Nitrous oxide may interfere with the reconsolidation of drinking memories in hazardous drinkers in a prediction-error-dependent manner.

Weakening drinking-related reward memories by blocking their reconsolidation is a potential novel strategy for treating alcohol use disorders. However, few viable pharmacological options exist for reconsolidation interference in humans. We therefore examined whether the NMDA receptor antagonising gas, Nitrous Oxide (N2O) could reduce drinking by preventing the post-retrieval restabilisation of alcohol memories in a group of hazardous drinkers. Critically, we focussed on whether prediction error (PE; a key determinant of reconsolidation) was experienced at retrieval. Sixty hazardous drinkers were randomised to one of three groups that retrieved alcohol memories either with negative PE (Retrieval + PE), no PE (Retrieval no PE) or non-alcohol memory retrieval with PE (No-retrieval +PE). All participants then inhaled 50% N2O for 30 min. The primary outcome was change in beer consumption and alcohol cue-driven urge to drink from the week preceding manipulation (baseline) to the week following manipulation (test). The manipulation did not affect drinking following the intended retrieval+/- PE conditions However, a manipulation check, using a measure of subjective surprise, revealed that the group-level manipulation did not achieve the intended differences in PE at retrieval. Assessment of outcomes according to whether alcohol-relevant PE was actually experienced at retrieval, showed N2O produced reductions in drinking in a retrieval and PE-dependent fashion. These preliminary findings highlight the importance of directly testing assumptions about memory reactivation procedures in reconsolidation research and suggest that N2O should be further investigated as a potential reconsolidation-blocking agent.

A meta-analysis of randomized, double-blind, placebo-controlled studies of the effect of buflomedil on intermittent claudication.

A meta-analysis was performed on the results of clinical trials of buflomedil in intermittent claudication. The analysis used results from 744 patients enrolled in ten studies, conducted at 42 centers in seven countries. All studies were randomized, double-blind, placebo-controlled trials which measured improvement in "pain-free" walking distance by treadmill ergometry as the primary measure of efficacy. The meta-analysis results were based on "effect size", a standardized difference in mean response between buflomedil and placebo. Results demonstrated a statistically superior response to buflomedil compared with placebo, indicating that the average buflomedil treated patient was likely to have a greater improvement in walking distance than at least 60% of the placebo treated patients. Results were corroborated using various weighting schemes proportional to study quality ratings and sample sizes.

Placebo-controlled study of terazosin in the treatment of benign prostatic hyperplasia with 2-year follow-up.

This randomised, placebo-controlled, double-blind study was performed to evaluate the efficacy and safety of once-a-day terazosin (10 mg/d) in ambulatory patients (n = 57) with benign prostatic hyperplasia (BPH). After a 4-week placebo lead-in and a 24-week treatment period with terazosin (with both phases being single-blind), 30 patients who responded to terazosin were randomly assigned to either the terazosin or placebo treatment group for 12 weeks. During the single-blind treatment period, the peak urine flow rate increased 54% from a baseline average of 7.76 ml/s to 11.92 ml/s after terazosin administration; the mean flow rate increased 55% from a baseline of 4.90 ml/s to 7.59 ml/s; and the residual volume decreased 56% from 93.1 ml to 40.7 ml. The mean obstructive symptom score, irritative symptom score and physician global assessment score improved by 68%, 34% and 27%, respectively. All these changes were significant when compared with baseline values. During the double-blind period, the improvement in all the variables was sustained in the terazosin group but not in the placebo group. Peak and mean urinary flow rates, and physician assessment showed significant differences at the end of the double-blind period. Adverse events occurred only during the single-blind period. The most frequently experienced events were headache (n = 6), asthenia (n = 3) and hypotension (n = 3). A follow-up study that initially included 12 patients showed no significant loss of improvement in symptoms and no change in urodynamic parameters with the 5 mg terazosin dose at 1 year. At 2 years, the 9 remaining patients showed sustained improvement and no signs of tachyphylaxis.

Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial.

This randomized, placebo-controlled, double-blind study was performed to evaluate the efficacy and safety of once-a-day terazosin (10 mg/day) in ambulatory patients (n = 57) with benign prostatic hyperplasia (BPH). After a 4-week placebo lead-in and a 24-week treatment period with terazosin (both single-blind), 30 patients who responded to terazosin were randomly assigned to either the terazosin or placebo treatment group for 12 weeks. During the single-blind treatment period, the peak urine flow rate increased 54% from a baseline average of 7.76 ml/sec to 11.92 ml/sec after terazosin; the mean flow rate increased 55% from a baseline of 4.90 ml/sec to 7.59 ml/sec; and the residual volume decreased 56% from 93.1 ml to 40.7 ml. The mean obstructive symptom score, irritative symptom score and physician's global assessment score improved by 68%, 34% and 27%, respectively. All these changes were significant (P less than 0.05) when compared to baseline values. During the double-blind period, the improvement in all the variables was sustained in the terazosin group but not in the placebo group. Peak and mean urinary flow rates, and physician's global assessment showed significant (P less than or equal to 0.05) differences at the end of the double-blind period. Adverse events occurred only during the single-blind period. The most frequent were headache (n = 6), asthenia (n = 3), and hypotension (n = 3). In summary, terazosin administered once-a-day improved the obstructive and irritative symptoms of BPH, urine flow rates and residual volume. Terazosin was well tolerated.

Non-invasive tests of neurovascular function: reduced axon reflex responses in diabetes mellitus of man and streptozotocin-induced diabetes of the rat.

The prevalence of neuropathy and microangiopathy complicating diabetes mellitus led to our development of non-invasive tests of neurovascular function. On the foot dorsum of consenting normal subjects, diabetic patients, normal and streptozotocin-induced (STZ) diabetic rats, transcutaneous electrical nerve stimulation (TENS) with 1, 2, 4, 8, 16 pulses at 150 V, 0.75 ms, at 2 Hz, evokes transient cutaneous axon reflex vasodilatation measured by a laser Doppler (Periflux Pfld). This tests the integrity of both the polymodal nociceptor/primary afferent nerves and microvessels in the skin. TENS-evoked axon reflexes are reduced in diabetics (particularly with neuropathy) and progressively in rats 40-100 days after STZ administration. This could be reversed in rats by a single injection of 3 units of soluble insulin at 100 days post STZ. The microvascular endothelium and smooth muscle are tested in man by measuring vasodilatation induced by iontophoretic application of 2 mC acetylcholine (ACh) and 4 mC sodium nitroprusside (NaNP), respectively. Diabetics show reduced ACh-evoked endothelium-dependent vasodilator responses, but the direct smooth muscle (endothelium-independent) responses evoked by NaNP are not reduced. Such functional neurovascular disturbances probably underlie many complications of diabetes mellitus, and the potential for these to be reversible with appropriate therapy can now be examined with such neurovascular tests.

Non-invasive tests of neurovascular function.

This paper describes the value of non-invasive neurovascular function tests in the clinical setting. Painful transcutaneous electrical nerve stimulation (TENS) of the dorsum of the foot evoked axon reflex vasodilatation, measured by laser Doppler flowmetry. In addition, acetylcholine and sodium nitrite (NaNO2) were iontophoresed to cause vasodilatation by endothelium-dependent and -independent mechanisms, respectively. Compared with healthy volunteers, diabetic patients with clinically diagnosed neuropathy showed reduced electrical axon reflex flare responses. These responses in one additional subject were absent in a region of denervated skin. Acetylcholine responses, but not NaNO2 responses, were also depressed in patients with diabetic neuropathy. Such reduced cutaneous nocifensor functions may contribute to some symptoms and complications of diabetes mellitus.