Long-acting Preparation Research Articles

Montelukast and Theophylline: No Use or Some Use in Persistent Asthma?

The recent study by the American Lung Association Asthma Clinical Research Centers suggests that prescribing montelukast or theophylline for symptomatic patients with asthma, irrespective of existing treatment, confers little further benefit (1). However, before extrapolating their findings into everyday clinical practice it is important to consider several points regarding the validity of the study. First, between 21 and 26% of randomized patients were not using regular inhaled corticosteroids, while the vast majority of these alarmingly appeared to be maintained on long-acting 2-agonists as monotherapy. Second, since the mean prebronchodilator FEV1 in the symptomatic patients with asthma enrolled was between 78 and 80% predicted, it would appear reasonable to consider that inhaled corticosteroids—a fundamental component in all but the mildest of asthma—should have been instituted in “real life” before consideration of montelukast or theophylline. Third, at the end of the 24-week study, as many as 40% of individuals failed to adhere to randomized treatment. Fourth, the spectrum of asthma severity appears to have varied considerably in the study, presumably with patients with an FEV1 of 50% of predicted up to normal values. Moreover, while some patients were receiving no treatment prior to study entry, up to 40%were receiving combined inhaled corticosteroid and long-acting 2-agonist preparations. Finally, the authors failed to evaluate effects on underlying airway inflammation or airway hyperresponsiveness, which are undoubtedly integral pathophysiological components of the underlying syndrome of asthma. In view of shortcomings such as inappropriate maintenance therapy during the study, patient heterogeneity, and failure to evaluate inflammatory biomarkers, it may be understandable that the authors failed to demonstrate any benefit with the addition of montelukast or theophylline. Moreover, these factors may also explain why the current findings appear to contradict those of others, in terms of beneficial effects of add-on montelukast in the correct clinical setting across a spectrum of asthma phenotypes (2).

ORIGINAL RESEARCH—ENDOCRINOLOGY: Improvement of Sexual Function in Men with Late-Onset Hypogonadism Treated with Testosterone Only

Late-onset hypogonadism is associated with relatively mild testosterone deficiencies. This study investigated the effects of restoring testosterone levels to normal in men with complaints of low sexual desire and erectile dysfunction. Sexual function was assessed with the International Index of Erectile Function (IIEF) at baseline and after 24 weeks of testosterone administration. Twenty-two hypogonadal men (mean age 58 years) with erectile dysfunction were studied. Fifteen patients had serum testosterone below 6.9 nmol/L, and seven between 7.2 and 11.7 nmol/L (reference values in our laboratory >/=12.0 nmol/L); there were considerable comorbidities. The duration of sexual complaints was on average 3.8 years. Patients received intramuscular long-acting testosterone undecanoate. In all patients, serum testosterone levels were restored to normal within 6-8 weeks. Twelve patients reported a significant improvement in the sexual desire domain (from 4.5 to 8.4) and experienced an improvement in the erectile function domain (from 12 to 25 [Questions 1-5 plus 15)], following treatment with this long-acting testosterone; in 9 of 12 patients, this occurred only after at least 12-24 weeks. The remaining 10 patients reported an improvement of sexual desire (from 4.5 to 7.5), but no significant improvement in the erectile function domain (from 12 to 14). No changes in serum prostate-specific antigen or prostate volume were noticed while receiving this long-acting testosterone preparation. Restoring testosterone levels to normal in men with proven subnormal testosterone levels improves libido in most subjects, and erectile function in more than 50% of these men. It may take 12-24 weeks before the effects of testosterone become manifest.

Presumptive Fluphenazine‐induced Hepatitis and Urticaria in a Horse

4-year-old Standardbred gelding (450 kg) was examined because of depression, poor appetite, and suspected liver disease. Eight days before examination, the horse had won a race. The next day, depression, muscle stiffness, and transient pyrexia (39.0uC) were observed. The horse was treated with single doses of flunixin meglumine a (1 mg/kg IV), phenylbutazone b (0.2 mg/kg PO), methocarbamol c (4.4 mg/kg PO), Nacetylcysteine d (6.6 mg/kg PO), and 5 L lactated Ringer’s solution IV. A CBC and serum biochemical profile performed 4 days before presentation revealed neutrophilia and moderate increases in serum concentration of the hepatic enzyme activities (Table 1). Moderate urticaria (hives) was present over the trunk of the horse. On examination, the horse was quiet but alert and was in good body condition. Initial physical examination revealed mild jaundice and mild clinical dehydration. The heart rate (36 bpm), respiratory rate (12 bpm), and rectal temperature (37.6uC) were within normal reference limits. Multiple raised, edematous, nonpruritic nodules (3–5 mm diameter), consistent with urticaria were observed over the trunk and the neck. Auscultation and percussion of the thorax and the abdomen was unremarkable. Neurologic examination was unremarkable. This was the only horse of 19 on the farm affected. Thirty-three days before referral, the horse had been empirically administered a single dose of a long-acting parenteral preparation of fluphenazine decanoate e (0.28 mg/kg IM) as a tranquilizer to control anxious behavior. The gelding had daily access to 2 species of weeds, which were estimated to occupy approximately 20% of the turnout paddock area. No grass was available in the paddock because of overgrazing. Nineteen other horses shared the same turnout paddock and had the same management. All horses had access over a fence to lush grass, which had been sprayed with a surfactant-free glyphosphate product f the week the subject horse was administered fluphenazine. Serum biochemical profiles conducted on the herdmates, 2 days before examination, revealed serum activity of hepatic enzymes and concentration of total bilirubin within reference limits. No other horses in the barn had been administered fluphenazine decanoate. Vaccines administered to the horse included equine influenza, rhinopneumonitis, tetanus toxoid, and West Nile virus. The last dose of which had been administered approximately 8 weeks before referral. Clinicopathologic abnormalities were limited to hyperbilirubinemia, increased serum activity of hepatic enzymes (glutamate dehydrogenase [GLDH], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], and alkaline phosphatase [AP]), and increased total bile acids concentration (Table 1). These findings were interpreted as indicative of impaired bile circulation and active hepatocellular damage. No changes compatible with an inflammatory process were identified. Plasma fibrinogen and blood ammonia concentrations were not determined at that time. Transabdominal ultrasound examination revealed normal hepatic architecture. A fecal bacterial culture for Salmonella spp. was negative. The initial therapy consisted of lactated Ringer’s solution (60 mL/kg/d IV), trimethoprim-sulfadioxine g (24 mg/kg IV q12h), and flunixin meglumine (1 mg/kg IV q24h). The diet was restricted to first-cut grass hay to avoid high dietary protein content. Taxonomic classification of the weed plant species reported by the owner revealed that the predominant plant was ‘‘redroot pigweed,’’ Amaranthus retroflexus (80% of weeds in paddock), and the other was ‘‘Lamb’s quarter,’’ Chenopodium album (20% of weeds in paddock). A. retroflexus has been associated with severe renal disease in cattle, 1 and C. album has been associated with nitrate toxicosis in cattle. 2 To the authors’

Effect of an Intramammary Teat Seal and Dry Cow Antibiotic in Relation to Dry Period Length on Postpartum Mastitis

Infusion of either a long-acting antibiotic preparation (cefalonium) or the same antibiotic preparation combined with an internal teat sealant (bismuth subnitrite) were compared for the effect on new intramammary infections at calving and clinical mastitis in the first 100 d of lactation, in relation to dry period length. For all cows, a significant reduction in the incidence of new infections in quarters at calving (3.7 vs. 7.3%) was found for the combination treatment group (150 cows) compared with the antibiotic-alone treatment (133 cows). With a dry period of 10wk or longer, significantly fewer new quarter infections (3.8 vs. 11.4%) were found in those cows receiving the combination treatment compared with antibiotic treatment alone. When the dry period was less than 10wk, the incidence of new infections in quarters treated with the combination treatment was lower than for the antibiotic treatment alone (3.7 vs. 6%) but this was not a statistically significant difference. Fewer infections caused by Streptococcus uberis and coagulase-negative staphylococci were found in cows receiving the combination treatment compared with the antibiotic treatment alone (not significant). Coliform isolates were less likely in cows receiving the combination treatment with the longer dry period but the numbers of new intramammary coliform infections were low for both dry period categories. Few infections were caused by coagulase-negative staphylococci. The incidence of clinical mastitis in the first 100 d of lactation in quarters infected at calving was significantly lower (4 vs. 15 cases) for the combination treatment than for the antibiotic treatment alone for both dry period lengths. The clinical incidence in quarters in which a pathogen was not detected in either of the samples taken after calving was comparable between groups. No significant difference was found in the total clinical incidence after calving for both groups irrespective of dry period length.

Insulin Therapy in Diabetes Mellitus

The era of animal source insulins has passed and human recombinant DNA insulins are gradually being replaced because of the superior efficacy of insulin analogues. Analogue insulins are available in both rapid- and long-acting preparations. Currently available rapid-acting insulins are lispro, aspart and glulisine, and the currently available long-acting analogue basal insulins are detemir and glargine. The rapid-acting insulin analogues are also available in combination with protamine in fixed-dose pre-mixed insulins to provide a more sustained action. The chemical structure, subcutaneous behaviour, time of onset, maximal effect and duration of action of both analogue and human insulins, and how these actions can be best utilised in the diabetic patient are discussed in this review. In addition, strategies where efficacy of the available analogue insulins can be maximally utilised in both type 1 and type 2 diabetes mellitus are described. Maximal utilisation of analogue insulins will result not only in better glycaemic control, but will also minimise the frequency and severity of hypoglycaemic episodes. In addition, maximisation of glycaemic control will result in prevention, delay of onset or amelioration of both the microvascular and perhaps the macrovascular complications of diabetes.

Medication Noncompliance and its Implications in Transplant Recipients

The transplant patient's therapeutic regimen consists of a lifelong drug therapy, including immunosuppressive drugs, prophylactic antimicrobials and often medications for the treatment of hypertension, diabetes mellitus and other comorbid diseases. Regular clinic appointments are required to monitor for signs and symptoms of immunological injury, recurrent disease and adverse drug effects. Patients are instructed to avoid risk factors for cardiovascular disease and cancer (e.g. diet, exercise, sun protection and not smoking). Noncompliance with all aspects of this regimen is substantial. Medication noncompliance leads to an increased incidence of acute rejection, chronic rejection and graft loss. Undoubtedly, many practitioners fail to appreciate the extent of noncompliance as the signs are often subtle and most patients are unwilling to disclose deliberate or widespread disregard for medication use. Newer immunosuppressive agents, particularly once-daily medications and long-acting antibody preparations offer convenience and monitoring that may improve compliance. This review focuses on the prevalence, correlates and consequences of medication nonadherence after organ transplantation. Current recommendations to enhance adherence are discussed.

Sustained-release self-dissolving micropiles for percutaneous absorption of insulin in mice

Microparticles-adsorbed insulin and zinc insulin (Penfil®N) were molded to self-dissolving micropiles (SDMPs) with chondroitin sulfate as the base for the percutaneous administration of insulin. Porous silicon dioxide (Sylysia® 320, 440 and 730) and porous calcium silicate (Florite®RE) were used as microparticles. As a reference, insulin loaded SDMPs were prepared. SDMPs were percutaneously administered to mice at the insulin dose level of 2.5 IU/kg. After the insertion of SDMPs to mouse skin, blood samples were collected for 8 h and plasma glucose levels were measured. There were not significant differences on minimum plasma glucose levels between the test preparations. However, Tmins, the time when the minimum glucose level appeared were 1.5 ± 0.2 h (Sylysia 320), 1.3 ± 0.2 h (Sylysia 440), 1.6 ± 0.4 h (Sylysia 730), 2.1 ± 0.3 h (Florite) and 1.7 ± 0.3 h (zinc insulin) which were greater than insulin SDMP, 0.8 ± 0.1 h. In addition, greater hypoglycemic effects were observed with SDMPs containing adsorbent-insulin and/or zinc insulin than insulin SDMP. The mean AACs (area above the plasma glucose level vs. time curve) of SDMPs containing adsorbent-insulin and zinc insulin were 357.8% h for Florite®RE, 333.1% h for Sylysia 320, 308.1% h for Sylysia 440, 328.1% h for Sylysia 730, and 374.7% h for zinc insulin, respectively, which were about two folds higher than that of insulin SDMN, 161.2% h. Those results suggest the usefulness of SDMPs composed of adsorbent-insulin as a long-acting percutaneous insulin preparation.

Thirty Years of Clinical Experience with Carbamazepine in the Treatment of Bipolar Illness

Carbamazepine began to be studied in a systematic fashion in the 1970s and became more widely used in the treatment of bipolar disorder in the 1980s. Interest in carbamazepine has been renewed by (i) the recent US FDA approval of a long-acting preparation for the treatment of acute mania; (ii) studies suggesting some efficacy in bipolar depression; and (iii) evidence of prophylactic efficacy in some difficult-to-treat subtypes of bipolar illness. A series of double-blind controlled studies of the drug were conducted at the US National Institute of Mental Health from the mid-1970s to the mid-1990s. This review summarises our experience in the context of the current literature on the clinical efficacy, adverse effects and pharmacokinetic interactions of carbamazepine. Carbamazepine has an important and still evolving place in the treatment of acute mania and long-term prophylaxis. It may be useful in individuals with symptoms that are not responsive to other treatments and in some subtypes of bipolar disorder that are not typically responsive to a more traditional agent such as lithium. These subtypes might include those patients with bipolar II disorder, dysphoric mania, substance abuse co-morbidity, mood incongruent delusions, and a negative family history of bipolar illness in first-degree relatives. In addition, carbamazepine may be useful in patients who do not adequately tolerate other interventions as a result of adverse effects, such as weight gain, tremor, diabetes insipidus or polycystic ovarian syndrome. We review our clinical and research experience with carbamazepine alone and in combination with lithium, valproic acid and other agents in complex combination treatment of bipolar illness. More precise clinical and biological predictors and correlates of individual clinical responsiveness to carbamazepine and other mood stabilisers are eagerly awaited.

Pharmacotherapies for Diabetes Management: An Update for the Practicing Clinician

Over the past several years, the pharmacologic options for the management of glycemic control have tremendously expanded. Whereas prior to the introduction of metformin therapy in 1995 the only alternatives were human insulin therapies and sulfonylurea drugs, we now have the option of using several different classes of oral antidiabetic drugs, injectable non-insulin therapies, and insulin analogs. In this article we present a functional classification of glycemic therapies available for the treatment of diabetes in an attempt to provide the clinician with a practical framework which optimize blood glucose management. Patients with diabetes, especially type 2 diabetes, are often managed with a wide variety of injectable and non-injectable options in the attempt to improve glycemic control and glycemic variability, minimize hypoglycemia (as well as weight gain) and prevent both micro- and macrovascular complications. We specifically focus on novel therapies and present macrovascular complications. We specifically focus on novel therapies and present information about their efficacy and safety, as well as potential contraindications. The last section of this paper will present some suggestions for how to manage glycemia in the in-patient setting, including the use of rapid and long-acting insulin preparations to cover fasting and nutritional needs, as well as the proper use of insulin scales.

Review of the evidence for the long-term efficacy of atypical antipsychotic agents in the treatment of patients with schizophrenia and related psychoses

In schizophrenia, the objectives of long-term maintenance therapy are to achieve continuous relief from psychotic symptoms, to prevent relapse, to optimize patient functioning and improve quality of life. It is now generally accepted that atypical antipsychotic agents are more effective than conventional agents in achieving these goals over the short term. In order to define the role of atypical antipsychotics as maintenance treatment for schizophrenia, studies published between January 1994 and November 2005 that evaluated the long-term efficacy (> or =1 year) of atypical antipsychotics for the treatment of schizophrenia were reviewed as identified from literature researches using MEDLINE and EMBASE. The primary research parameters were 'atypical', 'antipsychotic', 'schizophrenia', 'relapse', 'long-term', 'maintenance' and 'efficacy'. Aspects of safety were also considered for these agents. Results from these long-term studies consistently demonstrated that atypical antipsychotics have substantial advantages over oral conventional antipsychotics as proven by fewer relapses, more effective symptom control and a lower incidence of movement disorders, although some atypical agents were associated with a higher incidence of weight gain. However, due to issues of compliance, the clinical advantage of oral atypical antipsychotics has often been limited. As such, the use of long-acting preparations of atypical antipsychotics, which provide consistent and sustained drug coverage, warrants further investigation for the successful long-term management of patients with schizophrenia.

Pulsatile Secretion of Growth Hormone (GH) Persists during Continuous Stimulation by CJC-1295, a Long-Acting GH-Releasing Hormone Analog

Pulsatile GH secretion is considered important for many of the hormone's physiological effects. Short-term GHRH infusions enhance GH pulsatility and increase IGF-I, but the short GHRH half-life limits its therapeutic use. A synthetic GHRH analog (CJC-1295) that binds permanently to endogenous albumin after injection (half-life = 8 d) stimulates GH and IGF-I secretion in several animal species and in normal human subjects and enhances growth in rats. Our objective was to assess GH pulsatility after a single injection of CJC-1295 and determine which GH secretion parameters correlated to the increase in IGF-I production. GH pulsatility was assessed by 20-min blood sampling during an overnight 12-h period in healthy 20- to 40-yr-old men before and 1 wk after injection of either 60 or 90 microg/kg CJC-1295. GH secretion was increased after CJC-1295 administration with preserved pulsatility. The frequency and magnitude of GH secretory pulses were unaltered. However, basal (trough) GH levels were markedly increased (7.5-fold; P < 0.0001) and contributed to an overall increase in GH secretion (mean GH levels, 46%; P < 0.01) and IGF-I levels (45%; P < 0.001). No significant differences were observed between the responses to the two drug doses. The IGF-I increases did not correlate with any parameters of GH secretion. CJC-1295 increased trough and mean GH secretion and IGF-I production with preserved GH pulsatility. The marked enhancement of trough GH levels by continuous GHRH stimulation implicates the importance of this effect on increasing IGF-I. Long-acting GHRH preparations may have clinical utility in patients with intact pituitary GH secretory capability.

A comparison between pre-operative carprofen and a long-acting sufentanil formulation for analgesia after ovariohysterectomy in dogs

ObjectiveTo assess the analgesic efficacy and adverse effects of a novel, long-acting sufentanil preparation in dogs undergoing ovariohysterectomy (OHE). Study designBlinded, positively controlled, randomized field trial with four parallel treatment groups. AnimalsEighty client owned dogs undergoing elective OHE randomly allocated into four treatment groups (each n = 20). Materials and methodsThree groups received intramuscular (IM) sufentanil (at 10, 15 and 25 μg kg−1, respectively) and the control group received subcutaneous (SC) carprofen 4 mg kg−1 SC plus acepromazine 0.05 mg kg−1 IM as pre-anaesthetic medication. OHE was performed under thiopental/halothane anaesthesia. Visual Analogue Scale (VAS) scores for pain and sedation were awarded and mechanical nociceptive thresholds were measured at the wound and hock before surgery and up to 24 hours after tracheal extubation. Serum cortisol was measured before surgery, during surgery and up to 24 hours after tracheal extubation. Animals with inadequate post-operative analgesia were given rescue medication. ResultsIn the carprofen group, VAS pain scores were significantly higher, wound tenderness was greater and requirement for rescue analgesia was more than in the sufentanil-treated groups. Sufentanil produced dose dependent analgesia and sedation. All treatment groups showed similar patterns of change for cortisol concentrations. Use of the sufentanil preparation was associated with a relatively high incidence of adverse events. ConclusionsThe long-acting preparation of sufentanil provided excellent post-operative analgesia that was significantly better than that provided by carprofen. However, use of this formulation, in the anaesthetic technique used in the study, resulted in a relatively high incidence of adverse effects. Clinical relevanceFull mu (MOP) opioid agonists provide significantly better post-operative analgesia than nonsteroidal anti-inflammatory drugs after moderately painful surgery. However, the widely recognized adverse effects of opioids may preclude the use of these agents.

Intravitreal steroids in the management of macular oedema

The use of intravitreal corticosteroids in the management of macular oedema has recently gained widespread acceptance. New long-acting steroid preparations and methods of delivery have facilitated the use of these new modalities. This review describes the various types of macular oedema for which this therapeutic option is used and the results.

Methylphenidate Blood Levels and Therapeutic Response in Children with Attention-Deficit Hyperactivity Disorder I. Effects of Different Dosing Regimens

Methylphenidate (MPH) is a drug of choice for treating attention-deficit/hyperactivity disorder (ADHD), although its use has been complicated by its short duration of action. The development of ideal long-acting preparations requires detailed understanding of the pharmacokinetic and pharmacodynamic consequences of complex dosing regimens. The purpose of this study was to ascertain if administration paradigms that produce stable or rising MPH levels alter the rate with which MPH is absorbed, and to determine how effectively long-acting administration paradigms compare with thrice daily administration of immediate-release MPH. Forty-eight boys diagnosed with ADHD (mean age 10.6 +/- 1.1 year) participated in this double-blind, parallel group study to evaluate the pharmacokinetics and efficacy and of 1 mg/kg/day MPH administered in five different paradigms and placebo. Objective measures of activity and attention (McLean Motion Attention Test; M-MAT) and plasma measures of d- and l-MPH were obtained hourly during the course of a 12-hour laboratory session. The rate of absorption and elimination of d-MPH was dependent on the pattern of administration, particularly on the initial bolus concentration. This suggests that d-MPH may act on the gastrointestinal system to slow absorption of additional d-MPH. There were significant differences among regimens on time course and degree of therapeutic response. Pulsatile administration produced greater improvement than escalating levels.

Long-acting medications for the hyperkinetic disorders

A systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder is reported, giving effect sizes and numbers-to-treat for extended-release stimulant preparations and atomoxetine (ATX). A panel of experts from several European countries used the review to make recommendations about the use of these drugs in practice, and conclusions are reported: (1) Long-acting preparations should be available and used; (2) They should not replace short-acting drugs (which will be the initial treatment for many children for reasons of cost and flexibility of dosing). Individual clinical choice is needed. (3) Both ATX and extended-release preparations of stimulants should be available. The choice will depend upon the circumstances, and detailed recommendations are made.

Severe Serum Sickness Reaction to Oral and Intramuscular Penicillin

Serum sickness is a type III hypersensitivity reaction mediated by immune complex deposition with subsequent complement activation, small-vessel vasculitis, and tissue inflammation. Although the overall incidence of serum sickness is declining because of decreased use of heterologous sera and improved vaccinations, rare sporadic cases of serum sickness from nonprotein drugs such as penicillins continue to occur. Drug-induced serum sickness is usually self-limited, with symptoms lasting only 1-2 weeks before resolving. We report an unusual case of a severe and prolonged serum sickness reaction that occurred after exposure to an intramuscular penicillin depot injection (probable relationship by Naranjo score) and discuss how pharmacokinetics may have played a role. Clinicians should be familiar with serum sickness reactions particularly as they relate to long-acting penicillin preparations. Accurate diagnosis in conjunction with cessation of drug exposure and prompt initiation of antiinflammatory treatment with corticosteroids can produce complete recovery

Investigation, Treatment, and Monitoring of Late‐Onset Hypogonadism in Males: ISA, ISSAM, and EAU Recommendations

Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that the testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men (1–4). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs and the recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in ‘Testosterone and Aging: Clinical Research Directions’ (5). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (6–11). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed.

Open-Label Pilot Study of Testosterone Patch Therapy in Men With Opioid-Induced Androgen Deficiency

We conducted a 24-week open-label pilot study of testosterone (T) patch therapy in 23 men with opioid-induced androgen deficiency (OPIAD). The T dosage was 5 mg/day for the first 12 weeks and 7.5 mg/day for the second 12 weeks. Seven subjects discontinued prematurely: 4 for noncompliance, 2 for skin irritation and 1 for hepatitis C treatment. In the “completers” population (n = 16), mean (SD) free T levels (normal range 52 to 280 pg/mL) were 28.5 (18.6) pg/mL at baseline, 72.8 (29.6) pg/mL on 5 mg/day (P < .001 vs. baseline), and 120.2 (69.5) pg/mL on 7.5 mg/day (P < .001 vs. baseline and P < .01 vs. 5 mg/day). Total T, dihydrotestosterone, and estradiol showed parallel changes. Sex hormone–binding globulin levels were elevated at baseline and decreased modestly with treatment (P < .05 vs. baseline at 5 mg/day; P < .01 vs. baseline at 7.5 mg/day). Luteinizing hormone levels were in the low-normal range at baseline and suppressed markedly with treatment (P < .001 vs. baseline at both doses). Androgen deficiency symptoms (ADSQ), sexual function (Watts SFQ), mood (PGWB), depression (BDI-II), and hematocrit levels showed improvement during treatment, generally more so at the 7.5 mg/day dosage (P < .001 vs. baseline for most parameters). Pain scores (BPI-SF) decreased slightly on 7.5 mg/day (interference score: P < .05 vs. baseline and 5 mg/day); the use of opioids did not change appreciably. The testosterone patches were generally well tolerated. Perspective Long-acting opioid preparations suppress the hypothalamic-pituitary-gonadal axis in men and produce a symptomatic state of opioid-induced androgen deficiency (OPIAD). Testosterone patch therapy at a dose of 7.5 mg/day normalizes hormone levels and appears to improve a number of quality of life parameters (eg, sexual function, well-being, mood) in men with OPIAD.

It's Time to Throw Out Old-Fashioned Latin Abbreviations

It's Time to Throw Out Old-Fashioned Latin Abbreviations

Single‐ and Multiple‐Dose Pharmacokinetics of Long‐acting Injectable Naltrexone

Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence. The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol. After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred. This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.