A randomized controlled proof-of-concept trial of digoxin and furosemide in adults with cutaneous warts.

BACKGROUND: Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts. OBJECTIVES: To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT. METHODS: Treatment with ICVT was assessed for efficacy, safety and tolerability in a single- centre, randomized, double-blind, placebo-controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed-model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643. RESULTS: Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (-3·0 mm, 95% confidence interval -4·9 to -1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (-94%, 95% confidence interval -100 to -19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts. CONCLUSIONS: This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

Glutathione-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study.

AIMS: Intravenous high-dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing-remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione-PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy. This first-in-human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione-PEGylated liposomes containing MP (2B3-201). METHODS: The first part was a double-blind, three-way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3-201, active comparator (free MP) or placebo. Part 2 of the study was an open-label infusion of 2B3-201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross-over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests. RESULTS: The most frequent recorded AE related to 2B3-201 was an infusion related reaction (89%). 2B3-201 was shown to have a plasma half-life between 24 and 37 h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose. CONCLUSION: 2B3-201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects.

Topical ionic contra-viral therapy comprised of digoxin and furosemide as a potential novel treatment approach for common warts.

BACKGROUND: DNA viruses such as HPV rely on K+ influx for replication. Both digoxin and furosemide inhibit the K+ influx by interacting with cell membrane ion co-transporters (Na+ /K+ -ATPase and Na+ -K+ -2Cl- co-transporter-1, respectively). We therefore hypothesized that these two compounds in a topical formulation may be valuable in the treatment of HPV-induced warts. This new approach is called Ionic Contra-Viral Therapy (ICVT). OBJECTIVE: To evaluate systemic exposure, safety and tolerability of ICVT with a combination of furosemide and digoxin after repeated topical application in subjects with common warts. Furthermore, we aimed to evaluate pharmacodynamics effects of ICVT. METHODS: Twelve healthy subjects with at least four common warts on their hands were included in the study and treated with a fixed dose of 980 mg topical gel containing 0.125% (w/w) digoxin and 0.125% (w/w) furosemide for 7 consecutive days on their lower back to assess safety and systemic exposure. Two warts were treated with 10 mg each and two served as negative controls to obtain preliminary evidence of treatment effect. RESULTS: ICVT was well tolerated topically, and there was no evidence of systemic exposure of digoxin or furosemide. There were no clinical relevant safety findings and no serious adverse events (SAEs). A rapid and statistically significant reduction in diameter, height and volume of the warts was already observed at day 14. CONCLUSION: ICVT was found to be safe for administration to humans and 7 days of active treatment showed a statistical significant wart reduction compared to untreated control lesions, clearly indicating pharmacological activity.

Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach.

BACKGROUND/AIMS: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. METHODS: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. RESULTS: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. CONCLUSION: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects.

Obesity is associated with an altered autonomic nervous system response to nutrient restriction.

OBJECTIVE: Heart rate variability (HRV) reflects the balance of activities of sympathetic and parasympathetic components of the autonomic nervous system. We compared HRV parameters in response to a prolonged fast in obese versus normal weight humans. In addition, the effect of weight-loss was evaluated in obese individuals. DESIGN: Intervention study. PATIENTS: The study subjects included 14 nondiabetic obese (12 females/2 males, aged 30 ± 3 years, Body Mass Index (BMI) 35·2 ± 1·2 kg/m(2) ) and 12 lean subjects (10 females/2 males, aged 27 ± 3 years, BMI 23·3 ± 0·5 kg/m(2) ). MEASUREMENTS: HRV was examined 75 min after standardized breakfast and after a 48-h fast in 14 nondiabetic obese and 12 lean subjects. The postprandial measurement was repeated in 12 obese subjects after weight-loss. RESULTS: In lean subjects, fasting decreased high-frequency (HF) power by 43% (P < 0·05) and decreased low-frequency (LF) power by 37% (P = 0·1), leaving the LF/HF ratio unchanged (P = 0·7). In the obese group, autonomic nervous system tone shifted to sympathetic dominance as the LF/HF increased from 0·61 to 1·14 (P = 0·03). After an average weight-loss of 13·8 kg in obese subjects, a trend for sympathetic dominance was found; the LF/HF ratio increased by 56% (P = 0·06). CONCLUSION: Our data show that a 48-h fast leaves autonomic nervous system balance unaltered in lean subjects. In contrast, a 48-h fast, as well as weight-loss, induces sympathetic dominance in obese humans.

Pharmacokinetics and central nervous system effects of the novel dopamine D3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state.

GSK598809 is a novel selective dopamine D(3) receptor antagonist, currently in development for the treatment of substance abuse and addiction. In a blinded, randomized, placebo-controlled study, effects of single oral doses of 175 mg GSK598809 were evaluated in healthy volunteers. Pharmacokinetics, central nervous system (CNS) effects and potential for interactions with alcohol were evaluated, using an alcohol infusion paradigm and analysis of eye movements, adaptive tracking, visual analogue scales, body sway, serum prolactin and verbal visual learning test. Adverse effects of GSK598809 included headache, dizziness and somnolence. Plasma concentration of GSK598809 was maximal 2-3 hours postdose and decreased with a half-life of roughly 20 hours. CNS effects were limited to prolactin elevation and decreased adaptive tracking. Co-administration of GSK598809 and alcohol did not affect alcohol pharmacokinetics, but caused a 9% decrease of C (max) and a 15% increase of AUC of GSK598809. CNS effects of co-administration were mainly additive, except a small supra-additive increase in saccadic reaction time and decrease in delayed word recall. In conclusion, GSK598809 causes elevation of serum prolactin and a small decrease in adaptive tracking performance. After co-administration with alcohol, effects of GSK598809 are mainly additive and the combination is well tolerated in healthy volunteers.