Advances in Therapy

Blood pressure (BP) control is the main clinical goal in the management of hypertensive patients; however, BP in most of these patients remains uncontrolled, despite the widespread availability of antihypertensive drugs as free-combination therapy. This study compared the efficacy of a fixed-dose triple combination (FDTC) of antihypertensive drugs with that of a free combination of three antihypertensives in patients with uncontrolled hypertension. Ninety-two patients (mean age 60.8 ± 12.1, 58.0% male) with uncontrolled essential hypertension (office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) previously treated with a renin–angiotensin–aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDTC therapy with perindopril/indapamide/amlodipine (5–10/1.25–2.5/5–10 mg). Patients were age- and sex-matched with a control group of hypertensive patients receiving free-combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-h ambulatory BP monitoring (ABPM) were evaluated at baseline and after 1 and 4 months. Significant reductions in ambulatory 24-h, daytime, and nighttime systolic BP, and pulse pressure (PP) were found in the FDTC group relative to reductions seen with free-combination therapy, after the first month only of follow-up. Target BP values (mean 24-h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of FDTC than free-combination therapy (64.8% vs. 46.9%, p < 0.05) at month 4 of follow-up, despite reductions in 24-h ABPM values from baseline being similar in both groups at this time point. FDTC of perindopril/indapamide/amlodipine was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the free-combination of a RAAS inhibitor, a diuretic, and a calcium antagonist.

Subcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A. Two phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh. Primary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was − 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC0–tlast, AUC0–∞, and Cmax between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable. Ixekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation. ClinicalTrials.gov identifier NCT03848403, NCT04259346.

Alcohol dependence represents a severe pathological disorder associated with a significant rate of morbidity and mortality. To date, limited pharmacological agents exist to treat this disorder, and there is a growing interest for new therapies. In this context, pregabalin represents a promising strategy. Pregabalin, like gabapentin, selectively binds to the α2δsubunit of voltage-gated calcium channels, inhibiting release of excessive levels of excitatory neurotransmitters. The main focus of this review is the clinical use of pregabalin in alcoholic patients, but the authors also reported some data about chemistry, pharmacology, and pharmacokinetics of this drug. The authors conducted a PubMed search of clinical human studies published in English from January 2000 to August 2012 using the following search terms: pregabalin alcohol dependence, pregabalin alcohol withdrawal, pregabalin alcoholism. The search revealed a total of five studies: two trials for the treatment of alcohol relapse and three articles for the management of alcohol withdrawal syndrome with pregabalin. The critical review of the literature suggests that pregabalin could be a novel and effective treatment option for the management of alcohol relapse in detoxified patients, whereas until now there have been mixed results for the treatment of alcohol withdrawal syndrome. In particular, pregabalin showed a greater beneficial effect on patients with comorbid conditions such as alcoholism and generalized anxiety disorders. The exact mechanism of action of pregabalin in the management of alcoholism is not well understood but it is thought to be due mainly to the modulation of neurotransmitters such as glutamate and norepinephrine by inhibiting activity-dependent calcium influx in nerve terminals. Pregabalin, within a dosage of 150–450 mg/day, showed beneficial effects for alcohol relapse prevention and contrasting results for the treatment of the withdrawal syndrome. Its use appears to be safe and well tolerated.

Somatostatin analogues are used to treat symptoms and slow tumour progression in patients with neuroendocrine tumours (NETs) and carcinoid syndrome and to reduce hormone secretion and pituitary tumour volume in patients with acromegaly. A new syringe for lanreotide autogel/depot (LAN) was developed following feedback from a human factors study to improve ease of injection compared with previous syringes. PRESTO aimed to assess preferences of nurses between the LAN new syringe and the octreotide long-acting release (LAR) syringe. PRESTO, a multinational, multicentre, prospective, noninterventional, simulated-use study, enrolled nurses with ≥ 2 years’ experience injecting LAN and/or octreotide LAR in patients with NETs and/or acromegaly. Nurses administered injections into pads using the LAN new syringe and octreotide LAR syringe in a randomised sequence. In an anonymous web-based questionnaire, nurses reported their overall preference (‘strong’ or ‘slight’; primary endpoint) and rated and ranked the importance of nine attributes for each syringe (1 [not at all] to 5 [very much]). Overall, 90 nurses attended sessions and completed valid questionnaires. Most nurses (97.8%) expressed a preference (85.6% ‘strong’, 12.2% ‘slight’) for the LAN new syringe versus the octreotide LAR syringe (P < 0.0001). Attribute performance ratings (1 [not at all] to 5 [very much]) were consistently higher for the LAN new syringe versus the octreotide LAR syringe, with the greatest differences in ‘fast administration’ and ‘confidence the syringe will not be clogged’ (mean difference [SD]: 2.6 [1.2] and 2.3 [1.5], respectively; P < 0.0001). The attribute ranked most important was ‘confidence the syringe will not be clogged’ (24.4%); least important was ‘convenience of syringe format, including packaging, from preparation to injection’ (34.4%). Nurses preferred the user experience of the LAN new syringe compared with the octreotide LAR syringe, with a particular preference for attributes related to product delivery with the LAN new syringe.

Immediate-release sodium oxybate (SXB) has been Food and Drug Administration (FDA)-approved to treat narcolepsy since 2002; in 2020, a mixed-salt oxybates formulation was also approved. Both are taken at bedtime with a second dose taken 2.5–4 h later. A third oxybate option, an investigational extended-release SXB, may soon be available. This study was undertaken to understand clinicians’ preferences between these 3 different oxybate treatments. Clinicians in active clinical practice for 3–35 years and experience treating patients with narcolepsy were recruited. A 30-min web-based survey quantified narcolepsy disease-state attitudes, treatment perceptions, and satisfaction with oxybates on 9-point scales. A discrete choice experiment (DCE) of 12 choice sets, with 2 hypothetical treatment profiles in each, was used to capture clinician preferences about overall oxybate therapy preference, impact on patient quality of life (QoL), and patient anxiety/stress. Attributes associated with current therapies and those expected to be available in the near future were included in the design. The clinicians surveyed (n = 100) indicated that narcolepsy has a negative impact on patient QoL (mean rating, 7.7) and rated impact on QoL and treatment efficacy as the most important aspects of a narcolepsy treatment (mean rating, 7.3–7.7). Clinicians with experience prescribing oxybates had moderately high satisfaction with SXB and mixed-salt oxybates efficacy (mean ratings, 6.5–6.9) and safety (mean ratings, 6.1–6.7) and lower satisfaction with nightly dosing frequency (mean rating, 5.9 and 6.3, respectively). In the DCE, dosing frequency was the most important attribute driving overall product choice, patient QoL, and reducing patient anxiety/stress (relative attribute importance, 46.1, 41.7, and 44.0, respectively), with once nightly preferred over twice nightly. Clinicians indicated a significantly higher preference for the once-at-bedtime dosing schedule versus twice nightly in selecting oxybate therapies overall and when aiming to improve patient QoL or reduce patient anxiety. Current medications for narcolepsy include immediate-release sodium oxybate and mixed-salt oxybates. People taking these oxybates for narcolepsy take 1 dose at bedtime and must wake up 2.5–4 h later for the second dose. An investigational sodium oxybate, designed as a single bedtime dose, has been tentatively approved by the US Food and Drug Administration. This study used a 30-min web-based survey to learn what clinicians think about narcolepsy and narcolepsy medicines. A discrete choice experiment was used to identify which properties of current/future oxybate medicines are most important in a narcolepsy treatment. In this exercise, relevant properties of current/future oxybate medicines were mixed and matched to create hypothetical medicine profiles. Clinicians selected from these profiles which medication they preferred overall, which would improve patient quality of life, and which would reduce patient anxiety when thinking about taking the treatment. Clinicians were moderately satisfied with the effectiveness and safety of current narcolepsy medications. They strongly preferred oxybate treatments with fewer nightly doses and agreed that waking up for the second oxybate dose causes stress for patients. In the discrete choice experiment, the number of doses each night was the product characteristic that had the biggest impact on clinicians picking a medicine for narcolepsy. This was true for overall medicine choice, choosing a medicine that would improve patient quality of life, and choosing one that would reduce patient anxiety/stress. If granted marketing approval, extended-release sodium oxybate will be a once-at-bedtime option that may overcome challenges with current oxybate therapies.

The purpose of this study was to compare moxifloxacin’s rate of kill of susceptible and resistant Gram-positive organisms with that of ciprofloxacin and ofloxacin, using concentrations found in human conjunctiva after instillation of one drop. Staphylococcus aureus (S. aureus) and Streptococcus pneumoniae (S. pneumoniae) isolates were exposed to moxifloxacin, ciprofloxacin, or ofloxacin diluted to human conjunctival concentrations achieved after instillation of one drop. These treated isolates were cultured on blood agar plates at 0, 15, 30, and 60 minutes after exposure, and incubated to observe the number of surviving colony-forming units/mL. In susceptible S. pneumoniae, moxifloxacin showed the most rapid reduction of colonies at 15 and 30 minutes, with the fewest colonies at 60 minutes compared with ciprofloxacin and ofloxacin. In S. pneumoniae resistant to ciprofloxacin and ofloxacin, moxifloxacin had rapid reduction in colonies at each time point and near-eradication at 60 minutes, while ciprofloxacin and ofloxacin had an increase in colonies at 60 minutes. In susceptible S. aureus, moxifloxacin had a rapid decrease in colonies at 15 and 30 minutes, compared with a slight reduction in colonies at these intervals for the other antibiotics. In methicillin-resistant S. aureus with cross-resistance to fluoroquinolones and other antibiotics, moxifloxacin had a decrease in colonies at each time point compared with an increase at each time point for ciprofloxacin and ofloxacin. Moxifloxacin showed an increased speed of kill against both of the common susceptible Gram-positive conjunctival pathogens, compared with the inconsistency of killing activity of two other fluoroquinolones tested. In addition, at the concentration level achieved in the conjunctiva after the instillation of one drop, moxifloxacin effectively and rapidly killed resistant Gram-positive conjunctival pathogens, while ciprofloxacin and ofloxacin had no effect against these organisms.

Breast cancer (BC) is the most common type of cancer diagnosed among women worldwide with an estimated 2.3 million new cases every year. Almost two-thirds of all patients with BC have estrogen receptor-positive (ER+) tumors. In this review, the clinical evidence of exemestane in different treatment settings in ER+ BC is presented and summarized. A search strategy with the keywords “breast cancer [MeSH Terms]” AND “exemestane [Title/Abstract]” was devised and a search was performed in PubMed. The efficacy of exemestane in different treatment settings has been established by numerous clinical studies. Exemestane is recommended as an adjuvant treatment in postmenopausal women previously treated with tamoxifen in trials comparing 5 years of tamoxifen with 2–3 years of tamoxifen combined with 2–3 years of exemestane, which proved that treatment with exemestane provided better survival outcomes. Similarly, exemestane could be considered as a safe treatment option for neoadjuvant treatment, prevention of chemotherapy, and treatment of advanced BC either alone or in combination with other targeted therapy drugs in both pre- and postmenopausal women. Exemestane could be considered as a reasonable therapeutic option in the treatment of ER+ BC at any stage in pre- and postmenopausal women.

An anal fissure is a painful linear ulcer in the lower part of the anal canal. It is very often referred to as an ischemic ulcer. Anodermal blood flow is negatively correlated with resting pressure of the anus. Increased activity of the internal anal sphincter may decrease the anodermal blood supply by compressing arterioles. Surgical procedures and botulinum treatment for patients with chronic anal fissure produce a temporary reduction in anal pressure, reverse sphincter spasm, and promote fissure healing. However, recent studies have shown that fissure healing does not appear to be dependent on reduction in mean resting anal pressure. On the basis of the published literature, this article attempts to explain this phenomenon in detail. The mechanism of action of botulinum toxin on the internal anal sphincter is not yet fully understood. This review focuses on problems associated with anal fissure treatment and presents them from the wider angle of science about botulinum toxin. In our opinion, anodermal blood flow depends not only on the “mechanical” force of sphincters but also on biochemical processes that occur in the fissure region.