Mean Peak Change Research Articles

Long-term results of combination therapy using anti-VEGF agents and dexamethasone intravitreal implant for retinal vein occlusion: an investigational case series.

BackgroundOne limitation of anti-VEGF therapy is the need for monthly retreatment to maintain efficacy. The purpose of this study was to determine the duration of effect in eyes with macular edema (ME) secondary to branch or central retinal vein occlusion (BRVO or CRVO) treated with anti-VEGF therapy plus sustained-release dexamethasone (DEX implant; Ozurdex).Materials and methodsThis open-label, interventional case series included 62 eyes with ME due to RVO, central foveal thickness (CFT) >300 μm, and best-corrected visual acuity (BCVA) of 20/40 or worse. Each treatment cycle included an anti-VEGF injection followed 2 weeks later with DEX implant. Patients were eligible for retreatment if CFT increased to >290 μm or increased by >50 μm from the lowest measurement, or if BCVA decreased by six or more Snellen letters. Efficacy and safety were evaluated 2 and 4–6 weeks after the beginning of each treatment cycle and every 4 weeks thereafter until retreatment criteria were met. The primary outcome measure was time to retreatment. Secondary outcome measures included BCVA, CFT, and safety parameters.ResultsThe mean reinjection interval for all patients was 135.5±36.4 days. There was no statistically significant difference in mean intertreatment interval for up to six cycles of treatment or between eyes with BRVO or CRVO (P≥0.058). Mean peak change in BCVA was 13.8 letters, and 47.6% of eyes gained three or more lines of BCVA. The mean peak decrease in CFT across all treatment cycles was 200.9 μm for eyes with BRVO and 219.2 μm for eyes with CRVO. The percentage of patients with CFT ≤300 μm at any time during a given treatment cycle ranged from 78% to 94% among eyes with BRVO and from 85% to 100% among eyes with CRVO. Intraocular pressure increased in 19 of 62 eyes, and 26 of 44 phakic eyes underwent cataract surgery.ConclusionIn eyes with ME due to RVO, treatment with an anti-VEGF agent plus DEX implant provided a predictable duration of effect, as well as significant improvements in BCVA and CFT.

The use of phenylephrine to obtund oxytocin-induced hypotension and tachycardia during caesarean section

BackgroundOxytocin causes clinically significant hypotension and tachycardia. This study examined whether prior administration of phenylephrine obtunds these unwanted haemodynamic effects. MethodsForty pregnant women undergoing elective caesarean section under spinal anaesthesia were randomised to receive either an intravenous 50μg bolus of phenylephrine (Group P) or saline (Group S) immediately before oxytocin (3U over 15s). Systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate were recorded using a continuous non-invasive arterial pressure device. Baseline values were averaged for 20s post-delivery. Between-group comparisons were made of the mean peak changes in blood pressure and heart rate, and the mean percentage changes from baseline, during the 150s after oxytocin administration. ResultsThe mean±SD peak percentage change in systolic blood pressure was −16.9±2% in Group P, and −19.0±1.9% in Group S and the estimated mean difference was 2.1% (95% CI −3.5% to 7.8%; P=0.44); corresponding changes in heart rate were 13.5±2.3% and 14.0±1.5% and the mean estimated difference was 0.5% (95% CI −6.0% to 5%; P=0.87). The mean percentage change from the baseline measurements during the 150s period of measurement was greater for Group S than Group P: systolic blood pressure −5.9% vs −3.4% (P=0.149); diastolic blood pressure −7.2% vs −1.5% (P=0.014); mean arterial pressure −6.8% vs −1.5% (P=0.007); heart rate 2.1% vs −2.4% (P=0.033). ConclusionIntravenous phenylephrine 50μg immediately before 3U oxytocin during elective caesarean section does not prevent maternal hypotension and tachycardia.

Real-world assessment of intravitreal dexamethasone implant (0.7 mg) in patients with macular edema: the CHROME study.

BackgroundThe purpose of this study was to evaluate the real-world use, efficacy, and safety of one or more dexamethasone intravitreal implant(s) 0.7 mg (DEX implant) in patients with macular edema (ME).MethodsThis was a retrospective cohort study of patients with ME secondary to retinal disease treated at ten Canadian retina practices, including one uveitis center. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), glaucoma and cataract surgery, and safety data were collected from the medical charts of patients with ≥3 months of follow-up after the initial DEX implant.ResultsOne hundred and one patient charts yielded data on 120 study eyes, including diagnoses of diabetic ME (DME) (n=34), retinal vein occlusion (RVO, n=30; branch in 19 and central in 11), and uveitis (n=23). Patients had a mean age of 60.9 years, and 73.3% of the study eyes had ME for a duration of ≥12 months prior to DEX implant injection(s). Baseline mean (± standard error) BCVA was 0.63±0.03 logMAR (20/86 Snellen equivalents) and mean CRT was 474.4±18.2 μm. The mean number of DEX implant injections was 1.7±0.1 in all study eyes; 44.2% of eyes had repeat DEX implant injections (reinjection interval 2.3–4.9 months). The greatest mean peak changes in BCVA lines of vision occurred in study eyes with uveitis (3.3±0.6, P<0.0001), followed by RVO (1.3±0.5, P<0.01) and DME (0.7±0.5, P>0.05). Significant decreases in CRT were observed: −255.6±43.6 μm for uveitis, −190.9±23.5 μm for DME, and −160.7±39.6 μm for RVO (P<0.0001 for all cohorts). IOP increases of ≥10 mmHg occurred in 20.6%, 24.1%, and 22.7% of DME, RVO, and uveitis study eyes, respectively. IOP-lowering medication was initiated in 29.4%, 16.7%, and 8.7% of DME, RVO, and uveitis study eyes, respectively. Glaucoma surgery was performed in 1.7% of all study eyes and cataract surgery in 29.8% of all phakic study eyes receiving DEX implant(s).ConclusionDEX implant(s) alone or combined with other treatments and/or procedures resulted in functional and anatomic improvements in long-standing ME associated with retinal disease.

EFFICACY AND SAFETY OF TWO OR MORE DEXAMETHASONE INTRAVITREAL IMPLANT INJECTIONS FOR TREATMENT OF MACULAR EDEMA RELATED TO RETINAL VEIN OCCLUSION (SHASTA STUDY)

To evaluate the efficacy, safety, and reinjection interval of dexamethasone intravitreal implant (DEX implant) in branch retinal vein occlusion and central retinal vein occlusion patients receiving ≥ 2 DEX implant treatments. Multicenter (26-site), retrospective chart review study. Data were collected from baseline (at first DEX implant) through 3 months to 6 months after last DEX implant. Patients (n = 289) received 2 to 9 (mean, 3.2) DEX implants as monotherapy (29.1% of patients) or with adjunctive treatments/procedures. Mean duration of macular edema before first DEX implant was 18.4 months. Mean reinjection interval was 5.6 months. Mean peak change in best-corrected visual acuity from baseline through 4 weeks to 20 weeks after final DEX implant was +1.0 line (P < 0.001). Best-corrected visual acuity and central retinal thickness improved significantly from baseline after each of the first 6 DEX implant injections (P ≤ 0.037); 59.7% of branch retinal vein occlusion and 66.7% of central retinal vein occlusion patients achieved ≥ 2-line best-corrected visual acuity improvement. Intraocular pressure increase (≥ 10 mmHg) occurred in 32.6% of patients; 29.1% used intraocular pressure-lowering medication to treat increases associated with DEX implant. Only 1.7% of patients required incisional glaucoma surgery. Retinal vein occlusion patients treated with multiple DEX implant injections, either alone or combined with other therapies, had improved central retinal thickness and visual acuity with each subsequent injection. No new safety concerns developed with multiple implants.

Responses of Urinary N-Telopeptide and Renal Calcium Handling to PTH Infusion after Treatment with Estrogen, Raloxifene, and Tamoxifen

This prospective, randomized, placebo-controlled study investigated whether estrogen, tamoxifen, and raloxifene protect the skeleton from the acute catabolic effects of continuous PTH(1-34) infusion. It was infused over 24h in 25 postmenopausal women both before and while on medication for 16-20weeks (estrogen n=7, raloxifene n=5, tamoxifen n=7, placebo n=6). Blood and urine samples were collected at baseline and every 4h during the PTH(1-34) infusion and analyzed for calcium homeostasis, bone remodeling, and specific cytokines. Data for the premedication PTH(1-34) infusions were pooled. During the premedication PTH(1-34) infusions, serum calcium and urine phosphorus increased, while serum phosphorus and urine calcium declined. Osteocalcin decreased (mean 18%), while urine NTX increased (mean 315%). Serum IL-6 increased 260%, but there were no other cytokine changes as a result of the PTH(1-34) infusion. On medication, the mean peak change in NTX with PTH(1-34) infusion was less (77, 59, and 31nM/mM with raloxifene, tamoxifen, and estrogen, respectively). The reduction in urine calcium excretion was prolonged with each agent but only significantly with estrogen. There was no reduction in the IL-6 elevation induced by PTH(1-34) with any medication. The differential skeletal resorption response to PTH(1-34) infusion after the treatments may reflect different potencies of these agents or variability in interaction with the estrogen receptor. Renal calcium conservation and the blunted response of bone resorption to PTH(1-34) infusion may be mechanisms by which estrogen and estrogen agonist/antagonist agents preserve bone mass.

Genetic determinants of blood pressure responses to caffeine drinking

The widely observed between-subject variability in cardiovascular responses to coffee may have a genetic basis. We evaluated acute blood pressure (BP) responses to caffeine and explored whether they are influenced by candidate gene variants affecting caffeine metabolism (for cytochrome P450 1A2), adenosine metabolism (for adenosine receptor and AMP deaminase), or catecholamine receptors. We recruited 110 healthy male habitual moderate coffee drinkers who refrained from drinking coffee on the day preceding the study. Each subject underwent ambulatory BP monitoring at 6-min intervals for 2 h. Each participant was administered, in a double-blind design, 40 mL of either a decaffeinated coffee preparation plus 3 mg caffeine/kg (caf) or the corresponding vehicle (decaf). The protocol was repeated 24 h later with the alternative preparation. Blood samples were collected for genetic and plasma caffeine and catecholamine evaluations. Compared with decaf, caf was associated with a mean (± SD) significant increase in systolic BP of 4 ± 12 mm Hg and in diastolic BP of 3 ± 10 mm Hg (P < 0.001 for both). Plasma caffeine and adrenaline increased after caf, but not after decaf. Of 11 gene polymorphisms analyzed, a relation was observed between the ADORA2A TT variant and the change in SBP peak and between the ADRA2B I variant and the changes in both SBP mean and peak; mean peak change in SBP; these variants were associated with increased SBP responses to caf. Variability in the acute BP response to coffee may be partly explained by genetic polymorphisms of the adenosine A2A receptors and α(2)-adrenergic receptors. This trial is registered at clinicaltrials.gov as NCT01330680.

N‐Acetylcysteine Added to Volume Expansion with Sodium Bicarbonate Does Not Further Prevent Contrast‐Induced Nephropathy: Results from the Cardiac Angiography in Renally Impaired Patients Study

We reviewed data from the multicenter CARE (Cardiac Angiography in Renally Impaired Patients) study to see if benefit could be shown for N-acetylcysteine (NAC) in patients undergoing cardiac angiography who all received intravenous bicarbonate fluid expansion. Four hundred fourteen patients with moderate-to-severe chronic kidney disease were randomized to receive intra-arterial administration of iopamidol-370 or iodixanol-320. All patients were prehydrated with isotonic sodium bicarbonate solution. Each site chose whether or not to administer NAC 1,200 mg twice daily to all patients. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2-5 days after receiving contrast. The primary outcome was a postdose SCr increase 0.5 mg/dL (44.2 mumol/L) over baseline. Secondary outcomes were a postdose SCr increase 25% and the mean peak change in SCr. The NAC group received significantly less hydration (892 +/- 236 mL vs. 1016 +/- 328 mL; P < 0.001) and more contrast volume (146 +/- 74 mL vs. 127 +/- 71 mL; P = 0.009) compared with no-NAC group. SCr increases 0.5 mg/dL occurred in 4.2% (7 of 168 patients) in NAC group and 6.5% (16 of 246 patients) in no-NAC group (P = 0.38); rates of SCr increases 25% were 11.9% and 10.6%, respectively (P = 0.75); mean post-SCr increases were 0.07 mg/dL in NAC group versus 0.11 mg/dL in no-NAC group (P = 0.14). In conclusion, addition of NAC to fluid expansion with sodium bicarbonate failed to reduce the rate of contrast-induced nephropathy (CIN) after the intra-arterial administration of iopamidol or iodixanol to high-risk patients with chronic kidney disease.

Treatment of candidemia and invasive candidiasis in the intensive care unit: post hoc analysis of a randomized, controlled trial comparing micafungin and liposomal amphotericin B

IntroductionInvasive candidiasis and candidemia are life-threatening nosocomial infections in intensive care patients.MethodsA post hoc analysis of a phase 3 trial assessing micafungin (100 mg/day for subjects > 40 kg; 2 mg/kg/day for subjects ≤ 40 kg) versus liposomal amphotericin B (3 mg/kg/day). Subgroups were defined according to the type of ward on the first day of treatment: intensive care unit (ICU) or non-ICU. Multivariate regression was performed to identify factors associated with treatment success at end of therapy and all-cause mortality at days 8 and 30.ResultsIn non-ICU subjects, treatment success was significantly higher for micafungin versus liposomal amphotericin B (85% (n = 108/127) versus 72.1% (n = 98/136); P = 0.0113). However, for ICU subjects, treatment success rates for micafungin versus liposomal amphotericin B were similar (62.5% (n = 75/120) versus 66.4% (n = 73/110); P = 0.5828). Overall, treatment success was significantly lower in ICU subjects compared with non-ICU subjects (64.3% (n = 148/230) versus 78.3% (n = 206/263); P = 0.0006). Multivariate regression analysis revealed a lower likelihood of treatment success for: ICU versus non-ICU subjects; persistent neutropenia; and high versus low Acute Physiology and Chronic Health Evaluation (APACHE) II scores. However, when interactions between potential explanatory factors were included in the analysis model, ICU status no longer emerged as a significant associated variable but the association between APACHE II score and treatment outcome remained. Further analyses indicated that the likelihood of mortality at day 8 and day 30 was lower for subjects with lower APACHE II scores. Renal function was significantly better in micafungin versus liposomal amphotericin B subjects: a difference (liposomal amphotericin B - micafungin in mean peak change in estimated glomerular filtration rate (ml/minute/1.73 m2) of -18.2 (P < 0.0001) and -17.7 (P = 0.0124) in non-ICU and ICU subjects, respectively.ConclusionsOverall, ICU subjects had lower treatment success rates than non-ICU subjects for both liposomal amphotericin B and micafungin. Multivariate regression after controlling for potential confounding factors suggested the APACHE II score remained a potential explanatory factor associated with treatment success, mortality at day 8, and mortality at day 30.Trial registrationPost hoc analysis - clinicaltrials.gov trial NCT00106288.

Cardiac Angiography in Renally Impaired Patients (CARE) Study

No direct comparisons exist of the renal tolerability of the low-osmolality contrast medium iopamidol with that of the iso-osmolality contrast medium iodixanol in high-risk patients. The present study is a multicenter, randomized, double-blind comparison of iopamidol and iodixanol in patients with chronic kidney disease (estimated glomerular filtration rate, 20 to 59 mL/min) who underwent cardiac angiography or percutaneous coronary interventions. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2 to 5 days after receiving medications. The primary outcome was a postdose SCr increase > or = 0.5 mg/dL (44.2 micromol/L) over baseline. Secondary outcomes were a postdose SCr increase > or = 25%, a postdose estimated glomerular filtration rate decrease of > or = 25%, and the mean peak change in SCr. In 414 patients, contrast volume, presence of diabetes mellitus, use of N-acetylcysteine, mean baseline SCr, and estimated glomerular filtration rate were comparable in the 2 groups. SCr increases > or = 0.5 mg/dL occurred in 4.4% (9 of 204 patients) after iopamidol and 6.7% (14 of 210 patients) after iodixanol (P=0.39), whereas rates of SCr increases > or = 25% were 9.8% and 12.4%, respectively (P=0.44). In patients with diabetes, SCr increases > or = 0.5 mg/dL were 5.1% (4 of 78 patients) with iopamidol and 13.0% (12 of 92 patients) with iodixanol (P=0.11), whereas SCr increases > or = 25% were 10.3% and 15.2%, respectively (P=0.37). Mean post-SCr increases were significantly less with iopamidol (all patients: 0.07 versus 0.12 mg/dL, 6.2 versus 10.6 micromol/L, P=0.03; patients with diabetes: 0.07 versus 0.16 mg/dL, 6.2 versus 14.1 micromol/L, P=0.01). The rate of contrast-induced nephropathy, defined by multiple end points, is not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus. Any true difference between the agents is small and not likely to be clinically significant.

Hypertonic saline (7.2%) in 6% hydroxyethyl starch reduces intracranial pressure and improves hemodynamics in a placebo-controlled study involving stable patients with subarachnoid hemorrhage*

To compare the effects of a bolus infusion of hypertonic saline hydroxyethyl starch with the effects of normal saline (placebo) on intracranial pressure (ICP) and cerebral perfusion pressure in patients with spontaneous subarachnoid hemorrhage. Prospective, randomized, single-blinded, placebo-controlled study in a university hospital. A total of 22 mechanically ventilated patients with spontaneous subarachnoid hemorrhage with stable ICP between 10 and 20 mm Hg. During the course of 30 mins, 2 mL/kg of either 7.2% saline in 6% hydroxyethyl starch 200/0.5 (HSS) or of normal saline was infused. The effects were observed for another 180 mins. Mean change in ICP after intervention (DeltaICP) calculated from the average of all observations was -3.3 (sd 2.6) mm Hg in the HSS group vs. -0.3 (sd 1.3) mm Hg in the normal saline group. Mean difference between the groups (HSS - normal saline) was -3.0 mm Hg (95% confidence interval, -4.9 to -1.1; p = .004). Mean peak change after HSS was -5.6 (range, -0.8 to -12.2) mm Hg after 64 (range, 40 to 115) mins. Mean difference in cerebral perfusion pressure change between the groups (HSS - normal saline) was 5.4 mm Hg (95% confidence interval, 2.2 to 8.6; p = .002), and mean difference in cardiac index change, measured as the area under the curve for the whole study period, corresponded to 0.2 L.min.m (95% confidence interval, 0.03 to 0.4; p = .025). In this placebo-controlled study involving spontaneous subarachnoid hemorrhage patients with normal to moderately increased ICP, 2 mL/kg HSS reduced ICP and increased cerebral perfusion pressure significantly. Maximum effect was reached at twice the infusion time of 30 mins. There were also beneficial hemodynamic effects with increased cardiac index in the HSS group.

Relationship between respiratory symptoms and medical treatment in exacerbations of COPD

Exacerbations of chronic obstructive pulmonary disease (COPD) can be defined symptomatically or by healthcare contacts, yet the relationship between these events is unknown. Data were collected during a 1-yr study of the budesonide/formoterol combination in COPD patients, where exacerbations, defined by increases in treatment, were compared with daily records of respiratory symptoms, rescue medication use and peak expiratory flow (PEF). The relationship between changes in these variables and the medical event was examined using different modelling approaches. Data from the first exacerbation treated with oral corticosteroids and/or antibiotics and/or hospitalisation (event based) were available in 468 patients. Patients exacerbating were significantly more breathless and more likely to report cough than healthy patients, but did not differ in baseline spirometry. Exacerbations defined by changes in individual symptoms were only weakly related to event-based exacerbations; however, defined with 63% of such events being predicted from symptom changes. Changes in rescue medication use or PEF were poor predictors of event-based exacerbations. The mean peak change in symptoms was closely related to the onset of therapy. In conclusion, event-based exacerbations are a valid way of identifying acute symptom change in a chronic obstructive pulmonary disease population. However, daily symptom monitoring is too variable using the current diary cards to make individual management decisions.

Lutein and β-carotene from lutein-containing yellow carrots are bioavailable in humans

Lutein is a hydroxy-carotenoid constituting the macular pigment of the human retina. Increasing lutein intake from foods could increase the density of this pigment and decrease the risk of developing macular degeneration. Yellow carrots are a novel food source that could increase lutein consumption. We evaluated and compared lutein uptake and clearance in humans from genetically selected lutein-containing yellow carrots fed chronically and from a lutein supplement. Four women and 5 men aged 23-28 y participated in this randomized, blinded, 3 x 3 crossover intervention. Treatments consisted of yellow carrots (YC treatment, 1.7 mg lutein/d), white carrots as a negative control (WC treatment, 0 mg lutein/d), and a lutein supplement in oil as a positive control (LS treatment, 1.7 mg lutein/d). Each treatment lasted 7 d and was followed by a 7-d washout period. Mean (+/- SD) peak changes in serum lutein concentration from baseline were 0.31 +/- 0.08, 0.19 +/- 0.08, and -0.04 +/- 0.04 micromol/L for the LS, YC, and WC treatments, respectively. The areas under the curve for 0-14 d (AUC(0-14d)) differed significantly (P < 0.0001) between treatments. Lutein from the YC treatment was 65% as bioavailable as that from the LS treatment. The AUC(0-14d) for beta-carotene (-0.01 +/- 0.28 micromol.d/L) also showed that the YC treatment maintained peak serum beta-carotene concentrations at 0.35 +/- 0.30 micromol/L, whereas the LS treatment did not (AUC(0-14d) = -0.71 +/- 0.59 micromol.d/L). Lutein from this novel food source significantly increases serum lutein concentrations and does not result in the decrease in beta-carotene concentrations that accompanies administration of lutein supplements.

Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

The CRH test is in widespread use for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Despite the greater availability worldwide of human-sequence CRH (hCRH), there are no large series reporting the response criteria that best discriminate between Cushing's disease (CD) and the ectopic ACTH syndrome (EC) when using hCRH, rather than ovine-sequence CRH. We have, therefore, analyzed retrospectively the serum cortisol and plasma ACTH responses to hCRH in patients with ACTH-dependent CS, to develop response criteria that best discriminate between CD and EC. One hundred fifteen consecutive patients with proven ACTH-dependent CS were studied: 101 with CD (78 females; mean age, 40 yr; range, 10-73) and 14 with EC (7 females; mean age, 46 yr; range, 32-69). The response to hCRH was also studied in 30 normal volunteers (NVs; mean age, 29 yr; range, 20-44) with no clinical evidence of CS, and the results were compared. Following basal sampling at -15 and 0 min, hCRH (100 microg iv) was administered via an indwelling forearm cannula at 0900 h and serum cortisol and ACTH were measured at 15-min intervals for 2 h. The mean basal, peak, incremental, and percentage change in the serum cortisol and ACTH at all time points, and combination of time points, were calculated and analyzed to establish the best criteria to discriminate between CD and EC, and also between CD and NVs. The mean serum cortisol concentration in samples obtained at 15 and 30 min after CRH increased by at least 14% above the mean basal in 85 of 100 patients with CD, but in none with EC, giving a sensitivity of 85% at a specificity set at 100%. In contrast, the best plasma ACTH response of a rise of 105%, calculated from the maximal rise, gave only 70% sensitivity at 100% specificity. In the NVs, the maximum cortisol at the mean 15+30 min time point was 615 nmol/liter. Using the 15 and 30 min time points as the reference point, 71 of 100 patients with CD had a rise of serum cortisol greater than 14% and also showed an absolute cortisol level more than 615 nmol/liter. Serum cortisol responses to hCRH can be used to suggest the diagnosis of CD in the majority of patients with this condition, but it should only be used in conjunction with other biochemical and imaging modalities in establishing this important diagnosis. The measurement of plasma ACTH was less helpful in making this distinction, although it may have additional value in excluding ACTH-independent causes of CS. Although we believe that bilateral inferior petrosal sinus sampling remains the single most useful test in discriminating CD from EC in patients with ACTH-dependent CS, hCRH offers rapid diagnostic information and is a useful adjunctive test in establishing the presence of a possible ectopic source.

Responses To Yohimbine in Social Phobia

A recent report by Tancer et al.(1993) observed that the growth hormone response to clonidine was blunted in social phobics relative to controls. The current project aimed to further evaluate NE functioning in social phobia (SP) patients by administration of an IV challenge dose of the alpha 2 adrenoreceptor antagonist, yohimbine. METHOD: Six medication-free patients with a principal DSM-III-R diagnosis of SP (4 males, 2 females), without a history of spontaneous panic attacks, participated in the protocol. Two of the six patients met criteria for the specific SP subtype. Patients received 2 challenge tests approximately 1 week apart. On one test day yohimbine 0.4 mg/kg IV was infused, while a saline placebo was administered on the second day. Tests were administered in a double-blind, balanced manner. Within challenge measures included the Social Anxiety Questionnaire (SAQ) (0-10 intensity scale), a clinician-rated instrument designed to be sensitive to changes in social anxiety symptoms and a visual analog anxiety scale (VAS) rated by patients (0-100 mm scale). In addition blood samples were drawn serially for analysis of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). RESULTS: The mean peak change from baseline score in SAQ intensity was = 2.8±1.6 during the yohimbine test and = 0±0 (paired t-test t=3.8, df=4, p<0.05) during the placebo. The mean peak change±SD from baseline score in VAS anxiety was =10±12 mm for yohimbine vs 3±11 mm for placebo (t=0.89, df=5, p=0.42). Peak behavioral effects were noted 15 minutes post-yohimbine infusion. Peak change scores for plasma MHPG were = 2.1±0.9 ng/ml following yohimbine vs 0.7±0.9 ng/ml following placebo (t=2.7, df=4, p<0.06). CONCLUSIONS: These data suggest that yohimbine exacerbates social anxiety intensity and that this behavioral change is paralleled by concomitant increases in plasma levels of the NE metabolite, MHPG. Presynaptic dysfunction in the brain NE system may play a role in the pathophysiology of social phobia. Further studies are indicated to delineate the nature of this abnormality and its implications for treatment.

Absence of emergent suicidal ideation during treatment: A comparative, controlled, double‐blind analysis employing several distinct antidepressants

AbstractWe investigated 243 patients from a series of comparator and/or placebo‐controlled, double‐blind trials of several mechanistically distinct antidepressants. Data were analyzed for changes in suicidal ideation during trial participation.Ambulatory referrals with a current DSM‐III‐R major depression, corroborated by a structured interview, were screened; those fulfilling entrance criteria began a 1‐week, single‐blind placebo run‐in. Pool 1 (placebo comparator) subjects who continued to meet entrance criteria at their baseline visit were blindly randomized to receive either placebo (n = 49) or one of several novel antidepressant drugs (n = 81). Pool 2 subjects (active comparator) were randomized to either a novel antidepressant (n = 66) or a tricyclic antidepressant comparator (n = 57). Trial duration ranged from 5 to 8 weeks. Patient compliance was monitored by a regular pill count from each subject's blister pack.Analyses were conducted on Pool 1 and Pool 2 separately. Ego‐dystonic suicidal preoccupation or acts were not reported in either group. There was a statistically significant treatment difference in Hamilton Depression Rating Scale item 3 mean peak change (Pool 1); patients treated with a novel antidepressant demonstrated a mean decrease in HDRS item 3 (improvement), those patients randomized to placebo experienced a mean score increase (worsening). No statistically significant treatment difference in mean peak change difference factors (CDFs) between the novel antidepressants and conventional tricyclic antidepressant comparators (Pool 2) was observed. A statistically significant correlation between item 3 change and total HDRS‐17 change also emerged (both treatments within each pool).Increased suicidal ideas/behaviors may emerge during depression “treatment.” However, in this study it occurred more frequently among placebo recipients, suggesting a change in suicidal ideation was a reflection of the underlying disease process. Not surprisingly, antidepressants improved suicidal ideation to a greater extent than placebo. Depression 2:73–79 (1994). © 1994 Wiley‐Liss, Inc.

A Simple and Reliable Technique to Monitor Intracranial Pressure in the Rat

A technique for intracranial pressure (ICP) monitoring in the rat that uses a permanent cisterna magna cannula is described. The cannula is placed into the subarachnoid space through the atlanto-occipital membrane with the operating microscope and is secured with cement. The distal end is connected to a pressure transducer and a polygraph recorder. To study the consistency of this technique, 12 anesthetized adult rats were subjected to baseline ICP measurements 2 days after placement of the cannula. Baseline pressures ranged between 1.0 and 10.0 cm H2O, with a mean of 5.6 cm H2O. Respiratory variations were detected in all tracings, and manual abdominal compressions (Valsalva maneuver) correlated with immediate transient rises in ICP in all rats. While CSF pressure was being continuously monitored, rats were subjected to subarachnoid hemorrhage induced by transclival basilar artery puncture. Of the 12 rats, 10 showed a moderate transient rise in cerebrospinal fluid pressure, which peaked approximately 2 minutes after subarachnoid hemorrhage (mean peak change, 10.5 cm H2O; range, 0-32.5 cm H2O). Reliable pressure tracings were obtained in three of five animals examined 3 days after subarachnoid hemorrhage (ICP range, 4.0-4.5 cm H2O; mean, 4.2 cm H2O). We conclude that this cannula is easy and inexpensive to construct and that it provides reliable ICP tracings during experimental procedures in the rat.

NALOXONE‐INDUCED ACTH RELEASE IN MAN IS INHIBITED BY CLONIDINE

1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the alpha 2-adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone-induced ACTH secretion in normal human volunteers. 2. There was a significant blunting of the mean peak level of ACTH and the mean peak change of ACTH from basal as well as the area under the ACTH-time curve when clonidine was given prior to naloxone. 3. We conclude that clonidine, by blocking central noradrenergic pathways, which stimulate corticotropin-releasing hormone secretion, inhibits naloxone-induced ACTH secretion. This suggests that naloxone causes ACTH release through these same central noradrenergic pathways.

POTENTIATION OF FENFLURAMINE‐INDUCED ACTH RELEASE IN MAN BY NALOXONE

1. This study set out to compare the effect of the combination of fenfluramine (Fen) and naloxone (Nal) on ACTH and cortisol release with each of these agents alone in six normal volunteers. Three protocols were used: 1.5 mg/kg bodyweight oral Fen; 125 micrograms/kg bodyweight i.v. Nal; oral Fen plus i.v. Nal 135 min later. Plasma ACTH and cortisol were measured at intervals of 285 min over each test. 2. The mean peak levels and mean peak changes from basal in plasma ACTH and cortisol were significantly greater in the combination test (Fen/Nal) than in either the Fen alone or the Nal alone tests. Fen and Nal given together cause a synergistic release of ACTH and cortisol as determined by the areas under the ACTH-time and cortisol-time curves for Fen/Nal compared to the sums of Fen alone plus Nal alone curves for ACTH and cortisol. 3. We conclude that Fen and Nal acting synergistically work through different and potentiating mechanisms at the hypothalamic, central nervous system and/or pituitary levels to cause ACTH release.

NIFEDIPINE BLOCKS ACTH AND CORTISOL RELEASE IN MAN

1. The present study investigated the effect of prior administration of nifedipine on AVP-induced ACTH release in seven normal volunteers. Three protocols were used: 20 mg oral nifedipine; 0.14 pressor units intramuscular (i.m.) per kg bodyweight aqueous AVP; oral nifedipine plus i.m. AVP 90 min later. Plasma ACTH and cortisol were measured at intervals for 2.5 h during each test. 2. The mean peak plasma ACTH and cortisol levels and the mean peak changes from basal in these levels were significantly lower in the nifedipine/AVP test than in the AVP alone test. The integrated area under the cortisol time curve was significantly lower for the nifedipine/AVP test than that for the AVP test alone. Nifedipine alone caused no changes in ACTH or cortisol. 3. Acute administration of oral nifedipine caused an inhibition of AVP-stimulated ACTH and cortisol release in normal humans. This effect may be due to blockade of plasma membrane calcium channels normally activated during AVP stimulation of pituitary corticotrophs.

Single-dose and dose-response studies with oral pirbuterol, a new beta agonist in chronic heart failure

The hemodynamic effects of pirbuterol (PBL), an orally effective beta agonist that combines vasodilator and inotropic properties, were studied in 41 patients with severe congestive heart failure (CHF), New York Heart Association functional class III or IV. Single-dose studies were carried out in 12 patients to determine the magnitude and time course of the effects of PBL. Six patients received orally a single dose of 10 mg, and six received 20 mg. Measurements were made half hourly from control for 6 hours. Incremental-dose studies consisting of three sequential doses given at 1.5-hour intervals were carried out in 29 patients to determine the dose-response relationship. Nine of these patients received a low-dose regimen (PBL, 7.5, 7.5, and 15 mg orally), and 20 received a high-dose regimen (PBL, 10, 10, and 20 mg). Measurements were made every 1.5 hours from control for 6 hours. Blood samples for PBL concentration were taken hourly in the single-dose studies and every 1.5 hours in the incremental-dose studies. Single-dose studies showed that acute administration of PBL orally to patients with chronic CHF significantly improved hemodynamic performance without changes in heart rate or blood pressure. Control values were cardiac index (CI) 2 ± 0.1 L · min −1 · m −2, stroke index (SI) 21 ml · beat · m −2, left ventricular filling pressure (LVFP) 28 ± 4 mm Hg, and systemic vascular resistence (SVR) 1870 ± 130 dynes · sec · cm −5. The onset of action was rapid, and significant effects (p < 0.05 to 0.01) were found within 0.5 hours and persisted to 5.5 hours; mean peak changes were CI +45%, SI +45% LVFP −28%, and SVR −27%. Incremental-dose studies showed that increasing dose produced an increase in plasma PBL concentrations and CI; a dose of 20 mg is likely to be optimal. Because PBL is effective, well tolerated, and combines vasodilator and positive inotropic actions, it may have advantages over other drugs in chronic CHF treatment.