Epinephrine for the treatment of anaphylaxis: do all 40 mg sublingual epinephrine tablet formulations with similar in vitro characteristics have the same bioavailability?

Epinephrine autoinjectors are underutilized in the first aid emergency treatment of anaphylaxis in the community; so non-invasive sublingual epinephrine administration is being proposed. In order to determine the effect of changing excipients on the bioavailability of sublingual epinephrine, four distinct fast-disintegrating epinephrine 40 mg tablet formulations, A, B, C and D, were manufactured using direct compression. All formulations were evaluated for tablet hardness (H), disintegration time (DT) and wetting time (WT). In a prospective 5-way crossover study, four sublingual formulations and epinephrine 0.3 mg i.m. as a control were tested sequentially in a validated rabbit model. Blood samples were collected before dosing and at intervals afterwards. Epinephrine plasma concentrations were measured using HPLC-EC. All tablet formulations met USP standards for weight variation and content uniformity, and resulted in similar mean H, DT and WT (n=6). The area under the curve (AUC), maximum concentration (C(max)) and time at which C(max) was achieved (T(max)) did not differ significantly after the sublingual administration of formulation A and epinephrine 0.3 mg i.m. The AUC after B, C and D were significantly lower (p<0.05) than after epinephrine 0.3 mg i.m. These results suggest that the selection of excipients used in these tablet formulations can affect the bioavailability of sublingually administered epinephrine.     

Is the management of hepatitis C patients appropriate? A population‐based study

BACKGROUND: In order for hepatitis C patients to receive antiviral treatment, they must reach medical care. AIM: To assess the proportion of patients reaching medical care after hepatitis C diagnosis in a general population (1 006 171 inhabitants) in France. METHODS: Between 1994 and 1999, 1508 cases were diagnosed, of which 1251 were eligible for the study. RESULTS: Two-hundred and two patients did not have any medical care; among them, 55.4% had normal alanine transferase, 58.4% had risk factors related to lifestyle and 22.8% were alcoholics. Amongst the 1049 other patients, 41.6% had a liver biopsy, 25.0% were treated. Treatment was more often carried out in males than in females (OR: 1.59; P = 0.001), and in patients under 65 than in older patients (OR: 2.22; P < 0.008). Among non-treatment reasons, alcoholism (P = 0.001), drug-addiction (P = 0.04) and escaping monitoring (P = 0.04) were more frequent in males than in females, whereas normal alanine transferase was more frequent in females than in males (P = 0.004). Amongst 278 patients with a Metavir score >A1F1, 71 (25.5%) did not undergo treatment. CONCLUSION: In a general population, one patient in six did not receive on-going health care; a quarter of patients with a Metavir score >A1F1 did not receive any treatment. These results showed insufficient clinical management, which could compromise the effectiveness of treatment in general population.     

Is the vagina an adequate route for the administration of hormonal contraceptives?

The vaginal route of drug administration provides women with a valid alternative to more conventional methods of contraception. Drugs absorbed in the upper part of the vagina can bypass the liver and, if metabolized, are subject to a reduced hepatic first-pass effect. Current vaginally-administered contraceptive formulations deliver similar doses of gestagens to those provided by oral methods but release lower amounts of oestrogens. This results in a systemic exposure to gestagens similar to that achieved via other routes, thereby maintaining contraceptive efficacy while limiting systemic, but not uterine, exposure to oestrogen. In this way, the probability of systemic oestrogen-related adverse effects are theoretically reduced without compromising cycle control. In addition, the fact that the effects of a contraceptive ring last a complete cycle makes it more user-friendly than other methods and results in better patient compliance. The present review will explain in detail the specificities of this route of delivery of hormonal contraception and will compare it to more classic forms of contraception received via the oral (pill), intramuscular (injected), transdermic (patch) and subcutaneous (implants) routes of administration.     

Is tocilizumab an option for the treatment of arthritis?

Background: Some patients with rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis are resistant to inhibitors of interleukin-1 and tumour necrosis factor. Raised levels of interleukin-6 are associated with both these conditions. Tocilizumab is a humanised monoclonal antibody that binds to both forms of interleukin-6 receptor that has recently been used in Phase III trials in rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis. Methods: The study conducted an evaluation of Phase III trials with tocilizumab. Results: In the Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders the primary efficacy end-point was the proportion of subjects with a 20% improvement in their rheumatoid arthritis signs and symptoms according to the American College of Rheumatology criteria and, at 24 weeks, this value was 26% with placebo and was increased to 48 and 59% with tocilizumab at 4 and 8 mg respectively. In the trial of tocilizumab in systemic-onset juvenile idiopathic arthritis, the primary end-point in the open-label lead-in was the proportion of subjects achieving an American College of Rheumatology Pediatric 30 response and 91% of subjects had achieved this at 6 weeks. This response was maintained by the majority of subjects being treated with tocilizumab during a 12-week double-blind trial and 48 weeks of open trial follow-up. Small numbers of subjects developed infections in both studies. Conclusions: Provided long-term safety can be established, tocilizumab will probably become part of the treatment for rheumatoid arthritis and may become a major breakthrough for the treatment of systemic-onset juvenile idiopathic arthritis.     

Is auricular acupuncture beneficial in the inpatient treatment of substance-abusing patients? A pilot study

Patients with comorbid substance abuse problems who were admitted to a psychiatric unit of a general hospital over an 11-month period were offered treatment with auricular acupuncture. Subsequently and retrospectively, the medical records of these patients were examined to assess compliance, side effects, impact on course, and acceptance of discharge recommendations. Patient's continuation of treatment in destination programs was also followed. Seventy-seven patients were offered acupuncture: 30 patients refused or had four or fewer treatments (control group), and 47 had acupuncture five or more times (treatment group). The treatment group did significantly better than the control group as indicated by the following findings: compliance with psychiatric/substance abuse treatment on the unit was 75% in the treatment group vs. 20% in the control group, noncompliance or AMA discharge rate was 2% in the treatment group vs. 40% in the control group, acceptance of staff's discharge recommendations was 77% in the treatment group vs. 37% in the control group, and 58% of the treatment group patients remained in follow-up treatment for at least 4 months, vs. only 26% of the control group patients. Average inpatient length of stay was 22 days for the treatment group patients compared to 16 days for the control group patients. Side effects in the treated patients were negligible. Auricular acupuncture thus appears to be a safe and inexpensive treatment modality that is easily administered and produces significant results. Its wider application in substance abuse treatment appears warranted.     

Aspirin for the prevention and treatment of pre‐eclampsia: A matter of COX‐1 and/or COX‐2 inhibition?

Since the 1970s, we have known that aspirin can reduce the risk of pre‐eclampsia. However, the underlying mechanisms explaining this risk reduction are poorly understood. Both cyclooxygenase (COX)‐1‐ and COX‐2‐dependent effects might be involved. As a consequence of this knowledge hiatus, the optimal dose and timing of initiation of aspirin therapy are not clear. Here, we review how (COX‐1 versus COX‐2 inhibition) and when (prevention versus treatment) aspirin therapy may interfere with the mechanisms implicated in the pathogenesis of pre‐eclampsia. The available evidence suggests that both COX‐1‐ and COX‐2‐dependent effects play important roles in the early stage of aberrant placental development and in the next phase leading to the clinical syndrome of pre‐eclampsia. Collectively, these data suggest that high‐dose (dual COX inhibition) aspirin may be superior to standard low‐dose (selective COX‐1 inhibition) aspirin for the prevention and also treatment of pre‐eclampsia. Therefore, we conclude that more functional and biochemical tests are needed to unravel the contribution of prostanoids in the mechanisms implicated in the pathogenesis of pre‐eclampsia and the potential of dual COX and/or selective COX‐2 inhibition for the prevention and treatment of pre‐eclampsia. This information is vital if we are to deduce the suitability, optimal timing and dose of aspirin and/or a specific COX‐2 inhibitor (most likely using modified forms that do not cross the placenta) that can then be tested in a randomized, controlled trial instead of the current practice of empirical dosing regimens.     

What is the optimal dose of escitalopram for the treatment of obsessive-compulsive disorder? A naturalistic open-label study

This study explored the efficacy and tolerability of very high doses (maximum dose of >40 mg/day), high doses (maximum dose of 25-40 mg/day), and standard doses (maximum dose of ≤20 mg/day) of escitalopram (ESC) as an anti-obsessive-compulsive disorder treatment in a naturalistic clinical setting. We reviewed the medical records of all patients with obsessive-compulsive disorder (n=246) who had taken ESC between May 2006 and September 2009, and assigned Clinical Global Impression (CGI) scores, retrospectively. Of the total sample, 24.4, 38.2, and 37.4% patients received very high, high, and standard doses of ESC, and the mean daily maximum doses of ESC were 57.3±12.0 mg, 33.9±5.4 mg, and 13.4±5.8 mg, respectively. The CGI-Severity scores in each group decreased significantly after treatment with ESC, as evidenced by response rates (i.e. CGI-Improvement scores of 1 or 2) of 46.3, 43.2, and 26.2%, respectively. Although some adverse events increased in a dose-dependent manner, most could be managed with an ESC dose adjustment. These results imply that doses less than or equal to 40 mg/day ESC are sufficient for symptomatic improvement with good tolerability for most patients. Very high doses of ESC, on the other hand, can be considered for patients with inadequate therapeutic responses to the administration of 40 mg/day ESC.     

Is a regenerative approach viable for the treatment of COPD?

Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma-sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells.     

Is a 9‐month treatment sufficient in tuberculous enterocolitis? A prospective,randomized, single‐centre study

BACKGROUND: Tuberculosis has increased in parallel with the acquired immunodeficiency syndrome epidemic and the use of immunosuppressive therapy, and the growing incidence of extra-pulmonary tuberculosis, especially with intestinal involvement, reflects this trend. However, the duration of anti-tuberculous therapy has not been clarified in intestinal tuberculosis. AIM: To compare the efficacy of different treatment durations in tuberculous enterocolitis in terms of response and recurrence rates. METHODS: Forty patients with tuberculous enterocolitis were randomized prospectively: 22 patients into a 9-month and 18 into a 15-month group. Diagnosis was made either by colonoscopic findings of discrete ulcers and histopathological findings of caseating granuloma and/or acid-fast bacilli, or by clinical improvement after therapeutic trial. Patients were followed up with colonoscopy every other month until complete response or treatment completion, and then every 6 months for 1 year and annually. Complete response was defined as a resolution of symptoms and active tuberculosis by colonoscopy. RESULTS: Complete response was obtained in all patients in both groups. Two patients in the 9-month group and one in the 15-month group underwent operation due to intestinal obstruction and perianal fistula, respectively. No recurrence of active intestinal tuberculosis occurred during the follow-up period in either group. CONCLUSIONS: Tuberculous enterocolitis can be managed by 9-month chemotherapy without disease recurrence. Further investigations are needed in immunocompromised patients.     

Is transketolase like 1 a target for the treatment of differentiated thyroid carcinoma? A study on thyroid cancer cell lines

Summary  Radioactive iodine-refractory [¹⁸F] fluorodeoxy-glucose-positron emission tomography-positive thyroid carcinomas represent especially aggressive tumors. Targeting glucose metabolism by the transketolase isoenzyme transketolase like 1 (TKTL-1) which is over-expressed in various neoplasms, may be effective. The correlation of TKTL-1 expression and the response to oxythiamine as the currently best-characterized inhibitor of transketolases was studied in differentiated thyroid cancer cell lines. We determined TKTL-1 expression, proliferation, glucose uptake and GLUT-1 expression in non-treated thyroid cells and recorded the effect of oxythiamine on iodide uptake and on thymidine uptake. TKTL 1 was highest expressed in cell lines derived from more invasive tumors but the expression level was not strongly correlated to proliferation rate, to GLUT-1 expression or to the response to oxythiamine. Oxythiamine showed only a weak effect in the TKTL-1 expressing cell lines. Over-expression of TKTL-1 is not an indicator for responsiveness to oxythiamine. More specific inhibitors should be tested.     

Is 5-ASA still the treatment of choice for ulcerative colitis?

5-Amino-salacylic acid (5-ASA) is up to now the treatment of choice in the induction and maintenance of remission of mild-to-moderate ulcerative colitis (UC). Sulfasalazine, despite similar efficacy, is hampered by more side effects, but in presence of peripheral arthopaties it remains the treatment of choice. The new delayed release MMX formulation seems to be promising in reducing compliance problems, but further studies are warranted to show the superiority of new MMX formulation compared with the older formulations of 5-ASA. Some trials evaluated also the efficacy and safety of once-daily dosing of older 5-ASA formulations in maintenance of remission, finding a greater adherence to therapy in the group given the once daily regimen, compared with the classic twice daily groups. Regarding the efficacy of alternative treatment such us probiotics and antibiotics, the current data are not sufficient to promote their use in clinical practice. Clinical evidence supports the use of topical 5-ASA in active mild to moderate distal UC showing superior ef?cacy to placebo, topical corticosteroids, and oral 5-ASA. A combination of oral and rectal 5-ASA produces additional ef?cacy in both limited and extensive UC. Topical 5-ASA formulations are effective also for the maintenance of remission, however long term treatment may not be acceptable to many patients. Other topical drugs (E. Coli Nissle, propionyl-L-carnitine, butyrate, tacrolimus, rosiglitazone) have been investigated with conflicting results. The possible chemopreventive role of long term treatment with 5-ASA strengthens the indication to the long term use of 5-ASA.     

Is there a role for immunoconjugates in the treatment of AIDS?

The use of antibodies to deliver therapeutic agents to specific cells is a well-established concept in the treatment of malignancy. Therapeutic effects have been shown in both animal models and human clinical trials. By analogy, antibodies and other ligands may be used to treat AIDS by targeting cells that are actively producing HIV and spreading the infection. Immunoconjugates with specificity for HIV antigens or structures on the surface of HIV-infected cells have been made. These agents have undergone extensive in vitro testing. In tissue culture they can eliminate infected cells and halt the production of HIV. A number of agents have been shown to enhance the efficacy of anti-HIV immunoconjugates. Because animal models of HIV-infection are problematic, there has been little preclinical testing. Nevertheless, several clinical trials have begun.     

A role for retinoids in the treatment of COVID-19?

The 2020 global outbreak of the novel coronavirus (SARS-CoV-2 or COVID-19) is a serious threat to international health, and thus, there is an urgent need for discovery of novel therapies or use of repurposed drugs that can make a significant impact on slowing the spread of the virus. Type 1 interferons (IFN-I) are a family cytokines of the early innate immune response to viruses that are being tested against SARS-CoV-2. However, coronaviruses similar to SARS-CoV-2 can suppress host IFN-I antiviral responses. Retinoids are a family molecules related to vitamin A that possess robust immune-modulating properties, including the ability to increase and potentiate the actions of IFN-I. Therefore, adjuvants such as retinoids, capable of increasing IFN-I-mediated antiviral responses, should be tested in combinations of IFN-I and antiviral drugs in pre-clinical studies of SARS-CoV-2.     

A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient?

The field of erectile dysfunction (ED) has been revolutionised over the last two decades. Several treatment options are available today, most of which are associated with high efficacy rates and favourable safety profiles. A MEDLINE search was undertaken in order to evaluate all currently available data on treatment modalities for ED. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first-choice of most physicians and patients for the treatment of ED. PDE5 inhibitors have differences in their pharmacological profiles, the most obvious being the long duration of action of tadalafil, but there are no data supporting superiority for any one of them in terms of efficacy or safety. Sublingual apomorphine has limited efficacy compared with the PDE5 inhibitors, and its use is limited to patients with mild ED. Treatment failures with oral drugs may be due to medication, clinician and patient issues. The physician needs to address all of these issues in order to identify true treatment failures. Patients who are truly unresponsive to oral drugs may be offered other treatment options.Intracavernous injections of alprostadil alone, or in combination with other vasoactive agents (papaverine and phentolamine), remain an excellent treatment option, with proven efficacy and safety over time. Topical pharmacotherapy is appealing in nature, but currently available formulations have limited efficacy. Vacuum constriction devices may be offered mainly to elderly patients with occasional intercourse attempts, as younger patients show limited preference because of the unnatural erection that is associated with this treatment modality. Penile prostheses are generally the last treatment option offered, because of invasiveness, cost and non-reversibility; however, they are associated with high satisfaction rates in properly selected patients.All treatment options are associated with particular strengths and weaknesses. A patient-centred approach based on patient needs and expectations is necessary for the management of ED. The clinician must educate the patient and provide a supportive environment for shared decision making. The management strategy must be supplemented by careful follow-up in order to identify changes in patient health and relationship/emotional status that may necessitate treatment optimisation.