg and succinylcholine 2 mg/kg. Patients in Group 1 (the controls) were orally intubated via direct laryngoscopy using a Macintosh #3 blade. Patients in Group 2 (the experimentals) were intubated orally with the approach developed without the use of a laryngoscope. Intubations were deemed successful if they were performed within 1 minute after the mouth was opened. MEASUREMENTS AND MAIN RESULTS: All the patients in Group 1 were successfully intubated within 1 minute, while 49 of the 50 patients in Group 2 were successfully intubated within 1 minute. CONCLUSIONS: Blind oral tracheal intubation can be successfully performed in a safe and effective manner after appropriate teaching of the technique.     

鲑鱼降钙素注射治疗骨痛90例疗效观察

目的 有研究显示鲑鱼降钙素的活性是人降钙素的40～50倍,本研究是应用鲑鱼降钙素注射治疗各种原因引起的骨痛,以观察其镇痛疗效和安全性.方法 给予鲑鱼降钙素50 IU皮下注射,每天1次,2周后50 IU,隔日1次注射,共4周,期间每周复诊1次,记录疼痛强度,并观察不良反应.结果 90例患者治疗前均有中度以上疼痛,其疼痛强度为6.57±1.52,用药2周后疼痛明显好转,其强度下降为1.25±1.15,治疗前后差异有显著性(P<0.001).疼痛完全缓解率达37例(41.1%),明显缓解率为30例(33.3%),中度缓解率为18例(20%),无效5例(6.6%).其主要不良反应是轻度恶心11例(12.2%),继续用药后消失.结论 鲑鱼降钙素能够迅速缓解各种原因引起的骨痛,安全性良好.     

The effects of glycopyrrolate on oral mucous host defenses in healthy volunteers

We studied the effects of glycopyrrolate on oral mucous host defenses. Single IV doses of glycopyrrolate (4 microg/kg) or placebo were administered to 12 healthy volunteers in a randomized, double-blinded, cross-over study. Salivary flow rates and the concentrations/activities of total protein, amylase, and nonimmunologic (lysozyme, lactoferrin, myeloperoxidase, total salivary peroxidase, and thiocyanate) and immunologic (total immunoglobulin A, immunoglobulin G, and immunoglobulin M) mucous host defense factors were determined for paraffin-stimulated whole saliva before and 1, 3, 6, 12, 24, and 48 h after drug administration. Glycopyrrolate serum concentrations were determined before and 2, 4, 6, 10, 15, and 30 min and 1, 2, 3, 6, 12, and 24 h after IV drug injection. Salivary flow rates were decreased significantly for 12 h after glycopyrrolate injection, compared with saline injection. The concentrations of immunologic and nonimmunologic defense factors were increased in the glycopyrrolate group, and differences between the groups were found for all factors (P < 0.05-0.001) except lysozyme and total salivary peroxidase. In contrast, because of the reduced flow rate, the output of all defense factors into the saliva was decreased after glycopyrrolate injection, compared with saline injection. Glycopyrrolate thus decreases the output of salivary host defense factors into the oral cavity. Implications: Glycopyrrolate induces long-lasting hyposalivation and decreases the secretion of salivary immunologic and nonimmunologic defense factors in healthy volunteers.     

Chondroprotective action of salmon calcitonin in experimental arthropathies

Summary To assess whether calcitonin exerts an influence on cartilage, three models of arthropathies in rabbits—representing three different modes of cartilage destruction—were used: (1) corticosteroid administration (endocrinological disturbances model): (2) meniscectomy (mechanical stress model); and (3) immobilization of the hind leg (nutritional disorder model). After 12 weeks of methylprednisolone (MP) administration, the rabbit femur heads displayed cartilage erosions, marked decrease of glycosaminglycans (GAG) content, and narrowing of joint spaces. Elevation of serum uronic acid, activity of alkaline phosphatase, and calmodulin content was evident. All these changes were minimal—close to normal—in the group treated for 12 weeks with MP + salmon calcitonin (sCT). Partial meniscectomy and hind leg immobilization caused statistically significant loss of GAG from the cartilage and narrowing of the knee joint space during the same experimental period, 12 weeks. In both these models the groups of rabbits treated simultaneously with sCT showed only insignificantly smaller joint spaces and GAG content. These results support our hypothesis of a chondroprotective property of calcitonin. However, the mechanism through which calcitonin influences joint cartilage remains unknown. A direct effect of calcitonin on cultivated chondrocytes, as well as the role of calmodulin, beta-endorphins, calcium, and interleukin-1 in the process are discussed.     

鲑鱼降钙素在膝关节骨关节炎中的应用

目的 分析鲑鱼降钙素治疗膝关节骨关节炎的临床疗效.方法 将膝关节骨关节炎患者48例按随机数字表法随机分为A、B、C、D4组,每组各12例.每组患者给予不同的药物治疗.A组:对乙酰氨基酚+盐酸氨基葡萄糖;B组:美洛昔康+盐酸氨基葡萄糖;C组:鲑鱼降钙素+盐酸氨基葡萄糖;D组:鲑鱼降钙索.对乙酰氨基酚及美洛昔康在疼痛症状消失后即可停用.其他药物疗程为12周.治疗前后记录对比疼痛视觉模拟评分,用12条目健康调查简表评价患者生活质量变化.结果 12周后,A、B、C、D4组疼痛视觉模拟评分由治疗前5.6±1.2、5.5±1.2、5.4±1.0、5.1±1.2降至1.9±0.8、1.2±0.7、0.8±0.6、0.9±0.7;12条日健康调查简表评分由治疗前-23.4±3.1、-23.8±3.0、-24.8±3.8、-22.4±2.8降至-15.1±4.7、-14.5±4.7、-9.3±6.2、-10.2±5.3.各组治疗前后比较,差异明显具有统计学意义(P＜0.05).B、C、D组患者疼痛视觉模拟评分优于A组(P＜0.05).C、D组患者12条目健康调查简表评分优于A、B两组(P＜0.05).结论 鲑鱼降钙素治疗膝关节骨关节炎有较好的止痛作用.     

Absorption of a new oral formulation of cyclosporin A in a child on parenteral nutrition

A 2-year-old child underwent renal tranplantation in the presence of a post-viral enteropathy rendering him dependent on total parenteral nutrition. As part of his immunosuppression, he was given a new oral formulation of cyclosporin A (Neoral), which he was able to absorb satisfactorily, using conventional doses, during the 6 weeks he was dependent on intravenous nutrition and in the face of intermittent severe diarrhoea. An unusual pharmacokinetic profile was observed.     

The effects of a single oral dose of lorazepam and alprazolam on reaction times in young healthy volunteers

Lorazepam (Temesta) and alprazolam (Xanax) are two benzodiazepines which are widely used for their anxiolytic activity. In this study their effect on psychomotor functions was investigated. Eight young healthy volunteers participated in the experiments. Using a double-blind cross-over design, the effect of single oral doses of lorazepam (2.5 mg) and alprazolam (0.5 mg) on a choice reaction time test to visual stimuli (letter pairs presented on a computer screen), were assessed. The experimental procedure consisted of three sessions which differed from each other either by the stimulus presentation rate, or by the presence or absence of a warning signal. In all three sessions, lorazepam, when compared with placebo, significantly prolonged the reaction times (RT), while alprazolam did not. Increasing the interstimulus interval resulted in an equal increase of the reaction times in the three conditions. On the other hand, the introduction of a warning signal which preceded the presentation of the letter pairs, improved performance in the three conditions. This improvement was more pronounced after lorazepam than after placebo. This finding is interpreted as a partial recuperative effect for the impaired performance in the baseline condition after intake of lorazepam.