薯蓣皂苷元的制备及其抗甲亢活性研究

目的 考查薯蓣皂苷元对甲亢大鼠的活性。方法 穿山龙饮片用含1.5 mol·L^-1硫酸的75%乙醇水溶液在沸水浴中回流提取4.5 h,再经柱层析法分离、精制纯化得薯蓣皂苷元提取物,并进行结构表征。采用优甲乐灌胃法制作大鼠甲亢模型,并将大鼠随机分成正常对照组、甲亢模型组、甲巯咪唑治疗组、薯蓣皂苷元治疗组(低、中、高剂量),分别于给药21 d后测定大鼠血清中T₃、T₄及TSH值。结果 薯蓣皂苷元提取制备工艺正确适当,所得薯蓣皂苷元提取物经氢谱、碳谱、质谱和高效液相色谱表征确定为薯蓣皂苷元。与甲亢模型组比较,薯蓣皂苷元治疗组(低、中、高)血清中T₃、T₄和TSH值均有不同程度改善。结论 薯蓣皂苷元制备工艺合理可行,得率较高。薯蓣皂苷元可使甲亢大鼠的各项甲状腺功能血清值恢复正常,还可增加其体质量,功效与甲巯咪唑相似,值得进一步研究。     

“Low T3-syndrome” in acute myocardial infarction — Relationship to beta-adrenergic blockade and clinical course

Summary Serum levels of T₄, T₃ rT₃ and resin T₃ uptake were followed for 5 days in 40 patients with acute myocardial infarction (AMI) allocated to early treatment either with alprenolol or placebo. There was a significant fall in T₃ (P<0.05) and an increase in rT₃ (P<0.05) without any significant difference between the alprenolol — (n=19) and placebo — (n=21) treated groups. The risk of missing a further 20% change in se-T₃ and se-rT₃ after alprenolol compared to placebo treatment () was <0.10 and <0.50, respectively. In patients with a severe clinical course, the fall in T₃ and increase in rT₃ was significantly greater than in patients without complications. No change in T₄ was observed either with respect to the clinical course nor following alprenolol. The data suggest that alprenolol can be given in the acute phase of myocardial infarction without causing any additional disturbance in the serum levels of T₃ and T₄.     

Pharmacokinetics of Multiple Daily Transdermal Doses of Nicotine in Healthy Smokers

The plasma concentration–time profiles and pharmacokinetics were characterized for nicotine and its major metabolite, cotinine, after multiple daily application of a nicotine user-activated transdermal therapeutic system (UATTS) to nine healthy smokers. The volunteers abstained from smoking 24 hr prior to and during the course of the study. A 10-cm² system (designed to deliver 75 µg/cm²/hr) was applied every 24 hr for 5 days, with serial blood samples taken on Days 1 and 5 and after system removal on Day 5. Generally, the nicotine UATTS was well tolerated. Predose nicotine concentrations on Days 3 to 5 indicated that steady state was reached by Day 3. The nicotine pharmacokinetic parameters for Day 1 and Day 5 were similar: the mean (SD) AUC(0-24) values for Days 1 and 5 were 271.7 (50.7) and 311.7 (55.0) ng · hr/ml, the mean (SD) C _max values were 16.3 (2.6) and 16.8 (2.9) ng/ml, and the median (range) T _max values on Days 1 and 5 were 12 (9–24) hr and 12 (0–24) hr, respectively. There was only slight or no accumulation of nicotine after multiple dosing as indicated by the Day 5 to Day 1 AUC and C _max ratios of 1.15 (0.09) and 0.98 (0.06), respectively. Overall, the UATTS system maintained relatively constant plasma nicotine concentrations and is suitable for once-daily application.     

Long-term amiodarone therapy raises serum cholesterol

Summary Serum total cholesterol and triglyceride levels were measured in 12 patients before and 3, 6 and 9 months after treatment with amiodarone. In addition, we monitored serum T₄, T₃, reverse T₃ and TSH levels. Amiodarone and its desethyl metabolite levels were measured on each occasion.Serum total cholesterol and T₄ levels rose from 5.95 mmol/l, and 102.7 mmol/l respectively at baseline to 6.95 and 115.8 at 6 months and reverse T₃ increased at 3, 6 and 9 months from baseline. Serum triglycerides did not change. No relationship existed between cholesterol, T₄ and T₃ and amiodarone (or its metabolite) levels nor between cholesterol and thyroid hormone levels.These data demonstrate that amiodarone therapy is associated with an elevation in serum cholesterol. This may have clinical implications in view of the current widespread use of the drug.     

A possible mechanism for 2,2',4,4',5,5'-hexachlorobiphenyl-mediated decrease in serum thyroxine level in mice

Serum total thyroxine (T₄) level was markedly decreased, without significant increases in the levels of hepatic T₄-UDP-glucuronosyltransferase (T₄-UGT) and serum thyroid-stimulating hormone, 3 days after treatment with 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB153) (100 mg/kg, ip) in both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 and TCDD-resistant DBA/2 mice. Likewise, in either strain of mice, no CB153-mediated changes in the binding levels of [¹²⁵I]T₄ to serum proteins, such as transthyretin, albumin, and thyroxine binding globulin, were observed, while in CB153-pretreated C57BL/6 mice, but not in CB153-pretreated DBA/2 mice, the levels of biliary [¹²⁵I]T₄ and [¹²⁵I]T₄-glucuronide at 90-120 min after injection of [¹²⁵I]T₄ slightly increased, as compared with those in the corresponding control mice. Concerning tissue distribution of [¹²⁵I]T₄, liver-selective increases in the [¹²⁵I]T₄ accumulation by CB153-pretreatment were observed in both C57BL/6 and DBA/2 mice, and the hepatic levels of [¹²⁵I]T₄ in the C57BL/6 and DBA/2 mice became more than 44% and 34% of the [¹²⁵I]T₄ dosed, respectively. The present findings indicated that the CB153-mediated decreases in the level of serum total T₄ in C57BL/6 and DBA/2 mice occur mainly through an increase in the accumulation of T₄ in the liver.     

Influence of hyperthyroidism on the kinetics of methimazole,propranolol, metoprolol and atenolol

Summary The kinetic profiles of oral methimazole 40mg, propranolol 80mg, metoprolol 100mg and atenolol 100mg were compared in hyperthyroid patients both during the hyper-and euthyroid states. For methimazole, neither the peak concentration (C_max), the time to reach peak concentration (t_max), the elimination half-life (t_1/2) nor the area under the curve (AUC) value was affected by the hyperthyroid state. For propranolol and metoprolol, which undergo extensive presystemic clearance, the AUC values were lower (p<0.02) when the patients were hyperthyroid than when they had become euthyroid, but the t_1/2's were not significantly altered. For atenolol, there were no significant kinetic differences between the hyperthyroid and euthyroid states. The findings are compatible with the assumption that hyperthyroidism does not affect the kinetics of methimazole or atenolol, but that it may enhance presystemic clearance of propranolol and metoprolol.     

Thyroid status in chronic alcoholics

Serum thyroxine (T₄), triiodothyronine (T₃) and thyrotrophin (TSH) were measured by radioimmunoassay in 39 chronic alcoholics on admission.Two patients had a reduced circulating serum T₄ and eight showed a low serum T₃ level but basal TSH was not raised in any of the 39 patients. Interestingly, low T₄ and T₃ levels returned to normal after abstinence and high protein and vitamin supplemented diet for one week.It is clear from our observations that a normo- or hypo- rather than a hypermetabolic or hyperthyroid state is more common in drinking chronic alcoholics. Ethanol-induced “low T₃ syndrome” has also been described and a mechanism of its pathogenesis is suggested.     

Phase I trial of three-weekly Docetaxel,Carboplatin and oral lenalidomide (Revlimid®) in patients with advanced solid tumors

Summary Introduction: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different toxicity profile. In preclinical trials it has shown synergy with chemotherapy. Patients and methods: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically proven solid tumors, ≤2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled. Dose limiting toxicities (DLT) were defined as ≥ grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors were used during cycle 1. Results: Three of four patients treated at dose level 1, docetaxel 60 mg/m² and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1–14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level −1, docetaxel 60 mg/m² and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1–14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer. Conclusions: Docetaxel 60 mg/m² and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1–14 days of a 21 day cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted. Revlimid? is a registered trademark of Celgene Corporation.     

Comparative study on 2,2',4,5,5'-pentachlorobiphenyl-mediated decrease in serum thyroxine level between C57BL/6 and its transthyretin-deficient mice

The relationships between the changes in the levels of serum total thyroxine (T₄), serum T₄-transthyretin (TTR) complex, and accumulation of T₄ in tissues by 2,2′,4,5,5′-pentachlorobiphenyl (PentaCB) were examined using wild-type C57BL/6 (WT) and its TTR-deficient (TTR-null) mice. The constitutive level of serum total T₄ was much higher in WT mice than in TTR-null mice. In WT mice 4 days after a single intraperitoneal injection with PentaCB (112 mg/kg), serum total T₄ level was significantly decreased along with a decrease in serum T₄-TTR complex, and the levels of serum total T₄ in the PentaCB-treated WT mice were almost the same to those in PentaCB-untreated (control) TTR-null mice. In addition, a slight decrease in serum total T₄ by PentaCB treatment was observed in TTR-null mice. Furthermore, clearance of [¹²⁵I]T₄ from the serum after [¹²⁵I]T₄-administration was promoted by the PentaCB-pretreatment in either strain of mice, especially WT mice. On the other hand, accumulation level of [¹²⁵I]T₄ in the liver, but not in extrahepatic tissues, was strikingly enhanced in the PentaCB-pretreated WT and TTR-null mice. Furthermore, in both strains of mice, PentaCB-pretreatment led to significant increases in the steady-state distribution volume of [¹²⁵I]T₄ and the concentration ratio of the liver to serum. The present findings demonstrate that PentaCB-mediated decrease in serum T₄ level occurs mainly through increase in accumulation level of T₄ in the liver and further indicate that the increased accumulation of T₄ in the liver of WT mice is primarily dependent on the PentaCB-mediated inhibition of serum T₄-TTR complex formation.     

Post-surgical pain relief with zero-order intravenous infusions of meptazinol and morphine: a double-blind placebo-controlled evaluation of their effects on ventilation

Summary A double-blind, placebo-controlled study has been made of the analgesic and respiratory effects of constant rate infusions of meptazinol and morphine in 30 patients after abdominal surgery. Group I received meptazinol, loading dose 50 mg followed by i.v. infusion 0.5 mg · kg⁻¹ · h⁻¹, Group II received morphine, loading dose 5 mg and then an infusion of 0.05 mg · kg⁻¹ · h⁻¹, and Group III received saline. After recovery from inhalation anaesthesia (without opiates or a local anaesthetic) pain relief and chemoreceptor carbon dioxide tolerance were assessed before and at various times after starting the analgesic infusion. A similar degree of pain relief was found after 10 min in Groups I and II, which lasted until the end of observation period (20 h). Heart rate and systolic and diastolic blood pressures were lower in Group II than in Groups I and III, and respiratory rate fell in Groups I and II. After 6 h arterial carbon dioxide tensions (P_aCO₂) became significantly higher in Group II than Group III. The maximum percentage fall in mean tidal volume (V_T) and expired minute volume (0V_E) from the preinjection values was significant in Groups I and II. End-tidal carbon-dioxide (P_ETCO₂) and P_aCO₂ were significantly higher after 20 h of infusion in Group II compared to Group I. The slope of 0V_E/P_ETCO₂ (<S>) was increased in Group I and it was significantly reduced in Group II. Analysis of derived variables, such as the CO₂ intercept (CO₂I) and minute ventilation at 7 kPa (0V_E7), indicated a shift to the right of the slopes in Groups I and II, initially more so in Group I. It is concluded that constant rate infusions of meptazinol and morphine were effective in providing postoperative pain relief. However, their effects on the central regulation of respiration were different, as meptazinol did not impair CO₂ sensitivity whereas morphine did.     

One enzyme for the 5′-deiodination of 3,3′,5′-triiodothyronine and 3′,5′-diiodothyronine in rat liver

Many studies suggest that one enzyme is involved in the phenolic ring deiodination of iodothyronines in rat liver and kidney and another one in the tyrosyl ring deiodination. This study describes some characteristics of the phenolic ring (5′-) deiodination of rT₃ and 3′,5′-T₂ by rat liver microsomes. At pH 7.2 the K_m values of the 5′-deiodination of rT₃ and 3′,5′-T₂ were 0.103 and 0.77 μM, respectively. 3′,5′-T₂ and rT₃ inhibited the respective 5′-deiodination reactions competitively, the K_i values being 1.05 and 0.134 μM, respectively. Several radiographic contrast agents markedly inhibit the 5′-monodeiodination of rT₃ and 3′,5′T-₂, the type of inhibition being competitive. Of these compounds iopanoic acid, ipodic acid and iophenoxic acid are the most potent inhibitors with K_i values of approximately 2 μM for both reactions. The non-iodine containing compound 8-anilino-1-naphthalene sulphonic acid (ANS) appeared to be a very strong competitive inhibitor of both 5′-deiodinations (K_i 4.3–4.7 μM), whereas salicylic acid, which as ANS inhibits the binding of iodothyronines to T₄-binding globulin, inhibited these reactions to a much lesser extent (K_i 300–500 μM). On the other hand, diiodosalicylic acid was a very strong inhibitor. The β-adrenergic blocker d,l-propranolol was a weak noncompetitive inhibitor of both 5′-deiodinations (K_i 0.4–0.7 mM). These reactions were also inhibited by various 2,6-diiodophenol derivatives, triiodophenol being the strongest and diiodotyrosine the weakest inhibitor tested. Comparing the K_i values of various inhibitors for the 5′-deiodination of rT₃ and 3′,5′-T₂, a positive correlation between these values was found (r = 0.97). It was concluded that rT₃ (to 3,3′-T₂) and 3′,5′-T₂ (to 3′-T₁) monodeiodinating activities are very similar to each other and that there may just be one monodeiodinase catalyzing the 5′-deiodination of iodothyronines in rat liver.     

Teratogenicity of nitrofen (2,4-dichloro-4′-nitrodiphenyl ether) and its effects on thyroid function in the rat

Nitrofen is a herbicide with potent teratogenic activity in rodent species. Previous studies have indicated that this agent has a stereochemical structure similar to thyroid hormone, and that exposure of adult mice results in depression of thryoxine (T₄) levels. The present study was undertaken to determine if teratogenic exposure to nitrofen alters pituitarythyroid function in nonpregnant, pregnant, and fetal rats, and if these potential alterations could be related to induction of birth defects. In adult thyroparathyroidectomized (TPTX) female rats, nitrofen exposure for 2 weeks resulted in a significant suppression of thyrotropin-stimulating hormone (TSH) levels. When a single dose of nitrofen was administered to euthyroid female rats, a trend toward reduction (p = 0.058) in the release of TSH after a thyrotropin-releasing hormone )TRH) challenge was observed 4 and 5 hr after exposure. Pregnant euthryoid rats given a single dose of nitrofen on Day 11 of gestation had significantly depressed TSH and T₄ levels, and fetal T₄ levels were markedly depressed at term. Administration of T₄ on Day 2 through 22 of pregnancy plus nitrofen on Day 9 through 11 to TPTX dams resulted in a 70% reduction in the frequency of malformed fetuses, especially in regard to the frequency of heart anomalies, compared to nitrofen exposure alone. Competitive displacement studies in radioimmunoassays for T₄ and T₃ indicated that a nitrofen metabolite (4-hydroxy-2,5-dichloro-4′-aminodiphenyl ether) competed with [¹²⁵I]T₃ for antibody binding, while the parent compound and six isolated metabolites failed to compete with [¹²⁵I]T₄ for antibody binding. These results have been interpreted to indicate that nitrofen teratogenicity is mediated at least in part by alterations in maternal and/or fetal thyroid hormone status, and may be due to a premature and pharmacologic exposure to the embryo to a nitrofen-derived, T₃-active metabolite.     

Plasma concentrations of methimazole, a metabolite of carbimazole, in hyperthyroid patients

1 Carbimazole was administered to nine hyperthyroid patients, and blood samples were taken at various time intervals for analysis of carbimazole, and its metabolite methimazole.

2 A technique was developed for the measurement of methimazole in serum using a High-Pressure Liquid Chromatograph, which could detect nanogram quantities of this metabolite.

3 After a single oral dose, the patients' blood levels appeared to fall into two groups, either those with a maximum concentration of methimazole between 30 and 60 min, or those whose maximum was 2 to 3 hours.

4 The results would suggest that there could be a correlation between the high level of methimazole in serum and the high thyroxine concentration found in some patients.

     

Kanechlor 500‐mediated changes in serum and hepatic thyroxine levels primarily occur in a transthyretin‐unrelated manner

The effects of Kanechlor‐500 (KC500) on the levels of serum total thyroxine (T₄) and hepatic T₄ in wild‐type C57BL/6 (WT) and its transthyretin (TTR)‐deficient (TTR‐null) mice were comparatively examined. Four days after a single intraperitoneal injection with KC500 (100 mg/kg body weight), serum total T₄ levels were significantly decreased in both WT and TTR‐null mice. The KC500 pretreatment also promoted serum [¹²⁵I]T₄ clearance in both strains of mice administrated with [¹²⁵I]T₄, and the promotion of serum [¹²⁵I]T₄ clearance in WT mice occurred without inhibition of the [¹²⁵I]T₄‐TTR complex formation. Furthermore, the KC500 pretreatment led to significant increases in liver weight, steady‐state distribution volume of [¹²⁵I]T₄, hepatic accumulation level of [¹²⁵I]T₄, and concentration ratio of the liver to serum in both strains of mice. The present findings indicate that the KC500‐mediated decrease in serum T₄ level occurs in a TTR‐unrelated manner and further suggest that KC500‐promoted T₄ accumulation in the liver occurs through the development of liver hypertrophy and the promotion of T₄ transportation from serum to liver.     

The effect of serial administration of bicarbonate on plasma total CO2 concentrations in horses

The administration of alkalinising agents including bicarbonate is of concern to racing authorities because resultant alkalosis may enhance performance and interfere with the detection of drugs in post-race urine. A threshold for total carbon dioxide (TCO₂) of 36.0 mmol/L in plasma (with action limit of 37.0 mmol/L) has been set. Serial dosing of sodium bicarbonate has gained popularity in human athletes but has not been studied in horses previously. Sodium bicarbonate (200 g per horse) and 60 g of an electrolyte-vitamin complex was administered in 2-L water via nasogastric intubation to five Standardbred horses for three consecutive days (total dose bicarbonate 0.42 ± 0.02 g/kg). Serial blood samples were taken over Days 1–5, with the final day (5) intended to simulate a ‘clear day’, and TCO₂ was analysed. Following the first bicarbonate administration, plasma TCO₂ peaked at 6 h (34.8 ± 1.3 mmol/L), returning to baseline by 23 h. On Day 2, four out of the five horses showed a peak greater than 36.0 mmol/L (mean 37.0 ± 2.1 mmol/L). With daily repeated dosing, plasma TCO₂ peaked progressively earlier, and by Day 3, the peak occurred at 2 h and concentrations declined more rapidly. On Days 4 and 5, TCO₂ levels remained low (<32.1 mmol/L on Day 4 and between 27.0–31.2 mmol/L on Day 5). These studies demonstrate that serial dosing of a ‘split dose’ of sodium bicarbonate on three consecutive days does not result in the accumulation or carry-over of plasma TCO₂ levels beyond the levels observed following a single dose.     

A randomized controlled study comparing rofecoxib,diclofenac sodium,and placebo in post-bunionectomy pain

SUMMARY

Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.

Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50?mg (N = 85), enteric-coated diclofenac sodium 100?mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50?mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24?h. Primary endpoint was total pain relief over 8?h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5.

Results: For TOPAR8 scores, rofecoxib 50?mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo (?p = 0.003) and diclofenac (?p = 0.019); proportion of patients achieving onset within 4?h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03?h vs. 4:02?h, p < 0.001 and 1:41?h vs. 4:02?h, p < 0.001). Rofecoxib patients used significantly less (?p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1?tablets/day vs. 2.1?tablets/day) and Days 2–5 (0.9?tablets/day vs. 1.8?tablets/day). No significant differences in adverse experiences between treatments were seen.

Conclusion: Rofecoxib 50?mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50?mg was significantly more effective than diclofenac sodium 100?mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.     

Effects of amiodarone in a swine model of nortryptiline toxicity

Objectives

Antiarrhythmics can have devastating effects in cardiotoxic poisonings. Amiodarone is recommended for treatment of wide complex tachycardia, but its hemodynamic effects in wide complex tachycardia induced by tricyclic antidepressant poisoning are unknown. The objective of this study was to compare the effects of sodium bicarbonate, amiodarone, and normal saline in treating wide complex tachycardia secondary to nortriptyline poisoning.

Methods

This unblended randomized controlled animal study involved 18 anesthetized, intubated pigs with arterial and venous lines. Nortriptyline (2 mg/mL) was infused at 20 mg/min until the onset of toxicity, defined as a systolic blood pressure ≤50 mmHg or QRS ≥120 ms. At that point, the pigs were randomized into three groups of six. Group I received 0.9% normal saline, 10 ml/kg. Group II received hypertonic sodium bicarbonate, 1 mEq/kg. Group III received amiodarone, 15 mg/kg. The pigs were observed until death or survival at 60 minutes.

Results

After treatment, the changes in QRS were as follows: Group I, −2.0 ms; Group II, −33.0 ms; Group III, −21.7 ms. ANOVA demonstrated no significant difference between the groups (p = 0.28). Mean arterial pressures 10 minutes after treatment were as follows: Group I, 19.4 mmHg; Group II, 23.7 mmHg; Group III, 12.5 mmHg. Based on ANOVA, there was no significant difference between any of the groups (p = 0.50).

Conclusions

In this model of nortriptyline poisoning, the administration of amiodarone to correct wide complex tachycardia did not have a harmful effect.     

A possible mechanism for the decrease in serum thyroxine level by phenobarbital in rodents

Effects of phenobarbital (PB) on the levels of serum thyroid hormones such as total thyroxine (T₄) and triiodothyronine were examined in male mice, hamsters, rats, and guinea pigs. One day after the final administration of PB (80 mg/kg, intraperitoneal, once daily for 4 days), significant decreases in the levels of the serum total T₄ and free T₄ occurred in mice, hamsters, and rats, while a significant decrease in the level of serum triiodothyronine was observed in hamsters and rats among the animals examined. In addition, a significant decrease in the level of serum thyroid-stimulating hormone was observed in only hamsters among the rodents examined. Significant increases in the level and activity of hepatic T₄-UDP-glucuronosyltransferase (UGT1A) after the PB administration occurred in mice, hamsters, and rats, while the increase in the amount of biliary [¹²⁵I]T₄-glucuronide after an intravenous injection of [¹²⁵I]T₄ to the PB-pretreated animals occurred only in rats. In mice, rats, and hamsters, but not guinea pigs, PB pretreatment promoted the clearance of [¹²⁵I]T₄ from the serum, led to a significant increase in the steady-state distribution volumes of [¹²⁵I]T₄, and raised the concentration ratio (Kp value) of the liver to serum and the liver distribution of [¹²⁵I]T₄. The present findings indicate that the PB-mediated decreases in the serum T₄ level in mice, hamsters, and rats, but not guinea pigs, occur mainly through an increase in the accumulation level of T₄ in the liver.     

Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease

Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV₁ were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUC_ss/AUC₁, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV₁ 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.     

Diethyl hexyl phthalate-induced changes in insulin signaling molecules and the protective role of antioxidant vitamins in gastrocnemius muscle of adult male rat

Diethyl hexyl phthalate (DEHP) is an endocrine disruptor, it influences various organ systems in human beings and experimental animals. DEHP reduced the serum testosterone and increased the blood glucose, estradiol, T₃ and T₄ in rats. However, the effect of DEHP on insulin signaling and glucose oxidation in skeletal muscle is not known. Adult male albino rats were divided into four groups: Group I: Control; Groups II and III: DEHP treated (dissolved in olive oil at a dose of 10 and 100 mg/kg body weight, respectively, once daily through gastric intubation for 30 days); and Group IV: DEHP (100 mg/kg body weight) plus vitamins E (50 mg/kg body weight) and C (100 mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubation for 30 days. On completion of treatment, animals were euthanized and perfused (whole body); gastrocnemius muscle was dissected out and subjected to assessment of various parameters. DEHP treatment increased the H₂O₂, hydroxyl radical levels and lipid peroxidation which disrupt the membrane integrity and insulin receptor. DEHP impaired the insulin signal transduction, glucose uptake and oxidation through decreased expression of plasma membrane GLUT4, which may partly be responsible for the elevation of fasting blood glucose level. The present study suggests that DEHP exposure affects glucose oxidation in skeletal muscle and is mediated through enhanced lipid peroxidation, impaired insulin signaling and GLUT4 expression in plasma membrane. Antioxidant vitamins (C and E) have a protective role against the adverse effect of DEHP.