A single-dose, open-label, randomized, scintigraphic study to investigate the gastrointestinal behavior of 2 triple-combination cold products (acetaminophen, phenylephrine, and dextromethorphan) in healthy male volunteers.

BACKGROUND: Common cold symptoms may be mitigated by products in caplet, nasal spray, and oral solution formulations, although variations exist in the bioavailability of the active ingredients contained within these products. Rapid gastric emptying (GE) of these active ingredients is important for reducing the delay between drug absorption and onset of cold symptom relief. Hot drink cold remedies are associated with greater comfort and may enhance the bioavailability of active ingredients. The objective of this study was to characterize the gastrointestinal transit of powder (reconstituted in hot water) and caplet formulations of commercially available multisymptom cold medications. METHODS: This was an open-label, single-dose, parallel-group study. Healthy male adults under fasted conditions were randomized 1:1 to receive a single dose of radiolabeled Theraflu Daytime Severe Cold and Cough powder for oral solution or radiolabeled Theraflu ExpressMax Daytime Severe Cold and Cough caplet. External gamma scintigraphy was utilized to monitor GE and intestinal transit of two radiolabeled drug formulations. RESULTS: A total of 28 participants completed the study. The mean ± SE GE onset times were 1.1 ± 0.3 min and 8.5 ± 1.8 min for powder and caplet formulations, respectively. The mean ± SE GE completion times were 121 ± 13 min and 65 ± 13 min, respectively. Despite the similar mean times to GE25%, the powder had later mean GE50% (23 ± 3.0 vs 16 ± 3.2 min, respectively) and GE90% (85 ± 12 vs 36 ± 9 min, respectively) than caplets. Caplets had a shorter overall GE half-life, lower total gastric exposure, and faster transit time through the small intestine versus the powder formulation. No serious safety events were observed. CONCLUSION: The results of this study in healthy male adults suggest that the Theraflu powder formulation had a more rapid GE onset but longer time to GE completion than the caplet formulation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03415243.

Observational study of the effects of upper respiratory tract infection on hydration status.

BACKGROUND: A frequent treatment recommendation during acute respiratory infection is to increase fluid intake. This is the first study to investigate whether upper respiratory tract infections (URTIs) such as common cold can lead to dehydration, as commonly believed by the public. METHODS: This was an exploratory, noninterventional, observational, single-center study. Subjects made 2 visits to a UK study center for assessments of dehydration, once during URTI and then 2-3 weeks later when fully recovered. The primary endpoint was a comparison of serum osmolality during vs after URTI. Complete blood count, serum urea, serum electrolytes, urine parameters (eg, osmolality, specific gravity, color), body weight/BMI, subjective assessment of thirst, and physician assessment of dehydration were additional outcomes. Only descriptive statistics and shift tables were used. RESULTS: Fifty-five otherwise healthy adults with moderate to severe URTI of < 120 h in duration were enrolled (63.6% female, 94.5% white, mean [SD] age 21.0 [6.8] years). There was no evidence of dehydration based on serum osmolality (mean [SD] 287.63 [4.83] mosm/kg during URTI; 288.60 [5.99] mosm/kg after recovery). With only a few exceptions, complete blood count, serum urea, serum electrolytes, urine specific gravity, urine color, and physician ratings of hydration remained stable. Body weight decreased > 1% in 34.0% of subjects and increased > 1% in 17.0% between visits, with similar changes in BMI. Urine osmolality varied: 14 subjects showed a decrease and 5 showed an increase, resulting in a higher mean [SD] urine osmolality during URTI (700.50 [231.59] vs 618.47 [320.29] mosm/kg). Subjects perceived greater thirst during URTI. CONCLUSIONS: In this pilot observational study, we found no evidence that URTIs such as common cold are associated with dehydration, contrary to popular belief.

Efficacy of 8 mg lidocaine and 2 mg cetylpyridinium chloride (CPC) fixed-combination lozenges on sore throat pain intensity compared with 1 mg lidocaine and 2 mg CPC fixed-combination lozenges in subjects with sore throat due to upper respiratory tract infection: a randomized double-blind parallel-group single-dose study.

BACKGROUND: Lozenges containing lidocaine and cetylpyridinium chloride (CPC) are commonly used for the treatment of sore throat. The lidocaine acts locally to provide pain relief and the CPC has an antiseptic effect. Mebucaine CL, a well-established fixed-combination sore throat lozenge, contains 1 mg lidocaine and 2 mg CPC. Single-agent lozenges containing 8 mg lidocaine have also been demonstrated to be significantly superior to placebo in confirmatory pain intensity assessments. This study compared a new lozenge formulation, containing 8 mg lidocaine and 2 mg CPC, with the currently marketed lozenge for the treatment and relief of sore throat symptoms in subjects diagnosed with a sore throat due to an upper respiratory tract infection (URTI). METHODS: In this double-blind parallel-group study, 250 adults with a sore throat due to an URTI were randomized to receive a single lozenge containing either 8 mg lidocaine + 2 mg CPC (n = 125) or 1 mg lidocaine + 2 mg CPC (n = 125). The primary efficacy endpoint of the study was the change in sore throat pain intensity (STPI) between baseline (immediately pre-treatment) and the 2-h post-dose assessment, measured on a 100 mm visual analog scale. STPI was measured at baseline and regular intervals up to 240 min after the lozenge was administered (evaluated in clinic). Any difficulty in swallowing and time to onset and duration of the analgesic effect were also assessed. RESULTS: No increase in efficacy was demonstrated with the higher dose of lidocaine. The difference in the 2-h post-dose change in STPI was not statistically significant between the treatments. There was only one statistically significant difference between the treatments in all of the efficacy outcomes assessed: pain relief scores at 4 h post-dose were higher with 1 mg lidocaine + 2 mg CPC than with 8 mg lidocaine + 2 mg CPC (P = 0.0461). The most commonly reported adverse event (AE) was a headache; the only other AE experienced by more than one subject was throat irritation. No severe adverse events were reported during the assessment period. CONCLUSIONS: The modest difference in the pattern of effectiveness between the two treatments observed in this study does not support use of the 8 mg lidocaine + 2 mg CPC lozenge. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01265446 . Registered on 20 December 2010.

Time-to-onset of cold and flu symptom relief: A randomized, double-blind, placebo-controlled pilot study for a multi-symptom combination product.

OBJECTIVE: Evaluate effects of a multisymptom tablet on cold and flu symptoms within 4 hours post-administration. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled study in adults with cold and flu symptoms. Eligible participants with at least moderate common cold or flu symptoms and symptom onset ≤ 48 hours before screening were assigned to a single multiple-active-ingredient tablet (containing paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate) or placebo tablet. Participants rated severity of each symptom (sore throat, headache, extremity pain, nasal congestion, sneezing, runny nose, and cough) from 0 (absent) to 3 (severe) at 15 and 30 minutes and 1, 2, 3, and 4 hours post administration. The total symptom score (TSS) was calculated as the sum of the individual symptom scores (primary endpoint). Participants rated global response to treatment on a scale from 0 (ineffective) to 4 (excellent). Adverse events (AEs) were recorded throughout. RESULTS: Of 53 participants randomized, 52 received active tablet (n = 25) or placebo tablet (n = 27). Change from baseline in TSS throughout the 4-hour post-administration period was similar between groups. An efficacy criterion of 30% decrease in TSS at assessment points was not met (range, -1.91 to 8.94%). There were also no significant differences between groups in mean symptom scores for individual symptoms or global response to treatment. Four non-serious treatment-emergent adverse events occurred. CONCLUSION: In this exploratory pilot study, a multisymptom cold and flu tablet was well tolerated but did not differ from placebo tablet with regard to onset of action following a single dose.
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Evaluation of the warming sensation, acceptability, and local tolerability of an acetylcysteine oral solution containing the flavoring agent IFF flavor 316282 in the treatment of productive cough
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OBJECTIVE: This open-label study sought to evaluate the warming sensation produced by IFF flavor 316282 in an acetylcysteine oral solution in subjects with productive cough. MATERIALS: 2% ace-tylcysteine oral solution (200 mg per 10 mL) containing IFF flavor 316282. METHODS: Subjects (N = 57; mean age 38.7 years; 58% female) with a productive cough lasting < 7 days and rated as mild to moderate in severity received 10 mL of study product. Warming sensation intensity was assessed using a 100-mm visual analog scale, its onset and duration using stopwatches, its acceptability using a 9-point scale (from "dislike extremely" to "like extremely") and the taste, texture, and overall acceptability of the solution using 5-point scales (from "unacceptable" to "excellent"). RESULTS: 53 (93.0%) subjects perceived a warming sensation within 10 minutes of swallowing the solution; median onset was ~ 14 seconds, and median duration was ~ 2.8 minutes. Warming sensation intensity increased from baseline by a mean of 29.2 mm when evaluated 60 seconds after ingestion. 30 subjects (52.6%) thought the warming sensation was "just about right"; 25 (43.9%) considered it "too weak" or "much too weak." Most subjects had positive overall ratings ("fair," "good," or "excellent") of the taste (79.0%), texture (96.5%), and solution (91.2%). No treatment-emergent adverse events were reported, and no evidence of oral mucosal irritation was found. CONCLUSION: The addition of IFF flavor 316282 to a 2% acetylcysteine oral solution produced a warming sensation with rapid onset and relatively short duration, which the majority of subjects found acceptable.
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Soothing Properties of Glycerol in Cough Syrups for Acute Cough Due to Common Cold.

The treatment and management of acute cough due to common cold costs billions of dollars of healthcare expenditure and there is a growing opinion that a simple linctus containing glycerol with flavourings such as honey and lemon is a safe and effective treatment for acute cough in children and adults. Glycerol is a component of most cough syrups, and although it is often thought of only as a solvent or thickening agent in cough syrups, it may be a major component for the efficacy of cough syrups due to its special properties of lubrication, demulcency, sweetness, and acting as a humectant. The major benefit of cough syrups in soothing cough is likely due to the properties of the syrup rather than the active ingredients and this review discusses the special properties of glycerol in relation to the treatment of acute cough.

Effectiveness of cross polarized light and fluorescence diagnosis for detection of sub-clinical and clinical actinic keratosis during imiquimod treatment.

BACKGROUND: During treatment of actinic keratosis (AK) lesions with imiquimod sub-clinical lesions often become visible. It is, however, unclear whether these sub-clinical lesions would be detectable beforehand. OBJECTIVE: The aim of this pilot study was to compare two techniques, cross polarized light photography (CPL) and fluorescence diagnosis (FD) using methyllevulinic acid and illumination with Wood's lamp for their ability to detect sub-clinical lesions. These findings were also compared with biopsy results taken before and after treatment with imiquimod 5% cream or vehicle. METHODOLOGY: Twelve patients with at least five clinically visible AK lesions in a single contiguous 20 cm(2) area on the head were recruited. Patient eligibility was determined at the screening visit, when they were randomized to treatment. The randomization was 3:1, active to vehicle (nine treated with imiquimod, three with vehicle cream) for a total duration of 24 weeks (six clinic visits). Patients were assessed for baseline AK lesion counts (clinical and sub-clinical) at the screening visit and final counts at week 20. RESULTS: The number of clinically observed AK lesions was significantly lower at week 12 and week 20 compared with baseline following imiquimod treatment versus vehicle. The number of counted lesions were significantly higher using the CPL method compared with clinical counting with imiquimod treatment at baseline (8.3 +/- 3.4 vs 5.8 +/- 1.3; P = 0.027) and week 20 (4.8 +/- 2.4 vs 3.0 +/- 1.7; P = 0.02) but not in the vehicle group. The FD lesion counting method did not show a significant increase in the number of detected lesions compared with clinical analysis in the imiquimod and placebo groups but when comparisons were performed using pooled data (treatments and visits combined) the results were significant. CONCLUSION: The number of sub-clinical and clinical AK lesions detected during treatment with imiquimod can be better demonstrated using the methods of CPL and FD, but statistical significance was reached only using the CPL method. This is only a preliminary study with a small number of patients and as a result it is difficult to conclude both statistical and clinical significance. However, results were encouraging and indicate that larger studies are needed to demonstrate the relevance of these two new methods for improved detection of clinical and especially sub-clinical AK lesions.

Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream used to treat herpes simplex virus infection.

BACKGROUND: Herpes simplex virus infection (HSV) is a common and ubiquitous infection of the skin which causes mucocutaneous lesions called cold sores (herpes labialis) or fever blisters. It is estimated that approximately 80% of the population worldwide are carriers of the Herpes simplex virus, approximately 40% suffer from recurrent recurrent infections. This study evaluates the in vitro skin permeation and penetration of penciclovir and acyclovir from commercialized creams for the treatment of herpes labialis (cold sores), using non viable excised human abdominal skin samples, which were exposed to 5 mg/cm2 of acyclovir 5% cream or penciclovir 1% cream. METHODS: After 24 h of cream application, excess cream was washed off and layers of stratum corneum were removed by successive tape stripping. Amounts of active ingredients having penetrated through the skin were measured, as well as the amounts in the washed-off cream, in skin strips and creams remaining in the skin. Molecular modelling was used to evaluate physico-chemical differences between the drugs. Western blot analysis enabled to determine whether the marker of basal cells keratin 5 could be detected in the various tape strips. RESULTS: Application of penciclovir 1% cream yielded higher concentration of drug in the deeper layers of the epidermis as well as a higher drug flux through the skin. Molecular modelling showed two higher hydrophobic moieties for acyclovir. Presence of the basal cell marker keratin 5 was underscored in the deeper tape strips from the skin, giving evidence that both drugs can reach their target cells. CONCLUSION: Penciclovir 1% cream has the tendency to facilitate the diffusion of the drug through the stratum corneum into the deeper epidermis layers, in which it could reach the target basal cells at effective therapeutical concentration. The small difference in the surface properties between both molecules might also contribute to favour the passage of penciclovir through the epidermis into the deeper basal cells.