Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density.

During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open-label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino-terminal propeptide of type I procollagen (P1NP) and cross-linked C-telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown.

Role of NO in the control of choroidal blood flow during a decrease in ocular perfusion pressure.

PURPOSE: The study was conducted to investigate whether the L-arginine/nitric oxide system plays a role in choroidal blood flow (ChBF) regulation during a decrease in ocular perfusion pressure (OPP). METHODS: Experiments were performed on 3 days in a randomized double-masked, placebo-controlled, three-way crossover design. On different study days, subjects received intravenous infusions of N(G)-monomethyl-L-arginine (L-NMMA), phenylephrine, or placebo. Intraocular pressure was raised in stepwise increments using the suction cup METHOD: Choroidal blood flow (ChBF, laser Doppler flowmetry), mean arterial blood pressure (MAP), and IOP were assessed. Ocular perfusion pressure was calculated as OPP = 23(MAP - IOP). For correlation analysis all OPP/ChBF data pairs from all subjects were pooled independent of time point of measurement. Then, the pooled data were sorted according to OPP, and correlation analyses were performed. RESULTS: L-NMMA and phenylephrine increased resting OPP by +17% +/- 18% and +14% +/- 21%, respectively (P < 0.05). L-NMMA reduced resting ChBF by -21% +/- 17% (P < 0.05). The relative decrease in OPP during suction cup application was comparable with all drugs administered. The decrease in OPP was paralleled by a significant decrease in ChBF (maximum between -39% and -47%), which was less pronounced, however, than the decrease in OPP (maximum between -69% and -74%). Neither placebo nor L-NMMA, nor phenylephrine, influenced the OPP/ChBF relationship. CONCLUSIONS: The data confirm previously published observations that the choroid shows some regulatory capacity during reduced OPP. The L-arginine/nitric oxide-system plays a role in the maintenance of basal vascular tone but seems not to be involved in the choroidal vasodilator response when IOP is increased.

Influence of infusion volume on the ocular hemodynamic effects of peribulbar anesthesia.

PURPOSE: To test the hypothesis that ocular blood-flow response to peribulbar anesthesia can be reduced by using a smaller volume of anesthetic mixture. SETTING: Departments of Ophthalmology and Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. METHODS: Twenty patients scheduled for bilateral age-related cataract surgery were enrolled in a prospective randomized balanced observer-masked crossover study. Two study days with a 2 mL injection volume or 5 mL injection volume used for peribulbar anesthesia were scheduled. On 1 study day, patients received the 1-dose regimen and on the other study day, when the contralateral eye had surgery, patients received the other injection volume. On both study days, the anesthetic mixture consisted of an equal amount of lidocaine, bupivacaine, and hyaluronidase independently of the injection volume. Intraocular pressure (IOP), blood pressure, and pulse rate were measured noninvasively. Ocular fundus pulsation amplitude (FPA) and peak systolic and end diastolic flow velocities in the central retinal artery were measured with laser interferometry and color Doppler imaging, respectively. The results were recorded as means +/- SD. RESULTS: Peribulbar anesthesia increased IOP and reduced FPA and flow velocities in the central retinal artery. The effects on IOP (5 mL, 35.1% +/- 16.0%; 2 mL, 14.1% +/- 14.1%; P<.001) and ocular hemodynamic parameters (FPA: 5 mL, -17.5% +/- 7.8%/2 mL, -7.3% +/- 7.2%, P<.001; peak systolic velocity: 5 mL, -19.5% +/- 10.7%/2 mL, -10.6% +/- 9.8%, P = .013; end diastolic velocity: 5 mL, -16.7% +/- 6.2%/2 mL, -8.4% +/- 7.3%, P = .005) were more pronounced with the 5 mL injection volume than with the 2 mL injection volume. CONCLUSIONS: An injection volume of 2 mL instead of 5 mL reduced the ocular blood-flow response to peribulbar anesthesia. This procedure may be used in patients with ocular vascular disease to reduce the incidence of anesthesia-induced ischemia and loss of vision.

Effect of histamine and cimetidine on retinal and choroidal blood flow in humans.

Intravenous administration of histamine causes an increase in choroidal blood flow and retinal vessel diameter in healthy subjects. The mechanism underlying this effect remains to be elucidated. In the present study, we hypothesized that H2 receptor blockade alters hemodynamic effects of histamine in the choroid and retina. Eighteen healthy male nonsmoking volunteers were included in this randomized, double-masked, placebo-controlled two-way crossover study. Histamine (0.32 microg.kg(-1).min(-1) over 30 min) was infused intravenously in the absence (NaCl as placebo) or presence of the H2 blocker cimetidine (2.3 mg/min over 50 min). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of cimetidine or placebo, and after coinfusion of histamine. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser-Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser-Doppler velocimetry. Histamine increased subfoveal choroidal blood flow (+14 +/- 15%, P < 0.001), fundus pulsation amplitude (+11 +/- 5%, P < 0.001), retinal venous diameter (+3.0 +/- 3.6%, P = 0.002), and retinal arterial diameter (+2.8 +/- 4.2%, P < 0.01) but did not change retinal blood velocity. The H2 antagonist cimetidine had no significant effect on ocular hemodynamic parameters. In addition, cimetidine did not modify effects of histamine on choroidal blood flow, fundus pulsation amplitude, retinal venous diameter, and retinal arterial diameter compared with placebo. The present data confirm that histamine increases choroidal blood flow and retinal vessel diameters in healthy subjects. This ocular vasodilator effect of histamine is, however, not altered by administration of an H2 blocker. Whether the increase in blood flow is mediated via H1 receptors or other hitherto unidentified mechanisms remains to be elucidated.

Intravenous administration of L-arginine increases retinal and choroidal blood flow.

PURPOSE: Nitric oxide (NO) is among the most important regulators of ocular perfusion. L-arginine, an amino acid, is the precursor of NO synthesis. The aim of the present study was to determine whether administration of L-arginine affects ocular blood flow. DESIGN: L-arginine (1 g/min) or placebo was administered intravenously for 30 minutes in 12 healthy volunteers in a randomized, double-masked, two-way cross-over design. METHODS: Ocular hemodynamics were measured before, in the last 10 minutes of the infusion period, as well as 30 minutes after cessation of the administration. Retinal vessel diameters were measured with a retinal vessel analyzer, red blood cell velocities with bidirectional laser Doppler velocimetry, and pulsatile choroidal blood flow was measured using laser interferometry. RESULTS: L-arginine significantly decreased mean arterial pressure by -8 +/- 5% and -6 +/- 7% at the two time points (P < .01), respectively. Intravenous administration of L-arginine increased choroidal blood flow by +10 +/- 6% and +12 +/- 7%, respectively. Retinal venous diameters decreased by -2.5 +/- 2.1% and -1.4 +/- 2.7%, respectively, whereas red blood cell velocity significantly increased after administration of L-arginine by +22 +/- 23% and +20 +/- 19% at the two time points. Thus, calculated blood flow in retinal veins, increased by +21 +/- 18% and +21 +/- 19% before and after the end of L-arginine infusion. CONCLUSIONS: Intravenous administration of L-arginine increases retinal and choroidal blood flow in healthy volunteers. Whether this effect is related to an increased NO-production or an unidentified mechanism remains to be clarified. However, administration of L-arginine might be an interesting new approach to therapeutically increase ocular blood flow in ocular vascular disease.

Short-term increase of intraocular pressure does not alter the response of retinal and optic nerve head blood flow to flicker stimulation.

PURPOSE: It has been shown that stimulation with diffuse luminance flicker induces vasodilatation in the human retina and increases optic nerve head (ONH) blood flow. The present study was designed to investigate the influence of a short-term increase in intraocular pressure on flicker-induced changes in ONH blood flow and retinal vessel diameters. METHODS: In a group of 15 healthy volunteers, IOP was increased by the episcleral suction cup technique. ONH blood flow was assessed with a laser Doppler flowmeter, and retinal vessel diameters were measured with the retinal vessel analyzer. Flicker responses of retinal vessel diameters and ONH blood flow were determined at baseline conditions and during suction of 70 and 140 mm Hg. Flicker light consisted of 8-Hz square-wave flashes at a wavelength below 550 nm and produced a retinal irradiance of 140 muW/cm(2). RESULTS: Suction increased IOP from 12 +/- 2 to 27 +/- 4 mm Hg and 43 +/- 4 mm Hg. Stimulation with diffuse luminance flicker induced an increase in ONH blood flow of +24.0% +/- 20.7%. Increased IOP did not significantly change the flicker response in the ONH (+19.3% +/- 26.6% and +22.1% +/- 25.1%). In retinal veins, flicker induced an increase in vessel diameter of +3.0% +/- 2.0%. Flicker responses in retinal veins were not significantly altered after the IOP was increased, compared with those recorded at baseline IOP (+2.8% +/- 2.5% and +3.2% +/- 2.2%). The flicker response in retinal arteries at baseline IOP was +3.5% +/- 2.0%. Again, the increase in IOP did not significantly alter this flicker response (+2.8% +/- 1.6% and +3.1% +/- 2.4%). CONCLUSIONS: A short-term increase in IOP does not alter the response of retinal vessel diameters and ONH blood flow to diffuse luminance flicker, which indicates that increased IOP does not alter retinal or ONH regulation during neuronal stimulation.

Comparison of the autoregulatory mechanisms between middle cerebral artery and ophthalmic artery after thigh cuff deflation in healthy subjects.

PURPOSE: To compare dynamic autoregulation in the middle cerebral artery (MCA) and the ophthalmic artery (OA) after a step decrease in systemic blood pressure. METHODS: Eighteen healthy male young subjects were studied. Ultrasound parameters and systemic blood pressures were recorded in each subject before, during, and after a step decrease in blood pressure. Continuous blood pressure recordings were made with a finger plethysmograph system, and flow velocities in the MCA and the OA were continuously measured with Doppler ultrasound. Large bilateral thigh cuffs were inflated and a pressure approximately 20 mm Hg above peak systolic blood pressure was maintained for 3 minutes. A decrease in blood pressure was induced by rapid deflation of bilateral thigh cuffs. Experiments were performed separately for the OA and the MCA. RESULTS: Systemic blood pressure showed a step decrease immediately after thigh cuff release (9%-15%) and returned to baseline 7 to 10 pulse cycles later. Flow velocities in the MCA returned to baseline earlier than systemic blood pressure, indicating peripheral vasodilatation, with a maximum of five to six pulse cycles after the blood pressure decrease. By contrast, flow velocities in the OA returned to baseline later than systemic blood pressure, reflecting peripheral vasoconstriction with a maximum 10 to 15 pulse cycles after cuff release. There was a statistically significant difference in the time course of the resistance changes in the two selected arteries after thigh cuff release (P < 0.001). CONCLUSIONS: The results of the present study suggest substantial differences in the autoregulatory behavior of the vascular beds peripheral to the MCA and the OA. Results in the MCA would be compatible with either metabolic or myogenic vasodilatation, whereas the results in the OA could reflect sympathetic vasoconstriction. Further studies are needed to support this hypothesis. The thigh cuff technique may represent an interesting approach to the study of autoregulation in patients with ocular vascular disease.

LPS-induced microvascular leukocytosis can be assessed by blue-field entoptic phenomenon.

Administration of low doses of Escherichia coli endotoxin [a lipopolysaccharide (LPS)] to humans enables the study of inflammatory mechanisms. The purpose of the present study was to investigate whether the blue-field entoptic technique may be used to quantify the increase in circulating leukocytes in the ocular microvasculature after LPS infusion. In addition, combined laser Doppler velocimetry and retinal vessel size measurement were used to study red blood cell movement. Twelve healthy male volunteers received 20 IU/kg iv LPS as a bolus infusion. Outcome parameters were measured at baseline and 4 h after LPS administration. In the first protocol (n = 6 subjects), ocular hemodynamic effects were assessed with the blue-field entoptic technique, the retinal vessel analyzer, and laser Doppler velocimetry. In the second protocol (n = 6 subjects), white blood cell (WBC) counts from peripheral blood samples and blue-field entoptic technique measurements were performed. LPS caused peripheral blood leukocytosis and increased WBC density in ocular microvessels (by 49%; P = 0.036) but did not change WBC velocity. In addition, retinal venous diameter was increased (by 9%; P = 0.008), but red blood cell velocity remained unchanged. The LPS-induced changes in retinal WBC density and leukocyte counts were significantly correlated (r = 0.87). The present study indicates that the blue-field entoptic technique can be used to assess microvascular leukocyte recruitment in vivo. In addition, our data indicate retinal venous dilation in response to endotoxin.