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The effects of intra-articular deposition of betamethasone in the goat temporomandibular joint.

PURPOSE: This study evaluated the response of the articular surfaces of the normal goat temporomandibular joint (TMJ) to intra-articular injections of betamethasone suspension. METHODS: Thirty female goats were divided into four experimental groups of seven each and one control group of two animals. The design resulted in 24 joints receiving from one to nine weekly injections of betamethasone suspension, 0.085 mg/kg. The 24 contralateral joints received an identical array of saline injections. In the remaining 12 joints, four were unilaterally injected with saline, four were unilateral uninjected joints, and four were bilateral uninjected joints. All of the joints were inspected grossly and histologically assessed for any intra-articular changes associated with corticosteroid injections. RESULTS: Comparative examination of the gross and histologic features of the injected joints and the eight normal joints showed no significant adverse effects on nondiseased TMJs. CONCLUSION: Intra-articular injection of betamethasone suspension at the dosage and delivery rate used had no harmful effects on the TMJs of nondiseased adult female goats. Because of possible differences between species, these results should not be taken as an indication that betamethasone suspension will not have adverse effects in the human TMJ. These findings support the need for further investigations into the physical and biochemical responses of normal and diseased articular fibrocartilage to different glucocorticosteroids at various concentrations and delivery rates using the goat and other animal models.

Animals↗

The effects of betamethasone on plasma and intestinal calcium binding protein and on 25-hydroxyvitamin D3 metabolism in the pig.

Betamethasone (50 micrograms/kg body weight/day) given to young pigs reduced calcium absorption, growth and plasma vitamin D dependent calcium binding protein (CaBP) concentration. No changes occurred in plasma 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and intestinal CaBP concentrations. 1,25(OH)2D3 (0.1 microgram/kg body weight/day) given with betamethasone increased calcium absorption although growth and plasma CaBP concentrations remained low. Intestinal CaBP levels remained unchanged. Plasma CaBP concentrations were not consistently related to intestinal CaBP or calcium absorption in the presence of betamethasone. We conclude that betamethasone-induced depression of calcium absorption was not mediated by alterations in intestinal CaBP, but the mechanism remains obscure.

Animals↗

Transient reduction in fetal activity and heart rate variation after maternal betamethasone administration.

We studied the short-term effects of maternal betamethasone administration on fetal well-being by recording of fetal movement and heart rate patterns. In 13 women at high risk of preterm delivery (26-32 weeks), eighty 1-h recordings were made of fetal body and breathing movements and fetal heart rate (FHR) and its variation during 5 consecutive days. Betamethasone was administered in two doses 24 h apart after a control recording had been made. After two doses of betamethasone, fetal body and breathing movements and FHR variation were considerably reduced (P < 0.01), but returned to normal after treatment was discontinued. FHR variation was transiently below the lower normal range in 46% of the cases. We conclude that maternal betamethasone administration results in a considerable reduction in fetal movements and FHR variation which may erroneously be interpreted as deterioration of the fetal condition. Knowledge of these transient changes is of significant clinical importance as it may prevent iatrogenic delivery because of suspected fetal distress. The observed effects are possibly mediated by centrally located glucocorticoid receptors.

Betamethasone↗

A single course of antenatal betamethasone reduces neurotrophic factor S100B concentration in the hippocampus and serum in the neonatal rat.

The effects of a single course of antenatal betamethasone on S100B protein concentration were investigated in Fisher 344 rats. On day 20 of gestation, pregnant rats were injected twice 8 h apart with either (1) 170 microg kg(-1) body weight betamethasone ("clinically-equivalent dose", equivalent to 12 mg twice, 24 h apart in humans), (2) half of this dose (equivalent to 6 mg) or (3) vehicle. We report reference values for S100B protein in the serum and different brain regions in both genders at 1, 2, and 21 days after birth. Interestingly, S100B concentration showed a time-dependent and brain region-specific pattern of expression. At P1, S100B was higher in the serum of males compared to females. In addition, we show that both doses of betamethasone decreased S100B concentration in the serum of males at P1, whereas in the hippocampus, it was reduced by the clinically-equivalent dose only. This suggests that lowering the dose of antenatal betamethasone may be less detrimental for brain maturation and therefore we reiterate the need for clinical trials with a low dose regimen.

Animals↗

Quantification of betamethasone in human plasma by liquid chromatography-tandem mass spectrometry using atmospheric pressure photoionization in negative mode.

Betamethasone is a synthetic corticosteroid designed to exert a marked glucocorticoid activity. As the free alcohol, betamethasone finds widespread clinical applications related to its anti-inflammatory and immunosuppressant activity. In the present study, a fast, sensitive, robust method was developed for the determination and quantification of betamethasone in human plasma by liquid chromatography coupled with tandem mass spectrometry, using photospray ionization in negative mode. Betamethasone was extracted from 0.5 ml human plasma by liquid-liquid extraction (LLE) using chloramphenicol as internal standard. The method has a chromatographic run of 2.5 min using a C(18) analytical column (100 mm x 2.1 mm i.d.) and the linear calibration curve over the range was linear from 0.05 to 50 ng ml(-1) (r(2)>0.993). The between-run precision, based on the relative standard deviation replicate quality controls was 94.1% (0.15 ng ml(-1)), 90.7% (4.0 ng ml(-1)) and 97.2% (40 ng ml(-1)). The between-run accuracy for the above-mentioned concentrations was 11.9, 9.0 and 9.8%, respectively. The method herein described was employed in a bioequivalence study of two formulations of dexchlorpheniramine/betamethasone 2 mg/0.25 mg tablets.

Betamethasone↗

Systemic betamethasone accelerates functional recovery after a crush injury to rat sciatic nerve.

PURPOSE: The aim of the study was to evaluate the effect of perioperatively systemically administered betamethasone on nerve recovery (within or outside a confined space) after induced nerve crush injury. MATERIALS AND METHODS: The sciatic nerve of 40 adult Wistar rats was crushed. In half of the animals, the injured nerve was entrapped in a silicone tube to simulate the environment of a closed space, and in the other half the nerve was left to heal. Half of the rats in each group were treated with subcutaneous betamethasone (2 mg/kg body weight/day) during the first 24 hours, starting preoperatively, whereas the other half, the control animals, were given the same amount of physiological saline. All animals underwent preoperative and postoperative walking track analysis (toe spread [TS] and intermediate toe spread [ITS]) twice weekly for 6 weeks. RESULTS: For nonconfined space groups, there was no significant difference between the 2 groups (P = .052 for ITS and P = .315 for TS) during the first 2 weeks. Starting from the end of the second week, animals treated with betamethasone recovered more rapidly than did the controls (P < .001) and continued to do so until the end of the observation period. In the confined space groups, there was a significant difference between the 2 groups for ITS (P < .001) and for TS (P < .05) during the first 2 weeks. The difference continued at almost the same level of significance (P = .001) for ITS, whereas for TS, the difference disappeared after the second week. CONCLUSIONS: We conclude that short-term perioperative administration of betamethasone has a beneficial effect on the recovery of the injured rat sciatic nerve.

Animals↗

Administration of prenatal betamethasone suppresses the adrenal-hypophyseal axis in newborns with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a condition that is characterized by pulmonary hypoplasia and pulmonary hypertension. Prenatal betamethasone often is administered to fetuses with CDH to improve pulmonary function. In this study, the authors investigate the possible role of the adrenal-hypophyseal axis in CDH in an animal model and subsequently in human infants with CDH. METHODS: Twin fetal sheep underwent creation of DH or a sham thoracotomy, and levels of plasma and lung ACTH and plasma cortisol were compared. For the human studies, plasma levels of ACTH, cortisol, and DHEA were measured in cord blood samples collected from 9 CDH (5 that received prenatal betamethasone) and compared with those of 14 normal newborns. In both studies, ACTH and cortisol levels were determined by radioimmunoassay (RIA). Human (DHEA) levels were determined by ELISA. RESULTS: Plasma ACTH and cortisol levels were elevated in fetal DH sheep compared with sham-operated controls; however, levels of ACTH in lung tissues were not different. Human newborns with CDH who have been exposed to prenatal steroids have significantly lower plasma ACTH, cortisol, and DHEA levels than normal newborns and CDH newborns not exposed to prenatal betamethasone. CONCLUSIONS: In an ovine model of CDH, the adrenal-hypophyseal axis appears up-regulated in DH fetuses compared with sham-operated animals. Conversely, the adrenal-hypophyseal axis in human CDH newborns appears normal but is suppressed by the administration of prenatal betamethasone.

Adrenocorticotropic Hormone↗

The effects of betamethasone (BM) on endothelial nitric oxide synthase (eNOS) expression in adult baboon femoral arterial endothelial cells.

Glucocorticoids have significant effects on endothelium mediated vascular function throughout life. The baboon model has been used extensively to study cellular responses to glucocorticoids at several stages of the lifespan. Endothelial nitric oxide synthase (eNOS) is a major regulator of endothelium dependent arterial vasodilation. We have previously demonstrated that synthetic glucocorticoids down regulate eNOS in the baboon placenta. We have now conducted studies to determine whether glucocorticoids would alter eNOS expression in adult systemic vascular endothelial cells in this important animal model. We explored this potential mechanism in endothelial cells from femoral arteries of adult baboons at necropsy and cultured to the fourth passage. Endothelial cells were treated with 10-100nM betamethasone for 24h at 37 degrees C. Vascular endothelial growth factor (VEGF) was used as a positive control and medium as negative controls. The role of glucocorticoid receptor mediation in betamethasone-induced eNOS changes was investigated with the glucocorticoid receptor antagonist mifepristone. RNA (real-time quantitative RT-PCR) and protein (ELISA) were extracted and measured for eNOS. Expression and subcellular distribution of glucocorticoid receptor were detected with fluorescence labeled antibody microscopy. eNOS mRNA and protein in baboon endothelial cells were downregulated 25% by betamethasone treatment. This effect was attenuated by pre-incubation with mifepristone (P < 0.01). VEGF upregulated eNOS transcription and translation (P < 0.001), medium did not alter eNOS expression. We observed that mifepristone and VEGF increased glucocorticoid receptor cytoplasmic accumulation by fluorescence microscopy. We conclude that betamethasone can downregulate eNOS in cultured baboon endothelial cells via the glucocorticoid receptor pathway.

Animals↗

Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs.

OBJECTIVE: We hypothesized that fetal betamethasone exposure for < 24 hours would improve postnatal lung function in preterm lambs. STUDY DESIGN: Singleton fetal sheep were randomized to receive by ultrasonographically guided fetal injections of 0.5 mg/kg betamethasone or saline solution either 8 or 15 hours before preterm delivery and postnatal assessment of lung function. RESULTS: After the 15-hour fetal treatment-to-delivery interval, betamethasone-treated lambs had twofold improvement in compliance and lung volumes, a fourfold to fivefold decrease in edema index, and higher blood pressures than saline solution-treated lambs. Postnatal lung function or lung volumes did not improve for the 8-hour treatment-to-delivery interval, although betamethasone decreased the pulmonary edema and increased the postnatal blood pressure. CONCLUSIONS: The minimal interval from fetal exposure to corticosteroids to delivery for improved postnatal lung function was between 8 and 15 hours. Corticosteroid effects on pulmonary edema and blood pressure occurred within 8 hours.

Animals↗

Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome.

OBJECTIVE: The aim of the study was to determine whether reduced birth weight, adrenal suppression, and lung maturation occur in parallel and are cumulative with increasing courses of betamethasone. STUDY DESIGN: Time-bred rabbits were assigned to a control group or to receive saline solution or 1, 2, or 3 courses of betamethasone (early treatment, beginning day 19). Two additional groups (n = 5 per group) were given 1 or 2 late courses (late treatment). Birth weight, serum cortisol, adrenal 17alpha-hydroxylase (P450c17) messenger ribonucleic acid and fetal lung surfactant proteins A and B were quantified on day 27. RESULTS: Fetal weight was inversely proportional to the number of courses, with late treatment having a greater effect. Maternal cortisol and P450c17 levels were progressively suppressed with each early course, but fetal cortisol and P450c17 levels were only suppressed after 3 courses. A single late treatment profoundly suppressed both maternal and fetal cortisol and P450c17 messenger ribonucleic acid levels. In contrast, fetal lung surfactant proteins A and B increased progressively with betamethasone courses, regardless of timing. CONCLUSIONS: Time from last injection to delivery determined adrenal suppression, whereas total betamethasone courses determined surfactant protein production. Lower birth weight was dependent on the number of courses and was greater with late treatment.

3-Hydroxysteroid Dehydrogenases↗

Differentiation between dexamethasone and betamethasone in a mixture using multiple mass spectrometry.

The objective of this study was to provide LC and GC-multiple mass spectrometry (MSn) data in positive and negative ion modes to prove the distinction between dexamethasone and betamethasone in a mixture of both components. Using GC-MS, the differentiation was based on a difference in the ratio of the ion traces of the two chromatographic peaks of the alpha and beta epimer with m/z 310 and 330. A minimum of 15% dexamethasone should be present in a mixture of both to detect it as present with a probability of 95%. In the same way betamethasone can be detected from 15% on. Because of the very similar structures of the dexamethasone and betamethasone epimers, no reversed-phase (RP) separations have been reported. Normal-phase separations have been reported in other studies. However because of the compatibility of RP mobile phases in the coupling with MS, the latter was the method of choice. In LC-MSn positive ion mode the product ion 355 was plotted against the sum of 337 and 319. With this combination dexamethasone and betamethasone could be discriminated in a mixture of 20 to 80% of each combination of analytes. In negative ion mode only two product ions were formed from the fragmentation of the acetate adduct, [M-H]- and [M-H-CH2O]-. The intensity of the fragment 391 ([M-H]-) was determined in the discrimination of the two epimers.

Betamethasone↗

Repeated fetal betamethasone treatment and birth weight and head circumference.

OBJECTIVE: To assess the effect of repeated courses of betamethasone on birth weight and head circumference. METHODS: We conducted a historical cohort study of inpatients receiving betamethasone therapy over 5 years. We compared birth weights and head circumferences of infants whose mothers received one course of betamethasone with those of infants whose mothers received multiple courses. Multiple regression analysis was used to adjust for potential confounding variables. Sufficient power (80%) existed to detect a 20% difference between the groups (alpha = 0.05). RESULTS: Mean birth weights (+/-SD) were 1717 +/- 707 g in the single-course group (n = 107) and 1783 +/- 647 g in the multiple-course group (n = 45) (P =.59, Student t-test). Mean head circumference was 28.2 +/- 3.6 cm in the single-course group and 29.2 +/- 2.9 cm in the multiple-course group (P =.15, Student t-test). In regression analysis, birth weights (1757 g and 1752 g) and head circumferences (28.5 cm and 29.0 cm) did not differ significantly different between the single-course and multiple-course groups. CONCLUSION: Multiple courses of betamethasone do not reduce birth weight or head circumference in neonates compared with single-course therapy.

Betamethasone↗

Fetal monkey surfactants after intra-amniotic or maternal administration of betamethasone and thyroid hormone.

OBJECTIVE: To compare direct intra-amniotic injection of betamethasone and thyroxine (T4) with maternal treatment and controls for accelerating pulmonary surfactant production. METHODS: Twelve pregnant monkeys (Macaca mulatta) on gestational day 125 (term 165 +/- 10 days) had surfactant protein A and B concentrations measured in amniotic fluid. In four controls, normal saline was injected into the amniotic fluid; four others (intra-amniotic) received intra-amniotic betamethasone (1 mg) and T4 (60 microg); and in four others (maternal), the dam was given betamethasone (12 mg) intramuscularly, repeated in 24 hours, plus TRH (400 microg) intravenously, repeated every 6 hours for 24 hours. Seventy-two hours after the initial amniocentesis, a hysterotomy was performed and fetal tissue and amniotic fluid harvested for determination of surfactant protein A and B concentrations and immunohistochemical staining for surfactant protein A. RESULTS: Amniotic fluid surfactant protein A was higher with intra-amniotic injection than with maternal treatment (P <.04) or controls (P =.07). Amniotic fluid surfactant protein B was higher in the intra-amniotic group than in controls (P =.06). Immunohistochemical staining for surfactant protein A in the lung tissue was increased in the intra-amniotic group compared with controls (0.145 +/- 0.01 versus 0.097 +/- 0.001, percent positive staining for surfactant protein A cells per lung tissue cells; P <.03). Birth weight was greater in the intra-amniotic group compared with the maternal group (P <.03) although not different from the controls. Finally, gut motility and the presence of formed meconium were increased in the intra-amniotic group compared with the other groups (P <.05). CONCLUSION: Intra-amniotic injection of betamethasone and T4 enhanced lung (and possibly intestinal) maturation of the preterm rhesus fetal monkey compared with maternal injections.

Amniotic Fluid↗

Effect of antenatal betamethasone administration on placental vascular resistance.

BACKGROUND: High placental vascular resistance is an important cause of fetal growth restriction and subsequent perinatal mortality. Identification of affected pregnancies allows appropriate fetal surveillance and delivery, but there are no known therapeutic strategies to decrease resistance and improve blood flow. However, placental corticotropin-releasing hormone (CRH) is thought to be a potent fetoplacental vasodilator, and exogenous corticosteroids can increase placental CRH secretion. Therefore, we examined whether corticosteroids could improve fetoplacental blood flow in pregnancies with increased vascular resistance. METHODS: A retrospective review of umbilical-artery flow-velocity waveforms (FVWs) before and after betamethasone administration was undertaken in pregnancies with increased placental vascular resistance, as shown by umbilical-artery absent end-diastolic flow (AEDF). FVWs were obtained by pulsed-wave doppler ultrasonography. We studied all 28 pregnancies monitored at the maternal-fetal medicine unit of a university teaching hospital since 1995. FINDINGS: The median duration of gestation at presentation with AEDF was 27 weeks (range 23-33). In 19 (68% [95% CI 49-86]) pregnancies, umbilical-artery diastolic flow returned within 24 h after betamethasone administration, consistent with decreased resistance. The median duration of this effect was 3 days (range 2-7). There were no differences in duration of gestation at diagnosis or delivery, or in birthweight between fetuses showing a return of flow after betamethasone and those not showing a return of flow. INTERPRETATION: In pregnancies with umbilical-artery AEDF, betamethasone treatment is associated with decreased placental vascular resistance, possibly induced via increased placental CRH secretion. This study does not provide insights into whether this effect would be beneficial or harmful to the fetus.

Anti-Inflammatory Agents↗

Subconjunctival betamethasone is of benefit after cataract surgery.

Following cataract extraction, the intraocular inflammatory response is particularly marked in some patients, who then require more intensive post-operative care. This prospective randomised double-masked controlled trial of 246 patients undergoing cataract extraction assessed the efficacy and safety of a prophylactic subconjunctival injection of betamethasone (Betnesol, Glaxo) in improving the post-operative course. Betamethasone injected subconjunctivally at the end of cataract extraction significantly reduces anterior segment inflammation (p < 0.05) on the first post-operative day. It also reduces the need for additional steroid treatment and in-patient stay (p < 0.05). The benefits are most marked in those patients prone to a greater inflammatory response: especially those with previous intraocular inflammation (p < 0.01), but also those with racial pigmentation or difficult surgery. There was no evidence of adverse effects following betamethasone; in particular there was no endophthalmitis or steroid-induced elevation of intraocular pressure. We therefore conclude that subconjunctival injection of betamethasone is a practical, safe and effective means of improving the quality and efficiency of patient care.

Aged↗

When betamethasone and dexamethasone are unavailable: hydrocortisone.

OBJECTIVE: To review the literature on alternatives to betamethasone and dexamethasone for enhancement of fetal lung maturity. STUDY DESIGN: A medline search was conducted from 1966 to the present. Trials dealing with enhancement of fetal lung maturity using modalities other than betamethasone or dexamethasone were reviewed. RESULTS: Eight studies met inclusion criteria. Excluding betamethasone and dexamethasone, the most frequently studied glucocorticoids, for fetal lung maturation, are methylprednisolone and hydrocortisone. Methylprednisolone does not cross the placenta. Two grams of hydrocortisone has been shown to improve indices of fetal lung maturity (i.e., L/S ratio) and to improve fetal outcomes compared to no treatment. CONCLUSION: There is limited information about alternatives to betamethasone and dexamethasone for the enhancement of fetal lung maturity in women at risk of preterm delivery. In the absence of these two preferred drugs, hydrocortisone can be given at a dose of 500 mg intravenously every 12 hours for four doses for this indication.

Anti-Inflammatory Agents↗

Betamethasone modulation of sphingomyelin hydrolysis up-regulates CTP:cholinephosphate cytidylyltransferase activity in adult rat lung.

Glucocorticoids appear to play an integral role in stimulating surfactant synthesis by activating the rate-regulatory enzyme for phosphatidylcholine synthesis, CTP:cholinephosphate cytidylyltransferase (CT). The activity of liver CT, in vitro, has been shown to be inhibited by the sphingomyelin hydrolysis product, sphingosine. In order to investigate the mechanisms by which glucocorticoids alter CT activity, in vivo, we administered betamethasone (1 mg/kg intraperitoneally) sequentially to adult male rats for 5 days. Betamethasone increased CT activity 2-fold relative to control in whole lung. The hormone also increased membrane-bound activity, but did not affect cytosolic enzyme activity. Betamethasone modestly increased CT mRNA as determined by the reverse-transcription PCR and Southern analysis of PCR products, but did not alter the levels of immunoreactive enzyme in lung membranes as demonstrated by Western blotting. The hormone did, however, produce a nearly 3-fold increase in membrane-associated sphingomyelin, and co-ordinately a substantial decrease in the levels of sphingosine in lung membranes. Sphingosine, but not sphinganine, was a competitive, reversible inhibitor of lung CT with respect to the enzyme activator, phosphatidylglycerol. Betamethasone decreased the activities of the sphingomyelin hydrolases: acid sphingomyelinase by 33% and of alkaline ceramidase by 21%. The hormone also inhibited the generation of sphingosine from lysosphingomyelin in lung membranes. There was no significant effect of the hormone on serine palmitoyltransferase activity, the first committed enzyme for sphingolipid biosynthesis. Further, administration of L-cycloserine, an inhibitor of sphingosine formation, was shown to stimulate CT activity by 74% and increase disaturated phosphatidylcholine in alveolar lavage by 52% relative to control. These observations suggest that glucocorticoids up-regulate surfactant synthesis at the level of a key regulatory enzyme by significantly altering the availability of inhibitory metabolites resulting from sphingomyelin hydrolysis.

Amidohydrolases↗

A randomized double-blind study to compare the effects of nasal fluticasone and betamethasone on the hypothalamo-pituitary-adrenal axis and bone turnover in patients with nasal polyposis.

Treatment of nasal polyposis with topical betamethasone is associated with suppression of the hypothalamo-pituitary-adrenal (HPA) axis and, potentially, has adverse effects on bone turnover. Fluticasone propionate is a potent corticosteroid with negligible absorption across the nasal mucosa and extensive first-pass hepatic metabolism. We performed a randomized double-blind study, in patients with nasal polyposis, comparing the effects of 8 weeks' treatment with betamethasone drops or fluticasone nasules on the HPA axis using the 1 micro g tetracosactide test, and on bone turnover using two serum markers. Nine patients were allocated to each treatment. Betamethasone resulted in significant suppression in the tetracosactide test (P = 0.006), but fluticasone did not (P = 0.113). There were no differences in bone turnover or treatment efficacy between treatments. Treatment of nasal polyposis with topical betamethasone drops, but not with fluticasone nasules, suppresses the HPA axis and, given comparable efficacy, fluticasone administered via nasule should be the preferred agent.

Administration, Intranasal↗