Long-term Open-label Study Research Articles

Is treatment of cervical dystonia patients with botulinum toxin type B affected by a previous response to a botulinum toxin type A? Analysis of a long-term open-label study (AN072-401 EU/CD)

Objective: To evaluate the effects of previous response to botulinum toxin (BoNT) type A treatment on long-term BoNT-B therapy in patients with cervical dystonia (CD). Methods: BoNT-B-naive CD patients previously exposed to BoNT-A were enrolled in this 2-year open-label study. Patients were classified as BoNT-A-resistant (AR) or non-A resistant (NAR). All received an initial dose of 10,000 U BoNT-B; Investigators could subsequently increase/decrease the dose (maximum 25,000 U). Efficacy was assessed via a Patient Global Visual Analogue Scale (VAS) and a Treatment Assessment Scale (TAS). Safety was assessed by evaluating adverse events (AEs), clinical laboratory data and vital signs. Results: 130 BoNT-B naive patients (67 AR; 63 NAR) were enrolled. The mean dose of BoNT-B at treatment session 7 was not statistically different between AR and NAR groups (17,949 U vs. 17,256 U). There was no statistical difference between number of AR and NAR patients who withdrew from the study (29 vs. 26). Overall, BoNT-B treatment resulted in a statistically significant benefit at Week 4 following each injection in the Patient Global VAS and the TAS during the 2-year period. Regression analysis revealed no statistically significant differences between treatment response in the AR and NAR groups for Patient Global VAS or TAS. No study drug-related serious AEs were reported. No statistically significant differences in reports of moderate or severe xerostomia, dysphagia, or injection site pain occurred between AR and NAR groups. Conclusions: Prior response to BoNT-A does not affect the efficacy or safety profile of long-term BoNT-B treatment of CD patients. Supported by Eisai Europe Ltd.

(277) A multicenter open-label long-term study of the safety of NGX-4010 for the treatment of neuropathic pain in patients with painful HIV-distal sensory polyneuropathy (HIV-DSP) or postherpetic neuralgia (PHN)

(277) A multicenter open-label long-term study of the safety of NGX-4010 for the treatment of neuropathic pain in patients with painful HIV-distal sensory polyneuropathy (HIV-DSP) or postherpetic neuralgia (PHN)

Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies?

A review of long-term open-label studies was performed with the aim of detecting differences in efficacy and/or tolerability of new antiepileptic drugs (AEDs). From more than 500 open studies conducted to evaluate the efficacy and tolerability of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM) or zonisamide (ZNS), we selected all studies that reported or allowed us to calculate the number of patients who achieved seizure freedom for 6 months and/or the number of patients withdrawing for adverse effects and/or the number or percentage of patients continuing treatment after 1 year. No studies were found in which this information was available for OXC, PGB, TGB or ZNS. The number of patients who achieved seizure freedom for 6 months was reported in four studies each for GBP and TPM, five studies for LTG, and eight studies for LEV. The best efficacy profile using this end point was found for LEV, followed by TPM, LTG, and GBP. Twenty-two studies reported the number of patients withdrawing due to adverse effects. LEV was the best-tolerated AED, a little ahead of LTG, and significantly better than GBP or TPM . TPM was by far the least well-tolerated drug. Information concerning patients continuing treatment after 1 year was reported in two GBP studies, two TPM studies, six LEV studies and five LTG studies. GBP had a very low retention rate (between 20% and 25% of patients continued the drug), while TPM and LTG had a retention rate of 40-60% and LEV had a retention rate of 60-75%. One limitation of these rankings is that their statistical value is limited because of the indirect nature of the comparisons. Anyhow, this review covers the main studies published thus far on this subject and provides full updated information on the current literature about these drugs.

Comparison of the Efficacy and Safety of 0.1% Tacrolimus Ointment with Topical Corticosteroids in Adult Patients with Atopic Dermatitis

Tacrolimus (FK506) ointment is widely used in the treatment of patients with atopic dermatitis. The drug exerts its action by down-regulating antigen-specific T-cell activities and associated proinflammatory cytokine production. A number of clinical studies have evaluated the efficacy and safety of 0.1% tacrolimus ointment compared with vehicle or topical corticosteroids in adult patients with atopic dermatitis. These studies have suggested that topical tacrolimus has a rapid onset of action and exerts sustained therapeutic effects, with an efficacy similar to that of moderate to potent topical corticosteroids, but without causing skin atrophy. Two phase III randomised, controlled clinical trials have been conducted in Japanese adult patients with atopic dermatitis to compare the efficacy and safety of topical 0.1% tacrolimus with topical corticosteroid ointments. In the first study, patients with moderate or severe atopic dermatitis on the trunk and extremities were randomised to 3 weeks of treatment with topical 0.1% tacrolimus or the mid-potency topical corticosteroid 0.12% betamethasone valerate. Over 90% of the patients in each study group experienced at least a moderate improvement at the end of the study. In the second study, patients with moderate or severe atopic dermatitis on the head or neck were randomised to 1 week of treatment with 0.1% tacrolimus or the mild-potency corticosteroid 0.1% alclometasone dipropionate. Significantly greater improvements in individual symptom scores were observed with topical tacrolimus compared with alclometasone dipropionate, with overall global improvement at 1 week being statistically superior with tacrolimus. Furthermore, in a long-term open-label study involving 568 patients, at least a moderate global improvement in symptoms was observed in 85% of patients at 6 weeks, increasing to 91% at both 26 weeks and 52 weeks; this rate was maintained throughout the 2-year duration of the study. 0.1% tacrolimus ointment was considered to be safe in the majority of patients. The most prevalent adverse reactions were local application site irritations, which generally resolved with continued therapy. In summary, these findings suggest that 0.1% tacrolimus ointment is an effective and safe nonsteroidal alternative therapy for adult patients with atopic dermatitis.

Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes

The anti-anginal efficacy and safety of ranolazine in diabetic and non-diabetic patients included in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial (JAMA 2004;291:309) were studied. Glycaemic control was also assessed in CARISA and its long-term open-label extension study. Patients with chronic angina enrolled in CARISA (189 with diabetes, 634 without diabetes) on background atenolol, diltiazem, or amlodipine therapy were randomized to placebo, ranolazine 750 or 1000 mg twice daily for 12 weeks, during which exercise tolerance, angina frequency, nitroglycerin usage, glucose, HbA(1c), and lipids were measured. Patients completing the randomized study could enroll in an ongoing open-label extension study and were evaluated every 3 months. Ranolazine produced similar improvements in exercise parameters, nitroglycerin use, and angina frequency in diabetic and non-diabetic patients. Adverse events were similar between groups. Fasting glucose and lipids remained unaltered in diabetic patients after 12 weeks of therapy. In a post hoc analysis, ranolazine 750 and 1000 mg reduced HbA(1c) vs. placebo by 0.48+/-0.18% (P=0.008) and 0.70+/-0.18% (P=0.0002), respectively; the HbA(1c) levels appeared to remain unchanged over time during long-term therapy. Anti-anginal efficacy and safety of ranolazine for angina were similar between diabetic and non-diabetic patients. Ranolazine significantly improved glycaemic control in diabetic patients.

Defining success in clinical trials – profiling pregabalin, the newest AED

The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been established by four randomized, 12-week, double-blind, placebo-controlled trials (n = 1396) and four long-term open-label studies (n = 1480). Patients in the three fixed-dose trials were >/=12 years of age, had >/=6 partial seizures and no 4-week seizure-free period during the 8-week baseline period. Seventy-three per cent of patients were taking >/=2 concomitant antiepileptic drugs. Responder rates across the effective doses (150-600 mg/day) ranged from 14% to 51% and demonstrated a significant dose-response relationship. The most common adverse events were central nervous system related, generally mild or moderate, transient, and tended to be dose related. The fourth placebo-controlled trial compared a fixed dose of pregabalin 600 mg/day with a flexible-dose regimen (150-600 mg/day). Responder rates were greater for both the fixed dose (45.3%, P < 0.001) and flexible dose (31.3%, P < 0.001) when compared with placebo (11.0%). Compared with the fixed-dose group, the flexible-dose patients had a lower incidence of adverse events and study discontinuations. In long-term open-label trials, the efficacy of pregabalin was maintained with respect to 50% responder rates suggesting no obvious tolerance developing over 2 years. Seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment, respectively. Long-term open-label pregabalin treatment was well tolerated.

Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study

The present study reports the results of an open-label trial on the use of the combination of olanzapine (an atypical antipsychotic) serotonin reuptake inhibitors (SRIs) in 26 resistant outpatients affected by resistant obsessive-compulsive disorder (OCD). All patients had been suffering from OCD, according to DSM IV criteria, for at least 2 years and had different comorbid disorders; they had been treated with an SRI at adequate dosages for at least 6 months, or had tried different augmentation strategies with no or poor response. As a result, olanzapine was added and continued for 1 year. After 12 weeks of this regimen, most of the patients (17) had shown a reduction in OC symptoms, as assessed by a decrease in the Yale-Brown Obsessive Compulsive Scale total score, which continued throughout subsequent months. Only mild side-effects were recorded and no patient halted the treatment. The addition of olanzapine would appear to be a useful short- and long-term strategy for augmenting SRI effectiveness in resistant OCD patients, especially in those presenting comorbidity with bipolar disorders.

Correspondence of parent and teacher reports in medication trials

Although much has been written about the agreement of parents and teachers regarding the diagnosis of attention-deficit/hyperactivity disorder (ADHD), some uncertainty remains about their agreement when assessing change during drug treatment. To address this issue, we analyzed data from a placebo-controlled short-term study and an open-label long-term study of ADHD children treated with OROS methylphenidate (MPH). Both reporters agreed that OROS MPH was efficacious for symptoms of inattention/overactivity and oppositionality/defiance and that the effect was greater for inattention/overactivity than oppositionality/defiance. Thus, in clinical trials, having two reports may not be absolutely essential for assessing the efficacy of ADHD medications. We also computed diagnostic efficiency statistics and found a high probability that parents would confirm teacher reports of therapeutic improvement and a somewhat lower probability that teachers would confirm parent reports of therapeutic improvement. In contrast, neither reporter was likely to confirm the other reporter's report of no improvement or worsening. Thus, when given a report of no improvement from one setting, clinicians cannot be certain about clinical status in the other setting. For symptoms of oppositionality and defiance, we also saw that parent- teacher agreement about improvement was better than agreement about lack of improvement. However, for these symptoms, teacher reports were somewhat better predictors of parent reports than vice-versa.

Long-Term Open-Label Solifenacin Treatment Associated with Persistence with Therapy in Patients with Overactive Bladder Syndrome

Objective: To examine safety and tolerability findings as primary endpoints, and efficacy outcomes as secondary endpoints, of solifenacin treatment over a period of up to 1 year. Long-term efficacy in the treatment of overactive bladder (OAB) syndrome depends in part on the patient's persistence with pharmacologic therapy. Agents with a favourable therapeutic index supporting high levels of patient satisfaction and persistence are needed. Methods: The present study was a 40-week open-label extension of two 12-week, placebo-controlled, double-blind studies of solifenacin treatment in patients with OAB. Patients who completed the 12-week studies were offered participation in the open-label extension study. All patients who entered the open-label extension study initially received solifenacin 5 mg daily for 4 weeks, after which a flexible dosing regimen allowed patients to individualise their treatment (5 mg or 10 mg) at each of the 3 study visits. Safety and tolerability assessments (the primary variable) included adverse event reporting. Efficacy data were collected from micturition diaries completed at weeks 16, 28, 40, and 52. Results: Ninety-one percent (1637/1802) of patients who completed the two 12-week randomised studies chose to participate in the long-term open-label extension study. A total of 81% of patients completed 40 weeks of open-label treatment. Solifenacin treatment was safe and well tolerated, and rates of anticholinergic side effects were relatively low. Only 4.7% of patients discontinued treatment owing to adverse events. Improvements in major symptoms of OAB were noted for all patients for up to 52 weeks of treatment. In patients randomised to solifenacin in the double-blind studies, there were small incremental improvements in all efficacy parameters (reductions in episodes per 24 hours of urgency, reductions in frequency and urge incontinence, and increases in volume voided per micturition) over the course of the extension study. Efficacy was confirmed when outcomes were assessed as a function of total solifenacin exposure. Patient satisfaction with solifenacin tolerability (85%) and efficacy (74%) were high. These results indicate that long-term treatment with solifenacin was well tolerated and associated with improvements in efficacy parameters based on patient diary data recorded over the 12-month treatment period. Moreover, the high level of patient satisfaction reported appeared to correlate well with the quantified improvements in key symptoms demonstrated in this study. Conclusions: Long-term therapy with solifenacin resulted in a favourable tolerability profile, and was associated with improvements in efficacy parameters based on diary data recorded over a 12-month period. This balance of tolerability and efficacy with solifenacin was associated with excellent persistence with therapy. These results suggest that solifenacin may be useful for the long-term treatment of the chronic symptoms associated with OAB.

CLINICAL EXPERIENCES WITH DESMOPRESSIN FOR LONG-TERM TREATMENT OF NOCTURIA

To our knowledge we report the first long-term use of desmopressin for nocturia. Patients previously responding to desmopressin in short-term studies were enrolled in this long-term open label study. Patients received treatment for 10 or 12 months with the optimal desmopressin dose (0.1, 0.2 or 0.4 mg orally at bedtime). Patients were followed a further month without treatment. Of the patients completing the short-term study 132 males (92%) and 117 females (83%) were recruited, and 95 (72%) and 87 (75%), respectively, completed long-term treatment. The mean number of nocturnal voids was decreased in males and females throughout the study (1.3 to 1.6 and 1.2 to 1.3) compared with baseline (3.1 and 2.9, respectively). After followup the number of voids increased after treatment cessation. From baseline to 12 months the mean duration of the first sleep period gradually increased in males (157 to 288 minutes) and females (142 to 310 minutes). After followup the mean duration of the first sleep period decreased, confirming that it was a treatment related benefit. Desmopressin was well tolerated with few males (14%) or females (10%) withdrawing due to adverse events. Most adverse events were mild (44%) or moderate (44%) in severity. Four males experienced serious drug related adverse events, namely dizziness in 1, cardiac failure, headache and vomiting in 2, and chest pain and hypertension in 1. A female experienced 4 serious drug related adverse events, that is hyponatremia, headache, nausea and vertigo. Two patients had clinically significant hyponatremia. This long-term study shows that desmopressin is a generally well tolerated and effective treatment for nocturia.

Review of United States and European clinical trials of zonisamide in the treatment of refractory partial-onset seizures

Zonisamide is an antiepilepsy drug (AED) with both sodium and calcium channel-blocking properties. This dual mechanism may predict efficacy in some refractory patients, and a broad spectrum of action against different seizure types. Zonisamide has been commercially available in Japan since 1989, and became available in the United States for treatment of adults over the age of 12 with partial–onset seizures in March 2000. Several multicenter clinical trials have been conducted in the United States over the past 15 years. These have included three double-blind, placebo-controlled trials as well as long-term open-label studies. Zonisamide was characterized in these studies as a safe and effective adjunctive treatment for partial-onset seizures. Zonisamide has not yet been studied in the United States as an initial monotherapy, but in one long-term study, some patients were able to discontinue other AEDs and successfully transition to monotherapy. The most frequently reported adverse events were somnolence, dizziness, and anorexia. Current United States labeling states that 12 patients with epilepsy receiving zonisamide had symptomatic kidney stones; however, after more than a dozen years of zonisamide use in Japan, the incidence of kidney stones associated with zonisamide remains low.

Opioids in non-cancer pain: Impact of AVINZA on sleep in patients with osteoarthritis pain: the long-term treatment assignment compared to short-term treatment

Patients with pain due to osteoarthritis demonstrated improvements in sleep parameters during a previously reported long-term (26-week) study evaluating once-daily administration of Avinza (morphine-sulfate extended release) capsules. Patients had received 4 weeks of double-blind therapy with once-daily Avinza (AM or PM) or MS Contin BID active therapy (total daily dose of 30 mg) or equivalent blinded placebo. While the total active dose was fixed during the double-blind study, dose-escalation of Avinza to maximize patient benefit was allowed during the long-term open-label study. For this study an additional analysis was conducted to verify that sleep benefits were observed in all patient groups, irrespective of the previous therapy. Patients enrolled in the long-term study (n=181) all received Avinza once-daily. Patients were categorized into three groups based on their former double-blind therapy (Avinza, MS Contin, or placebo). Changes in the responses to questions on overall quality of sleep, trouble falling asleep, awakenings due to pain in evening or morning, sleep medication use, and hours of sleep during the long-term study relative to baseline (the final assessment of the double-blind study) were determined on multiple occasions. Overall improvements in pain scores and trends for improvements in these sleep parameters were observed in all groups. The largest improvements were observed in patients who had previously received placebo therapy, e.g., “awakening in the morning due to pain” was significantly superior to baseline at weeks 1, 4, 8, and 26 of the extension. Adverse events during the open-label study were generally mild to moderate in nature: constipation, nausea, diarrhea, and somnolence. These data suggest that long-term administration of once-daily Avinza may result in persistent improvements in sleep parameters in patients with pain due to osteoarthritis. Supported by Ligand Pharmaceuticals.

Moclobemide: therapeutic use and clinical studies.

Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively studied in anxiety disorders. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression this drug is more efficacious than placebo and as efficacious as tricyclic (or some heterocyclic) antidepressants or selective serotonin reuptake inhibitors (SSRIs). There is a growing evidence that moclobemide is not inferior to other antidepressants in the treatment of subtypes of depression, such as dysthymia, endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded depression as with other antidepressants limited evidence suggests that moclobemide has consistent long-term efficacy. However, more controlled studies addressing this issue are needed. For patients with bipolar depression the risk of developing mania seems to be not higher with moclobemide than with other antidepressants. The effective therapeutic dose range for moclobemide in most acute phase trials was 300 to 600 mg, divided in 2 to 3 doses. While one controlled trial and one long-term open-label study found moclobemide to be efficacious in social phobia, three controlled trials subsequently revealed either no effect or less robust effects with the tendency of higher doses (600 - 900 mg/d) to be more efficacious. Two comparative trials demonstrated moclobemide to be as efficacious as fluoxetine or clomipramine in patients suffering from panic disorder. Placebo-controlled trials in this indication are, however, still lacking. A relationship between the plasma concentration of moclobemide and its therapeutic efficacy is not apparent but a positive correlation with adverse events has been found. Dizziness, nausea and insomnia occurred more frequently on moclobemide than on placebo. Due to negligible anticholinergic and antihistaminic actions, moclobemide has been better tolerated than tri- or heterocyclic antidepressants. Gastrointestinal side effects and, especially, sexual dysfunction were much less frequent with moclobemide than with SSRIs. Unlike irreversible MAO-inhibitors, moclobemide has a negligible propensity to induce hypertensive crisis after ingestion of tyramine-rich food ("cheese-reaction"). Therefore, dietary restrictions are not as strict. However, with moclobemide doses above 900 mg/d the risk of interaction with ingested tyramine might become clinically relevant. After multiple dosing the oral bioavailability of moclobemide reaches almost 100%. At therapeutic doses, moclobemide lacks significant negative effects on psychomotor performance, cognitive function or cardiovascular system. Due to the relative freedom from these side effects, moclobemide is particularly attractive in the treatment of elderly patients. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6, relatively few clinically important drug interactions involving moclobemide have been reported. It is relatively safe even in overdose. The drug has a short plasma elimination half-life that allows switching to an alternative agent within 24 h. Since it is well tolerated, therapeutic doses can often be reached rapidly upon onset of treatment. Steady-state plasma levels are reached approximately at one week following dose adjustment. Patients with renal dysfunction require no dose reduction in contrast to patients with severe hepatic impairment. Cases of refractory depression might improve with a combination of moclobemide with other antidepressants, such as clomipramine or a SSRI. Since this combination has rarely been associated with a potentially lethal serotonin syndrome, it requires lower entry doses, a slower dose titration and a more careful monitoring of patients. Combination therapy with moclobemide and other serotonergic agents, or opioids, should be undertaken with caution, although no serious adverse events have been published with therapeutic doses of moclobemide to date. On the basis of animal data the combined use of moclobemide with pethidine or dextropropoxyphene should be avoided. There is no evidence that moclobemide would increase body weight or produce seizures. Some preclinical data suggest that moclobemide may have anticonvulsant property.

Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks

Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority of patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective for short periods but results in the emergence of drug-resistant HBV in a substantial number of patients within 1 year of therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type and lamivudine-resistant HBV, but it is unclear whether resistance mutations will emerge after long-term therapy with this drug. To determine whether extended treatment with ADV led to the emergence of drug-resistant populations of HBV, we analyzed virus isolated from patients currently enrolled in a long-term open-label study. The reverse transcriptase domain of HBV polymerase was amplified and sequenced from patients that had received a cumulative exposure of up to 60 weeks of ADV. During our analyses, several previously unreported amino acid substitutions were observed in the reverse transcriptase domain of HBV. Importantly, none of the observed mutations occurred in more than 1 patient, nor were they associated with an adefovir-resistant phenotype in vitro. Furthermore, none of the patients from whom these mutant viruses were isolated had evidence of virologic rebound. In conclusion, these results, although based on a limited number of patients, suggest that treatment with ADV does not lead to the emergence of resistant virus after up to 60 weeks of therapy. (H EPATOLOGY 2002;36:464-473.)

Atopic Dermatitis

Atopic dermatitis is a common, chronic, relapsing cutaneous disease with typical cellular and humoral immunologic abnormalities that can result in significant physical and psychological morbidity to the patient. Atopic dermatitis typically begins in childhood and can often persist through adolescence into adulthood. Although there are a variety of treatments for atopic dermatitis, many patients' symptoms do not improve or they have adverse reactions to medications, requiring the search for other, effective therapeutic agents. A number of inflammatory and immunological abnormalities have long been noted in patients with atopic dermatitis. Although great strides have been made in understanding the causes, the complex pathophysiology of atopic dermatitis is still not completely understood. Most notably, patients with atopic dermatitis often have an elevation of serum immunoglobulin (Ig) E levels, depressed cellular immunity, elevated blood eosinophilia, and increased interleukin (IL)-4 production. In addition, peripheral blood mononuclear cells of patients with atopic dermatitis produce reduced levels of interferon-gamma spontaneously and in response to stimuli. Due to this constellation of features, atopic dermatitis was initially viewed as a prototypical type 2 helper T lymphocyte (T(h2)) disease. These immunological findings led to a number of clinical trials with recombinant interferon-gamma in patients who had severe, unremitting atopic dermatitis. Treatment with recombinant interferon-gamma was postulated to be able to correct the immunological imbalances in patients with atopic dermatitis by decreasing serum IgE levels, IL-4 levels, restoring immune balance, and thereby leading to clinical improvement. Initial open-label studies, a double-blind placebo trial, and long-term open-label studies have demonstrated the clinical efficacy and tolerability of recombinant interferon-gamma in a subset of patients with severe, unremitting atopic dermatitis. Patients receiving treatment often had marked decreases in severity of clinical parameters: erythema, edema/indurations, pruritus, excoriations, dryness, lichenification and associated reduction in total body surface area involvement. Surprisingly, treatment with recombinant interferon-gamma did not lower serum IgE levels refuting the hypothesized mechanism by which interferon-gamma would bring about clinical improvement in patients with atopic dermatitis. Instead, decreases were noted in absolute white blood cell and eosinophil counts that tended to correlate with clinical improvement. Although the exact mechanism by which recombinant interferon-gamma brings about clinical changes in patients with atopic dermatitis is unknown, recombinant interferon-gamma should be considered a possible therapy for patients with atopic dermatitis.

Vasomax for the treatment of male erectile dysfunction.

This paper reviews laboratory and clinical data concerning oral phentolamine mesylate, Vasomax, an alpha-1, alpha-2 adrenergic receptor antagonist developed specifically for treatment of erectile dysfunction. A contemporary view of the neurovascular mechanisms in penile erection includes the effects of both smooth muscle relaxation and contraction. Contraction of the cavernosal arteries and trabecular smooth muscle appears to be predominantly under the control of alpha-adrenergic innervation. Conversely, adrenergic blockade of alpha-1 and alpha-2 receptors has been shown to facilitate penile erection in both animal and human models. The pharmacokinetic profile of Vasomax appears well suited for an oral erectogenic agent. Vasomax is rapidly absorbed and eliminated in normal males. Peak plasma concentrations are achieved in 30-60 min, and the half-life approximates 5-7 h. Food decreases the rate, but not the extent of bioavailability. Vasomax has low protein binding and is excreted primarily via urine and feces. There is a strong dose-response relationship in maximum plasma concentration (Cmax) and area under the curve (AUC), and there are no clear age-related differences in absorption or elimination rates. Efficacy of Vasomax has been systematically evaluated in two (ZON300, ZON301) large-scale, placebo-controlled trials, in addition to two long-term open-label studies. In both studies, Vasomax was associated with significant improvements in the erectile function domain scores of the International Index of Erectile Function (IIEF). Further improvements were noted as the duration of treatment and dose level were increased. The percentage of successful penetration attempts was also significantly improved with Vasomax compared to placebo. For patients who continued in open-label treatment with Vasomax, efficacy was generally well maintained. Vasomax was well tolerated by the majority of patients. The most common side effects observed were nasal congestion (10%), headache (3%), dizziness (3%), tachycardia (3%) and nausea (1%). Side effects were generally dose-related and in the mild-to-moderate range in all three studies. Furthermore, side effects seldom resulted in treatment discontinuation. Very few serious adverse events were observed in these trials. In summary, Vasomax appears to be effective in the treatment of male erectile dysfunction and well-tolerated by the majority of patients. The drug has a satisfactory side effect profile, without significant risk of cardiovascular effects. Results of clinical trials with Vasomax support the concept of adrenergic-blockade as a clinically relevant mechanism in the control of penile erection.

Effect pf anti-dementia drugs on the daily routine and attitude of dementia patients

The introduction of acetylcholinesterase inhibitors has greatly improved therapeutic opportunities for patients with dementia, in particular with Alzheimer's disease. The most likely outcome of treatment with these compounds is a maintenance of cognitive ability and/or activities of daily living over at least 6 months. Regarding the progressive nature of the underlying neurodegenerative process a temporary stabilization of symptoms is a clear treatment success. Approximately 25 per cent of patients experience a significant improvement in cognitive ability. They show more attentiveness, interest, activity, orientation, communicative ability, as well as better memory. In addition, the new medications can ameliorate non-cognitive symptoms including apathy, agitation, delusions, hallucinations, and disinhibition. Open-label long-term studies have demonstrated that patients receiving treatment with an acetylcholinesterase inhibitor cross their baseline cognitive ability at week 40 to 50 and continue to decline thereafter. In spite of this slow deterioration treated patients perform better than untreated individuals. Since ethical reasons do not permit to include placebo control groups in long-term trials it is not known presently how long the benefit from treatment lasts.

CREATINE SUPPLEMENTATION DURING PRE-SEASON FOOTBALL TRAINING DOES NOT AFFECT FLUID OR ELECTROLYTE STATUS

1485 Anecdotal reports suggest that creatine supplementation during intense training in the heat may alter electrolyte status and/or promote dehydration. This study examined the effects creatine supplementation on fluid and electrolyte status during two phases of pre-season college football training. 53 Division IA football players (19.9±0.2 yrs; 185±1 cm, 103±2.6 kg) participated in the first phase of a long-term open label study to evaluate the medical safety of creatine supplementation. 34 subjects ingested a commercially available supplement containing 15.75 g/d of creatine for 5-d followed by ingesting 5.25 g/d of creatine for 20-d. Remaining subjects were provided a carbohydrate/protein supplement containing no creatine. Supplements were administered following daily training sessions. Training during phase 1 consisted of 4-5 d/wk (70±7 min per workout) of resistance-training indoors (28±1°C, 79±2% RH) and sprint/agility conditioning outdoors (32±0.9°C, 84±3% RH). Training during phase II involved subjects practicing 2 to 3 times per day for 1.5 to 3.5 h (207±17 min/d, 6 d/wk) during 17-d of preseason football camp in which environmental conditions ranged from 29 to 37°C, 58 to 91% R.H. (33.7±0.6°C, 79±2.4% R.H.). During phase II, subjects in the creatine group ingested a carbohydrate/protein supplement containing 8.3 g/d of creatine. Prior to and following each phase of training, body weight, total body water via bioelectrical impedance, fasting blood, and 24-hr urine samples were obtained. During camp, pre-and post practice body weights were recorded on all players (n=100). Data were analyzed by repeated measures ANOVA. Results revealed no significant interactions (p>0.05) between groups in total body weight, total body water; urine output, specific gravity; hematocrit, hemoglobin, blood volume, plasma volume or serum sodium, chloride, potassium, phosphorus, calcium, total protein, and albumin. No significant differences were observed between creatine users and non-users in weight loss (kg or %) during practices. Results indicate that creatine supplementation during 25-d of preseason conditioning and 17-d of football camp in an hot/humid environment does not affect markers of fluid or electrolyte status. Supported by Experimental & Applied Sciences, Golden CO & University of Memphis.

Open-label dosage and tolerability study of tiagabine monotherapy in patients with refractory complex partial seizures

This study was designed to determine the highest tiagabine dosage that could be administered as monotherapy to patients with complex partial seizures refractory to treatment with other antiepileptic drugs (AEDs) without unacceptable adverse events. Thirty-one patients, 18–47 years of age, participated at three sites. During a 3-week initiation phase, tiagabine was started and the dosage increased while concomitant AED dosage was reduced. During a 7-week dose-evaluation phase, dosage was adjusted until the maximum tolerated dosage was reached. During the dose termination phase, patients tolerating the drug entered a long-term open-label study of tiagabine monotherapy. Of 31 patients, 19 converted to monotherapy; in 12 cases, monotherapy was tolerated well enough to be continued for 7 weeks. Of the 12 nonconverters, seven left during the initiation phase due to adverse events and five due to inadequate seizure control. Most events were mildly or moderately severe and were associated with the central nervous system. Plasma tiagabine concentrations were similar in both converters and nonconverters. Conversion to tiagabine monotherapy was accomplished in most patients with difficult-to-control seizures when previous AED monotherapy was replaced in under 4 weeks. The ideal dosage appeared to be approximately 38 mg/day given in three divided doses.

The economic consequences of Alzheimer's disease in the context of new drug developments.

The first national symptomatic treatment for Alzheimer's disease has received a very mixed and perhaps ageist reception from purchasers of health care in the UK. This is largely because detailed information on the long-term effects of this class of drugs is scarce. However, by looking at the published evidence on the economic burden of Alzheimer's disease, some observations and assumptions can be made as to the influence of the new drug treatments. The drug therapies available and those most likely to become licensed are reviewed and the potential economic impact is discussed. Long-term outcome studies would properly address this, but as these drugs have now demonstrated efficacy, particularly in non-cognitive behaviours, it will be ethically more difficult to maintain patients on placebo for long periods. Some assumptions therefore have to be made from long-term open-label studies. Those drugs currently available, and those in development, may offer effective treatment for some of the core symptoms of Alzheimer's disease, slowing the rate of cognitive decline and preserving competence in activities of daily living for longer. If handled correctly, these treatments have the potential to offer cost savings for many patients, and cost-effectiveness improvements look probable.