CDB-2914: anti-progestational/anti-glucocorticoid profile and post-coital anti-fertility activity in rats and rabbits

Our goal was to determine the endocrine and post-coital anti-fertility activity of CDB-2914. Concurrent administration of progesterone to rats on day 4 post-mating blocked the anti-fertility activity of a single oral 2 mg dose of CDB-2914. CDB-2914 did not exhibit progestational activity in the oestradiol-primed immature female rabbit at doses that exhibited anti-progestational activity. CDB-2914 antagonized exogenous and endogenous progesterone-stimulated uterine haptoglobin synthesis and secretion in immature and adult mated rabbits respectively. Neither CDB-2914 nor mifepristone exhibited glucocorticoid activity as determined by thymus involution in rats; mifepristone was twice as potent as CDB-2914 in antagonizing glucocorticoid action. Post-coital CDB-2914 treatment resulted in a dose-dependent reduction in implantation sites and pregnancy rates in rabbits. CDB-2914-induced inhibition of uterine weight increase, endometrial glandular arborization and uterine haptoglobin synthesis/secretion correlated with inhibition of pregnancy in mated rabbits. A single oral dose of 64 mg CDB-2914/rabbit was effective at blocking pregnancy when administered on day 4, 5, or 6 post-mating, whereas 32 mg/rabbit was only partially effective in this regard. These data demonstrate that CDB-2914 is a potent, orally active anti-progestin with weak anti-glucocorticoid activity. CDB-2914 inhibited implantation in adult rats and rabbits demonstrating its potential as a post-coital contraceptive drug.     

A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women

Previous studies in women have shown that the antiprogestin mifepristone delays or inhibits folliculogenesis. The purpose of this study was to explore whether a new analogue, CDB-2914, has similar effects on folliculogenesis, ovulation, or on subsequent luteal phase endometrial maturation. Forty-four normally cycling, healthy women recorded urine LH and vaginal bleeding during pre-treatment, treatment, and post-treatment cycles. At a lead follicle diameter of 14-16 mm, a single oral dose (10, 50, 100 mg) of CDB-2914 or placebo was given, and daily ultrasound, oestradiol and progesterone were obtained until follicular collapse; an endometrial biopsy was obtained 5-7 days later. Single doses of CDB-2914 were well tolerated. Mid-follicular CDB-2914 suppressed lead follicle growth, causing a dose-dependent delay in folliculogenesis and suppression of plasma oestradiol. At higher doses, a new lead follicle was often recruited. Although luteinized unruptured follicles were observed at the 100 mg dose, all women had follicular collapse. There was a significant delay in endometrial maturation after CDB-2914 at all doses. The treatment cycle was lengthened by 1-2 weeks in 30% at 100, 27% at 50 and 9% at 10 mg. CDB-2914 altered ovarian and endometrial physiology without major effects on menstrual cyclicity and may have therapeutic utility.     

Luteal phase dose-response relationships of the antiprogestin CDB-2914 in normally cycling women

BACKGROUND: Progesterone receptor modulators have potential therapeutic use in progesterone-dependent conditions such as endometriosis, fibroids and induction of labour. The synthetic steroid CDB-2914 binds to the progesterone and glucocorticoid receptors. In animals it has antiprogestational activity at doses 50-fold less than those required for antiglucocorticoid effects. METHODS AND RESULTS: We evaluated the biological activity, blood levels and safety of CDB-2914 at escalating single doses, in 36 normally cycling women at mid-luteal phase. CDB-2914 at doses of 1-100 mg did not change luteal phase length, but after 200 mg, all women had early endometrial bleeding. Four women with early menses had concurrent functional luteolysis (one at 10, 50, 100 and 200 mg). There were no biochemical or clinical signs of toxicity, and no effect on urinary cortisol or circulating thyroxine, prolactin, adrenocorticotrophic hormone or renin levels. Higher serum equivalents of CDB-2914 were observed by radioimmunoassay than by high performance liquid chromatography detection, indicating a considerable contribution of metabolites. CONCLUSIONS: Mid-luteal administration of CDB-2914 antagonizes progesterone action on the endometrium, in a dose-dependent fashion, without apparent antiglucocorticoid effects. Further study of CDB-2914 is needed to determine its clinical role.     

Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells

BACKGROUND: This study was conducted to evaluate the effects of graded concentrations (10(-8), 10(-7) and 10(-6) M) of progesterone receptor (PR) modulator CDB-2914 on the protein contents of PR, of vascular endothelial growth factor (VEGF), adrenomedullin (ADM) and their receptors in cultured human uterine leiomyoma and matching myometrial cells. METHODS: PR-A, PR-B, VEGF-A, VEGF-B, VEGF receptor (VEGFR)-1, VEGFR-2, ADM and ADM receptor (ADMR) contents were assessed by Western blot analysis. RESULTS: Treatment with 100 ng/ml progesterone increased VEGF-A, VEGF-B and ADM contents in cultured leiomyoma cells and normal myometrial cells. The concomitant treatment with 10(-6) M CDB-2914 significantly decreased the progesterone-induced VEGF-A, VEGF-B and ADM contents in cultured leiomyoma cells but not in normal myometrial cells. CDB-2914 treatment alone decreased VEGFR-1, VEGFR-2 and ADMR contents in cultured leiomyoma cells but not in normal myometrial cells. CDB-2914 treatment increased PR-A and decreased PR-B contents in cultured leiomyoma cells in a dose-dependent manner compared with untreated cultures, whereas no significant changes in PR isoform contents were observed in normal myometrial cells. CONCLUSIONS: These results suggest that CDB-2914 down-regulates VEGF, ADM and their receptor contents and modulates PR isoform contents in cultured leiomyoma cells in a cell-type-specific manner.     

Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells

Effects of progesterone receptor modulator CDB-2914 on the expression of the extracellular matrix (ECM) components were examined in cultured human uterine leiomyoma and myometrial cells. ECM metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagen levels were assessed by Western blot analysis, MMP activity assay and real-time RT-PCR. RNA interference (RNAi) of EMMPRIN was performed using small interfering mRNA. In cultured leiomyoma cells, CDB-2914 treatment at concentrations greater than or equal to 10(-8) M significantly increased EMMPRIN, MMP-1 and MMP-8 protein contents and MMP-1, MMP-2, MMP-3 and MMP-9 mRNA levels, and activity of MMP-1, MMP-2, MMP-3 and MMP-9 in the medium. TIMP-1 and TIMP-2 were significantly decreased at mRNA and protein levels by CDB-2914 treatment at concentrations > or =10(-7) M in these cells. CDB-2914 treatment decreased types I and III collagen protein contents. However, CDB-2914 treatment did not affect the ECM component expression in cultured myometrial cells. RNAi of EMMPRIN abrogated CDB-2914-mediated both induction of MMPs and reduction of TIMPs and collagens in cultured leiomyoma cells. These results suggest that CDB-2914 modulates the expression of EMMPRIN, MMPs, TIMPs and collagens in cultured leiomyoma cells without comparable effects on myometrial cells.     

Determination of 2-hydroxyflutamide in human plasma by high-performance liquid chromatography and its application to pharmacokinetic studies

Flutamide is a potent antiandrogen used for the treatment of prostatic cancer. Flutamide undergoes extensive first-pass metabolism to the pharmacologically active metabolite 2-hydroxyflutamide. A simple, sensitive, precise, accurate and specific HPLC method, using carbamazepine as the internal standard, for the determination of 2-hydroxyflutamide in human plasma was developed and validated. After addition of the internal standard, the analytes were isolated from human plasma by liquid-liquid extraction. The method was linear in the 25 to 1,000 ng/ml concentration range (r>0.999). Recovery for 2-hydroxyflutamide was greater than 91.4% and for internal standard was 93.6%. The limit of quantitation was 25 ng/ml. Inter-batch precision, expressed as the relative standard deviation (RSD), ranged from 4.3 to 7.9%, and accuracy was better than 93.9%. Analysis of 2-hydroxyflutamide concentrations in plasma samples from 16 healthy volunteers following oral administration of 250 mg of flutamide provided the following pharmacokinetic data (mean+/-SD): Cmax, 776 +/- 400 ng/ml; AUC(0-infinity), 5,368 +/- 2,689 ng h/ml; AUC(0-t) 5,005 +/- 2,605 ng h/ml; Tmax 2.6 +/- 1.6 h; elimination half-life, 5.2 +/- 2.0 h.     

环孢素软胶囊人体生物等效性研究

评价两种环孢素软胶囊(受试制剂和参比制剂)在健康中国人体内的生物等效性。建立测定人全血中环孢素A的高效液相色谱-紫外(HPLC-UV)检测法,并进行方法学验证,采用随机双交叉自身对照试验设计,24名男性健康受试者分别口服受试制剂和参比制剂400mg后,测定环孢素A的血药浓度,计算药动学参数,评价两制剂的生物等效性。环孢素软胶囊(受试制剂)和环孢素软胶囊(参比制剂)中环孢素A主要的药动学参数如下:消除半衰期T1/2分别为(10.114±6.329)h和(9.717±4.076)h,达峰浓度Cmax分别为(2 021.235±298.581)ng.ml-1和(1 992.192±286.923)ng.ml-1,达峰时间Tmax分别为(1.729±0.361)h和(1.813±0.323)h;药时曲线下面积AUC0→t分别为(9 824.811±1 633.026)ng.h.ml-1和(10 316.514±1 395.955)ng.h.ml-1。以AUC0→t计算,环孢素软胶囊的相对生物利用度为(97.2±22.1)%。结果表明两制剂在健康中国人体内具有生物等效性。     

Kinetics of serum soluble tumour necrosis factor receptor (TNF-R) type-I and type-II after a single interferon-alpha (IFN-alpha) injection in chronic hepatitis C.

Circulating soluble TNF receptors, which act as TNF inhibitors, increase following the administration of IFN-alpha. Whether this is due to a direct IFN action or to indirect mechanisms involving the release of other cytokines is unclear. The kinetics of serum IFN, TNF, IL-6, IL-10, soluble TNF receptor type-I (sTNF-RI) and sTNF-RII were evaluated by enzyme immunoassays in 11 patients with chronic hepatitis C, following the first dose of recombinant human IFN-alpha2b (3 MU given subcutaneously). sTNF-RI concentrations paralleled IFN concentrations, rising from a mean +/- s.e.m. value of 3.5 +/- 0.3 ng/ml at baseline to a peak value of 5.5 +/- 0.5 ng/ml after 9 h, followed by a return to 4.1 +/- 0.4 ng/ml after 24 h (P = 0.0001). sTNF-RII concentrations, which were 7.6 +/- 0.5 ng/ml at baseline, fell initially to 6.9 +/- 0.5 ng/ml, to reach a peak at 24 h of 9.0 +/- 0.7 ng/ml (P < 0.0001). In contrast, the concentrations of TNF, IL-6 and IL-10 fluctuated with no significant changes at any time point. The area under the curve (AUC) of incremental IFN values had a strong positive correlation with the AUC of incremental sTNF-RI values (r = 0.75, P < 0.01). In patients with hepatitis C, IFN concentrations reached after a single dose of IFN were paralleled by correlationally increased concentrations of sTNF-RI, which are a much better marker of administered IFN than sTNF-RII, IL-6 or IL-10.     

The kinetics of serum hCG and progesterone in response to oral and vaginal administration of misoprostol during medical termination of early pregnancy

BACKGROUND: Misoprostol is widely used in combination with mifepristone for medical termination of pregnancy. We studied the endocrine parameters of trophoblast function during medical termination of early pregnancy using mifepristone in combination with oral or vaginal misoprostol. The effect of prolonged misoprostol administration was also examined. METHODS: Thirty-four women, requesting termination of pregnancy and with 相似文献   

Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome

The suppression of the pituitary-gonadal axis by the administration of gonadotrophin-releasing hormone agonists (GnRH-a) is used occasionally as an adjunct therapy with gonadotrophins for ovulation induction in women with polycystic ovarian syndrome (PCOS). A number of recent clinical studies have suggested that women with polycystic ovaries (PCO) may have disturbances of normal growth hormone (GH) kinetics and alterations in the GH/insulin-like growth factor (IGF)-I system. The purpose of this study was to determine the effect of GnRH-a administration on GH-releasing hormone (GHRH)-stimulated GH release in women with PCOS. Eight women with PCO and six control women were studied before and after 2 months of treatment with the long acting GnRH-a triptoreline (3.75 mg monthly injections). GHRH was given as a single i.v. injection and blood samples for GH measurements were obtained at -15, 0, 30, 60, 90 and 120 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (delta(max)). The GH response to GHRH (mean +/- SEM) was lower in women with PCO (AUC 114.9 +/- 43.1 versus 206.2 +/- 28.7 ng/ml/120 min, P < 0.05 and delta(max) 31.6 +/- 8.2 versus 49.4 +/- 5.8 ng/ml, P < 0.05). After treatment with the GnRH-a, the GH response to GHRH was significantly smaller than before treatment in both groups (PCO AUC 34.6 +/- 9.0 ng/ml/120 min and delta(max) 12.4 +/- 3.1 ng/ml; controls AUC 148.8 +/- 28.4 ng/ml/120 min and delta(max) 31.2 +/- 6.1 ng/ml), but the PCO group had a significantly smaller response. These data demonstrate that women with PCO have a reduced GH response to GHRH compared with normal controls and that GnRH-a administration causes a further GH reduction in both groups. Women with PCO have a greater suppression of GH response to GHRH during treatment with GnRH-a. This suggests that a different level of sensitivity in the somatotrophic axis exists in PCOS.      

Growth hormone response to thyrotrophin releasing hormone in women with polycystic ovarian syndrome.

Recent clinical studies have suggested that women with polycystic ovarian syndrome (PCOS) may have disturbances of growth hormone (GH) kinetics and the GH/insulin-like growth factor (IGF)-I system. The knowledge that in various metabolic abnormalities there is a paradoxical sensitivity of pituitary somatotrophs to thyrotrophin releasing hormone (TRH) administration led to this investigation of the GH secretory response to TRH in women with PCOS. Twenty-four women with PCOS and 18 control women were studied. TRH was given as a single i.v. injection (time 0) and blood samples for GH measurements were obtained at -15, 0, 15, 30, 60 and 90 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (Deltamax). The GH response to TRH (mean +/- SEM) was greater in women with PCOS (Deltamax 2.47 +/- 1. 73 versus 0.47 +/- 0.06 ng/ml, P < 0.05 and GH AUC 8.05 +/- 2.10 versus 2.58 +/- 0.18 ng/ml/90 min, P < 0.05). According to GH response to TRH, two PCOS subgroups were identified: (i) normal responders (n = 14) who showed Deltamax GH response (0.36 +/- 0.06 ng/ml)and GH AUC (1.93 +/- 0.64 ng/ml/90 min) similar to that in the controls and (ii) over-responders (n +/- 10) who showed a paradoxical increase in GH concentrations in response to TRH (Deltamax GH response 5.43 +/- 1.27 ng/ml and GH AUC 16.62 +/- 3.51 ng/ml per 90 min) that was significantly higher than in normally responding PCOS patients (P < 0.0001) or in controls (P < 0.0001). These data demonstrate an enhanced GH response to TRH administration in a subgroup of women with PCOS.     

17Beta-estradiol delivered by three different matrix patches 50 microg/day: a three way cross-over study in 21 postmenopausal women

The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17beta-estradiol (E2) after the application of three matrix patches for the transdermal delivery of E2: Menorest, Tradelia, and Estraderm MX claiming to deliver a dosage of 50 microg E2/day. All three patches were each worn randomly by 21 postmenopausal women volunteers over a 4-day period (i.e. 96 h). Each of the three treatment periods were separated by an at least 7 day wash out period according to a randomized, 3-way crossover design. Blood samples were taken from the antecubital vein before and 3, 6, 9, 12, 24, 28, 33, 48, 57, 72, 81, and 96 h after application. E2 plasma values were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h, Cmax, Tmax, Cmin, C(average). The time to reach the maximal E2 value of 32 h was the only pharmacokinetic parameter which was identical for all three patches. Menorest produced the highest E2 bioavailability judged by the AUC0-96h = 3967.8 +/- 1651.8 pg/ml, C(average) = 41.3 +/- 21.3 pg/ml, Cmin = 36.8 +/- 8.6 pg/ml. Tradelia showed statistically not significantly smaller C(average) = 38.9 +/- 17.0 pg/ml, AUC0-96h = 3737.9 +/- 1637.6 pg/ml x per h, and Cmin = 33.8 +/- 26.7 than Menorest. Estraderm MX showed lowest E2 plasma profiles Cmax = 38.9 +/- 25.1 pg/ml, C(average) = 33.2 +/- 17.1 pg/ml, AUC0-96 = 3192.1 +/- 1646.0 pg/ml per x h. Menorest showed the smallest fluctuation over the entire test period, similar to Estraderm MX, while Tradelia showed the highest E2-fluctuation (P < 0.01): Tradelia exhibited the highest Cmax = 48.0 +/- 20.3 pg/ml. When E2 baseline levels, prior to patch application are subtracted individually from the produced E2 plasma level, Estraderm MX is not bioequivalent to Menorest (P < 0.05). A circadian curve pattern of the E2 plasma level was observed for all patches: in the evening higher E2 plasma level were always detected compared with the morning, however, less pronounced with Estraderm MX. Individual comparison of AUC0-96h of each patch exhibited a large interindividual variability of 2000-8000 pg/ml per h for all three patches but relatively small individual variability: women with high E2 bioavailability (high responders) maintained high bioavailability in all applied patches, women identified as low and medium responders remained the same regardless of the applied patch. Menorest produced in 2/3 of all postmenopausal women with the highest E2 bioavailability (AUC0-96h), Tradelia was found in less than 1/3 (28.6%), and Estraderm MX in only one postmenopausal woman. Menorest only produced the highest reduction in postmenopausal symptoms together with Tradelia. Estraderm MX produced a smaller reduction in postmenopausal symptoms compared to Menorest and Tradelia. The observed side-effects were approximately equal in all three patches, with a maximum value after 72 h. It can be concluded that the three patches for the transdermal delivery of E2 claiming to deliver 50 microg E2/day differed from each other in their pharmacokinetic performance, although statistically not significant: Menorest exhibited the highest C(average), AUC and Cmin, and the lowest fluctuation, followed by Tradelia and Estraderm MX.     

Pharmacokinetics of doxycycline in broiler chickens

Doxycycline was given to two groups of eight chickens at a dose of 20 mg/kg of body weight, intravenously (i.v.) or orally. Plasma concentration was monitored serially for 12 h after each administration. Another group of 30 chickens was given 20 mg/kg orally every 24 h for 4 days, and plasma and tissue concentrations determined serially after the last administration. Concentrations of doxycycline were measured using high-performance liquid chromatography. Pharmacokinetic variables were calculated, using a two-compartment open model. The elimination half-life and the mean residence time for plasma were 6.03 +/- 0.45 and 7.48 +/- 0.38 h, respectively, after oral administration and 4.75 +/-0.21 and 2.87 +/-0.11 h, respectively, after i.v. administration. After single oral administration, doxycycline was absorbed rapidly, with T(max) of 0.35 +/- 0.02 h. Maximum plasma concentration was 54.58 +/- 2.44 mu/ml. Oral bioavailability of doxycycline was found to be 41.33 +/- 2.02%. Doxycycline was widely distributed in tissues and considerable concentrations were found following oral administration of 20 mg/kg on four successive days. The results indicate that doxycycline concentrations were cleared slowly and were at or below the accepted drug tolerance levels in the marker tissues within 5 days after dosing.     

罗红霉素分散片的人体生物等效性研究

研究两种罗红霉素分散片的人体生物等效性。采用高效液相色谱(HPLC)电化学检测法测定20名健康男性受试者单剂量口服罗红霉素分散片受试制剂和参比制剂后,体内罗红霉素的血药浓度,用DAS药动学程序处理试验数据,并对试验结果进行统计分析。罗红霉素受试制剂和参比制剂的峰浓度(Cmax)分别是10．16±1．46、10．34±1．66μg·ml-1;达峰时间(tmax)分别是2．33±0．61、2．28±0．62 h;药时曲线下面积(AUC0→Tn)分别为143．32±25．80、138．93±22．49μg·h·ml-1,AUC0→∞分别为158．63±26．86、153．77±24．75μg·h·ml-1;半衰期(t1／2)分别是:9．00±1．58、8．68±1．66 h。按罗红霉素血药浓度计算,相对生物利用度为103．63％±14．04％,经统计分析两制剂药动学参数均无显著性差异,表明受试制剂和参比制剂生物等效。     

Pharmacokinetics of different routes of administration of misoprostol

BACKGROUND: The pharmacokinetic parameters of four different routes of administration of a single dose of 400 microg of misoprostol were studied. METHODS: A total of 40 women undergoing termination of pregnancy by suction evacuation was randomized by computer model to receive 400 microg of misoprostol by one of four routes: (i) sublingual (ii) oral (iii) vaginal and (iv) vaginal with addition of water. Venous blood samples were taken at 0, 1, 2, 5, 10, 20, 30, 45, 60, 120, 240 and 360 min after the administration of misoprostol. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. RESULTS: Sublingual misoprostol achieved the highest serum peak concentration (Cmax) (574.8 +/- 250.7 pg/ml) of MPA and this was significantly higher than those in the other groups [Oral: 287.6 +/- 144.3 pg/ml (P < 0.01), vaginal: 125.2 +/- 53.8 pg/ml (P < 0.001) and vaginal with water: 162.8 +/- 57.1 pg/ml (P < 0.001)]. The time to peak concentration (Tmax) was similar in both the sublingual (26.0 +/- 11.5 min) and oral groups (27.5 +/- 14.8 min) and was significantly shorter than those in both vaginal groups. The area under the MPA concentration versus time curve up to 360 min in the sublingual group (743.7 +/- 291.2 pg.h/ml) was significantly greater than those in oral (402.8 +/- 151.6 pg.h/ml, P < 0.05) and vaginal (433.7 +/- 182.6 pg.h/ml, P < 0.05) groups, but no significant difference was found between sublingual and vaginal administration if water (649.3 +/- 333.8 pg.h/ml) was added. CONCLUSION: The new sublingual route of administration of misoprostol demonstrated a great potential to be developed into a method of medical abortion.     

Sublingual epinephrine tablets versus intramuscular injection of epinephrine: dose equivalence for potential treatment of anaphylaxis

BACKGROUND: Epinephrine autoinjectors are underused in the emergency treatment of anaphylaxis in the community, perhaps in part because of fear of needles. OBJECTIVES: To determine the sublingual epinephrine dose from a novel fast-disintegrating tablet required to achieve epinephrine plasma concentrations (EPPCs) similar to those obtained after epinephrine 0.3 mg intramuscular injection. METHODS: In a prospective 5-way crossover study, sublingual tablets containing epinephrine 0, 10, 20, and 40 mg, and epinephrine 0.3 mg intramuscular in the thigh (EpiPen) were compared in a validated rabbit model. Blood samples were collected before dosing and 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, and 180 minutes afterward. EPPCs were measured by using high-performance liquid chromatography-electrochemical detection. Pharmacokinetic parameters were calculated by using WinNonlin. RESULTS: The area under the curve (AUC), maximum concentration (C(max)), and time at which C(max) was achieved (T(max)) did not differ significantly (P > .05) after epinephrine 40 mg (AUC = 1861 +/- 537 ng/mL/min, C(max) = 31.0 +/- 13.1 ng/mL, and T(max) = 9 +/- 2 minutes) and epinephrine 0.3 mg intramuscular (AUC = 2431 +/- 386 ng/mL/min, C(max) = 50.3 +/- 17.1 ng/mL, and T(max) = 21 +/- 5 minutes). The AUC after tablets containing epinephrine 0 mg (AUC = 472 +/- 126 ng/mL/min), epinephrine 10 mg (AUC = 335 +/- 152 ng/mL/min), and epinephrine 20 mg (AUC = 801 +/- 160 ng/mL/min) did not differ significantly from each other, but were significantly lower (P < .05) than the AUC after epinephrine 0.3 mg intramuscularly. CONCLUSION: Sublingual administration of epinephrine 40 mg from this tablet formulation resulted in EPPCs similar to those obtained after epinephrine 0.3 mg intramuscular injection in the thigh. CLINICAL IMPLICATIONS: For treatment of anaphylaxis in the community, self-injectable epinephrine is underused. This novel, fast-disintegrating epinephrine tablet formulation for sublingual administration is a feasible alternative that warrants further development.     

Pharmacokinetics of amoxicillin in broiler chickens

Amoxicillin was given to two groups of eight chickens at a dose of 10 mg/kg of body weight, intravenously (i.V.) or orally. Plasma concentration was monitored serially for 24 h after each administration. Concentrations of amoxicillin were measured using high-performance liquid chromatography. Pharmacokinetic variables were calculated, using a two-compartment open model. The elimination half-life, and the mean residence time for plasma were 8.17 +/- 0.31 and 10.46 +/- 0.51 h, respectively, after i.v. administration and 9.16 +/- 0.60 and 12.26 +/- 0.81 h, respectively, after oral administration. After single oral administration, amoxicillin was rapidly absorbed, with T(max), of 1.00 +/- 0.06 h. Maximum plasma concentration was 160.40 +/- 4.67 mug/ml and mean amoxicillin concentrations > 15 mug/ml persisted for 24 h. Oral bioavailability of amoxicillin was found to be 63.00 +/- 4.58%. The results indicate that a dosage of 10 mg/kg administered orally at 24 h intervals should be effective in treating a variety of systemic infections in poultry.     

阿酚咖片中阿司匹林的相对生物利用度研究

对阿酚咖片中的阿司匹林进行相对生物利用度研究。采用反相高效液相色谱法测定 2 4名健康志愿受试者单剂量口服阿酚咖片供试制剂与参比制剂后 ,阿酚咖片中阿司匹林体内活性代谢物水杨酸的血药浓度的变化。用 3P97药动学程序处理试验数据 ,并对试验结果进行方差分析和双单侧 t检验。水杨酸的相对生物利用度为 :10 5 .36 %± 14 .15 % ;两种制剂水杨酸的药时曲线下面积 (AUC0→ T)分别为 :10 3.10± 11.92 μg· h/ ml与 98.4 5±13.4 9μg· h/ ml;达峰时间 (tmax)分别为 :1.5± 0 .5 h与 1.5± 0 .5 h;峰浓度 (Cmax)分别是 :19.31± 2 .4 7μg/ ml与18.95± 2 .4 9μg/ ml。两种制剂中的水杨酸 AU C0→∞ 、AUC0→ T、Tmax及 Cmax经双单侧 t检验进行生物等效性评价 ,表明以制剂中阿司匹林活性代谢产物水杨酸为指标 ,两种制剂生物等效 (t1 ≥ t1 - 0 .0 5( 2 2 ) ,t2 ≥ t1 - 0 .0 5( 2 2 ) )     

Predictive value of a single serum pregnancy associated plasma protein-A or progesterone in the diagnosis of abnormal pregnancy

The value of a single measurement of serum levels of pregnancy associated plasma protein-A (PAPP-A) or progesterone (P4) in predicting abnormal gestations was assessed in 65 patients. P4 was greater than 20 ng/ml (mean +/- SEM 61.2 +/- 6.6 ng/ml, range 22.4-100.0 ng/ml) in all patients with normal intrauterine pregnancies (n = 21), and greater than 20 ng/ml (mean +/- SEM 8.5 +/- 3.9 ng/ml, range 0.1-68.8 ng/ml) in 16 out of 17 patients destined to abort spontaneously. Patients with ectopic gestations (n = 27) exhibited P4 values less than 20 ng/ml (mean +/- SEM 6.4 +/- 1.2 ng/ml, range 0.1-17.2 ng/ml). P4 levels in normal pregnancies were significantly higher (P = 0.001) than those of abnormal gestations. PAPP-A levels ranged from undetectable to 6448 mIU/ml in normal gestations. In 42 out of 44 abnormal pregnancies levels of PAPP-A were less than 100 mIU/ml, as were 7 out of 14 normal intrauterine pregnancies of less than 7 weeks gestational age. No ectopic demonstrated a value of PAPP-A greater than 50 mIU/ml and in 23 out of 27 ectopics, levels were undetectable. However, PAPP-A was less specific than P4 in correctly discriminating normal from abnormal gestations and exhibited lower positive and negative predictive values. It can be concluded therefore that a single PAPP-A measurement is of limited value in discerning normal from abnormal pregnancy prior to 8 weeks gestation. However, a single serum P4 is highly accurate and specific in detecting abnormal pregnancy, regardless of gestational age.     

Studies on the microheterogeneity of chorionic gonadotrophin secreted by the human cytotrophoblast in culture.

In the present study, we investigated the biological characteristics of different molecular forms of chorionic gonadotrophin (HCG) secreted by the human cytotrophoblast during its morphological and functional differentiation in culture. Highly purified cytotrophoblasts were prepared from term placentae and cultured for 24 to 96 h in the absence or presence of 8-bromo-3',5'-cAMP. Media were collected at 24 h intervals and the secreted isoforms of HCG were then separated by polyacrylamide gel isoelectric focusing (pH range 8.0-3.0) and quantified by radioimmunoassay. The secretion of HCG was significantly increased by 8-bromo-cAMP (from 23.5 +/- 6.3 ng/ml at 24 h to 1619 +/- 835.8 ng/ml at 96 h; controls, 9.3 +/- 0.1 ng/ml at 24 h and 26.6 +/- 3.5 ng/ml at 96 h, mean +/- SD). Analysis of media concentrates from cAMP-stimulated cultures by isoelectric focusing revealed the presence of several distinct peaks of HCG within the pH range of 7.3-4.8; major peaks consistently exhibited isoelectric points (pI) of 7.3-7.0 (peak 1), 5.6-5.4 (peak 2) and 5.1-4.8 (peak 3). The relative HCG content of the most acidic peak (as % of total on gel) progressively increased with time of exposure to the cAMP analogue (from 19.8 +/- 1.6% at 24 h to 34.4 +/- 4.3% at 96 h, mean +/- SEM, P less than 0.01). HCG recovered from peak 1 exhibited the highest receptor-binding capacity and in-vitro biological potency.(ABSTRACT TRUNCATED AT 250 WORDS)