The Pharmacokinetics of Recombinant Human Relaxin in Nonpregnant Women After Intravenous,Intravaginal, and Intracervical Administration

The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V _ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V _ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., 20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal.     

Failure of clonidine treatment in benzodiazepine withdrawal

Six subjects, dependent on benzodiazepines for at least 2 years, were gradually withdrawn, using placebo substitution, while taking clonidine. After withdrawal was complete, subjects were switched to clonidine-placebo. Despite administration of clonidine at doses sufficient to produce a fall in blood pressure, an abstinence syndrome was seen in five of the subjects. In none of these cases was the withdrawal syndrome exacerbated by changing from clonidine to clonidine-placebo. Scores of depression, subjective anxiety, observed anxiety and somatic symptoms did not change throughout the study.     

Bioequivalence of Two Recombinant Human Growth Hormones in Healthy Male Volunteers after Subcutaneous Administration

The bioequivalence of recombinant human growth hormone (rhGH) (somatropin) and its N-methionyl variant (Met-hGH) [Protropin((R)) (somatrem for injection)] was determined in 42 healthy male volunteers (n = 21 per treatment) who were randomized to receive either protein by subcutaneous administration of 0.1 mg kg(minus sign1). Serum samples were collected over 24 h after the injection, and the concentration of human growth hormone (hGH) were determined by an immunoradiometric assay. Bioequivalence of the two proteins was assessed by determining whether the 90% confidence limits for the ratio of geometric means using logarithmically transformed AUC and C(max) parameters (log(10)AUC(0--24), log(10)AUC(0--infty infinity), and log(10)C(max)) were within the 80--125% range. The bioequivalence of the two treatments was also tested by calculating a bioequivalance index (xi(2)) that measured the difference between the two mean concentration-time profiles. The 90% confidence intervals for the ratios of the geometric means for AUC were within the prescribed 80--125% range for bioequivalence. The upper limit of the 90% confidence interval for the ratio of the geometric means for C(max) fell slightly outside the 125% criterion even though the geometric mean itself, 106.6%, was very close to the ideal of 100%. There was a larger standard error associated with C(max) than with the AUCs, and this marginally larger confidence limit for C(max) resulted more from the variance among the subject than to the difference in the means. In fact, the bioequivalence index, xi(2), was 0.075, indicating that the mean curves after rhGH and Met-hGH are essentially superimposable.     

Recombinant human growth hormone in infants and young children with chronic renal insufficiency

Children with chronic renal insufficiency (CRI) secondary to congenital structural abnormalities frequently have significant growth retardation by 2 years of age. In a multicenter placebo-controlled study of the use of recombinant human growth hormone (rhGH), 30 of 125 (24%) participants were<2.5 years of age at enrollment. Since the treatment arms of the study were balanced for age at randomization, data for these patients were examined for efficacy and safety. During the first 2 years of the study, approximately two-thirds of the patients (n=19) received rhGH 0.05 mg/kg per day subcutaneously and one-third (n=11) received placebo injections. At entry into the study, the mean (± SD) calculated creatinine clearance was 29.2±14.3 (range 12.0–63.7) ml/min per 1.73 m² in the rhGH-treated group and 23.3±15.1 (range 8.0–59.4) ml/min per 1.73 m² in the placebo-treated group. The 1st year growth rate was 14.1±2.6 cm/year for the rhGH-treated group and 9.3±1.5 cm/year in the placebo-treated group (P<0.00005). During the 2nd year of the study, the growth rate was 8.6±1.2 cm/year in the rhGH-treated group compared with 6.9±1.0 in the placebo groupP=0.025). The height standard deviation score was +2.0±0.7 for the rhGH-treated group compared with –0.2±1.1 in the placebo-treated group (P<0.00005) during the 2 years of the study. Minor adverse events occurred with similar frequency in both groups. These data suggest that rhGH is efficacious and safe in children with CRI under age 2.5 years. rhGH therapy may correct significant loss of growth at this age when used in conjunction with optimal medical management.     

Synchronization of the G1/S transition in response to corneal debridement.

PURPOSE: This study's intention was to examine the progression of ocular surface epithelium through the G1/S transition of the cell cycle after corneal epithelial debridement. METHODS: Three-millimeter debridements were made in central rat cornea and allowed to heal 4 to 48 hours in vivo. Unwounded contralateral eyes served as controls. Two hours before the animals were killed, 5-bromo-2-deoxyuridine (BrdU) was injected to detect S-phase cells. Incorporated BrdU was visualized by indirect immunofluorescence microscopy, and expression of G1 cell-cycle markers cyclins D and E was examined by indirect immunofluorescence and immunoblotting. RESULTS: The number of BrdU-labeled cells in conjunctival, limbal, and peripheral epithelium peaked at 28 hours after wounding (3.9-, 4.5-, and 3.2-fold increases, respectively). In unwounded eyes, cyclin D showed diffuse cytoplasmic localization with occasional basal cells exhibiting a nuclear localization, while anti-cyclin E showed intense localization in limbal and conjunctival basal cells but only minimal labeling in corneal epithelium. Within 8 to 12 hours after wounding, the nuclei of most corneal basal cells outside the wound area were bound intensely by anti-cyclins D and E. Immunoblotting revealed that cyclin D and E protein levels increased 4.5- and 12.1-fold after wounding, respectively. Epithelium migrating into the wound area did not incorporate BrdU and did not exhibit nuclear localization of cyclins D and E. CONCLUSIONS: Corneal epithelial debridement stimulates basal cells outside the wound area to synchronously enter the cell cycle. However, cells migrating to cover the wound area do not progress through the cell cycle. These data suggest a compartmentalization of the proliferative and migratory phases of wound repair.     

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of

Purpose

To study the haemodynamic effects of intrathecal meperidine, administered either alone or mixed with bupivacaïne.

Methods

We studied 42 Chinese patients, aged 59–87 yr, scheduled for transurethral bladder or prostate surgery, randomized into three equals groups, that received either meperidine 0.8 mg · kg^{?1 meperidine 0.4 mg} · kg^?1 plus 1.5 ml of 0.5% heavy bupivacaïne or 3 ml of heavy bupivacaïne 0.5%. Non-invasive systolic (SAP) and mean (MAP) arterial pressures, central venous pressure and cardiac index, stroke index and heart rate (HR) measured by the BoMed NCCOM3-R7S bioimpedance device, were recorded over the first 25 min. Systemic vascular resistance index (SVRI) was derived. Onset of sensory and motor block was also measured. Decreases in MAP of 25% were treated with colloid and metaraminol. Results: The onset of block was slower in the meperidine group (P < 0.05). Decreases in SAP, MAP and SVRI (all; P < 0.001) occurred within five minutes in all three groups. The HR was increased in the bupivacaïne group (P = 0.03), but bradycardias treated with atropine occurred in six patients receiving meperidine and four patients receiving the mixture. Six patients receiving meperidine and two patients receiving the mixture required general anaesthesia for inadequate block. The incidence of nausea and vomiting was higher in the patients receiving meperidine (P < 0.05). No other complications were encountered.

Conclusions

Intrathecal meperidine used alone or mixed with bupivacaïne has no intra-operative advantage over heavy bupivacaïne 0.5%.     

A comparison of the haemodynamic effects of intrathecal meperidine,meperidine-bupivacaine mixture and hyperbaric bupivacaïne

Purpose

To study the haemodynamic effects of intrathecal meperidine, administered either alone or mixed with bupivacaïne.

Methods

We studied 42 Chinese patients, aged 59–87 yr, scheduled for transurethral bladder or prostate surgery, randomized into three equals groups, that received either meperidine 0.8 mg · kg^{?1 meperidine 0.4 mg} · kg^?1 plus 1.5 ml of 0.5% heavy bupivacaïne or 3 ml of heavy bupivacaïne 0.5%. Non-invasive systolic (SAP) and mean (MAP) arterial pressures, central venous pressure and cardiac index, stroke index and heart rate (HR) measured by the BoMed NCCOM3-R7S bioimpedance device, were recorded over the first 25 min. Systemic vascular resistance index (SVRI) was derived. Onset of sensory and motor block was also measured. Decreases in MAP of 25% were treated with colloid and metaraminol. Results: The onset of block was slower in the meperidine group (P < 0.05). Decreases in SAP, MAP and SVRI (all; P < 0.001) occurred within five minutes in all three groups. The HR was increased in the bupivacaïne group (P = 0.03), but bradycardias treated with atropine occurred in six patients receiving meperidine and four patients receiving the mixture. Six patients receiving meperidine and two patients receiving the mixture required general anaesthesia for inadequate block. The incidence of nausea and vomiting was higher in the patients receiving meperidine (P < 0.05). No other complications were encountered.

Conclusions

Intrathecal meperidine used alone or mixed with bupivacaïne has no intra-operative advantage over heavy bupivacaïne 0.5%.