Levrini L, Azzi L, Bossi S. The efficacy of a dietary supplement with carnosine and Hibiscus sabdariffa L. (AqualiefTM) in patients with xerostomia: a randomized, placebo-controlled, double-blind trial. Clin Ter. 2020;171(4):e295-301.
To determine if a combination of Hibiscus sabdariffa L. and carnosine significantly improves dry mouth compared to placebo
Prospective, double-blind, placebo-controlled trial at a single center (Clinica Odontoiatria dell’Università degli Studi dell’Insubria, Varese, Italy)
Sixty patients, gender not stated, with xerostomia according to the Dry Mouth Questionnaire
Xerostomia grades 1–2 according to RTOG/EORTC (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer)
Using medication to treat hyposalivation (eg, pilocarpine), xerostomia grade 3 or worse, and patients with hyposalivation or a saliva flow less than 0.1 mL/min
Study Parameters Assessed
Modified Thomson’s questionnaire for subjective information about the severity of dry mouth pre- and post-treatment. Researchers used a dry mouth questionnaire (DMQ) to assess oral dryness, swallowing issues, dryness during eating, dryness of the face, dryness of the eyes, dryness of the lips, and dryness of inside of the nose, initially and after 6 days of treatment, using a 1–3 scale (1=never, 2=sometimes, 3=very often). They determined saliva production by the spit method every 30 seconds for 5 minutes in a tube without stimulation for a resting saliva measure. Then there was a rest of 2 minutes, stimulation of saliva by chewing of paraffin wax, and a repeat of the spit method for 5 minutes to give a stimulated saliva sample. Researchers measured the pH of resting and stimulated saliva using a pH electrode.
AqualiefTM (Helsinn Healthcare SA, Lugano, Switzerland) is a 400-mg mucoadhesive smooth tablet. Under normal salivation, it dissolves in about 2 hours. It contains carnosine and dried calyces of Hibiscus sabdariffa. Placebo tablets had the same look and size without the 2 ingredients. Participants took the tablets 3 times per day after meals for 6 consecutive days.
Researchers analyzed data using descriptive statistics. They analyzed DMQ scores by the Wilcoxon signed-rank test. They used the Mann-Whitney U test for 2 independent samples to compare the 2 groups at baseline. Students’ t test was used for stimulated and unstimulated salivary flow rates and pH values. Statistical significance, P, was set at less than 0.05. Researchers performed statistical analysis on GraphPad Prism version 6.00.
The researchers screened 64 patients and enrolled and assigned them to either the treatment or placebo group. No patients were lost to follow-up. On the DMQ, 32% reported a dry mouth very often and 68% reported it sometimes. Mean saliva pH was 6.2 at baseline. Mean saliva flow rate at baseline was 0.43 + 0.22 mL/minute. Average age was 53 + 20 years in the treatment group and 50 + 20 years in the placebo group. Prescriptions used were similar between the 2 groups.
Saliva production in the treatment group was nearly 3 times that of the placebo group, along with an improvement in saliva pH that could reduce dental caries formation.
pH: 6 days of treatment led to a significant increase in saliva pH from 6.2 + 0.5 to 6.4 + 0.6, P<0.05. At baseline, 4 of the participants in the treatment group had a cariogenic pH of <5.5; all improved with treatment. In the placebo group pH was 6.2 + 0.5 and increased not significantly to 6.3 + 0.5. Stimulated saliva in the treatment group rose significantly from 6.3 + 0.5 to 6.6 + 0.5, P<0.01. Those with a stimulated pH at baseline were corrected with treatment.
Saliva Quantity: Resting saliva production in the placebo group increased 19%, P<0.05, while in the treatment group production increased 56%, P<0.0001. Stimulated saliva production was unchanged in the placebo group but increased from 0.85 to 1.08 mL (27%) in the treatment group, P<0.05.
Symptomology: Based on the DMQ, only the treatment group had significant improvement in dry mouth, difficulty swallowing dry food, and dryness inside the nose. No patients in either group reported adverse events during or after the trial.
The placebo group had improvement only in saliva production, but the authors argued it may have been due to mechanical stimulation from a foreign object in the mouth. The treatment group had improvement in saliva pH, pH of saliva production, and stimulated saliva production. Saliva production in the treatment group was nearly 3 times that of the placebo group, along with an improvement in saliva pH that could reduce dental caries formation.
Xerostomia can be caused by burning mouth syndrome (as it was for 8 patients in this study), oncology treatment including radiation and chemotherapy (28 in this study), humane immunodeficiency virus (HIV; 2 in this study), antihypertensive and selective serotonin reuptake inhibitor (SSRI) medications (13 in this study), lateral cheilitis (2 in this study), and other (7 in this study), as well as diabetes, stroke, dementia, tobacco, alcohol, botulism poisoning, cystic fibrosis, aging, some antihistamines, appetite suppressants, tranquilizers, anxiety, stress, and unknown causes.1 In this trial nearly half of the cases were due to side effects of cancer treatment.
Carnosine (beta-alanyl-L-histidine) is a dipeptide discovered by the Russian chemists Gulewitsch and Amiradzižbi in 1900 and is found in the brain, kidney, and skeletal muscles of fish, birds, and mammals.2 It can scavenge reactive oxygen species and reactive nitrogen species, bind aldehydes and ketones, chelate metal, buffer hydrogen ions, regulate factor 4E protein, and increase cell life spans.3,4 Its concentration is higher in postmitotic adult cells compared to actively dividing cells.3 Muscle carnosine levels are low in young children (4–5 years old), much higher during the early teenage growth spurt (14 years old), and then decline in adulthood.5 Thus it appears to be beneficial in oxidative phosphorylation for ATP (adenosine triphosphate) production and is higher in fast-twitch than in slow-twitch muscles.6
Neurological studies of carnosine have shown suppression of amyloid accumulation in mouse models of Alzheimer's dementia,7 Parkinson's disease in humans,8,9 and schizophrenia in humans.10,11 Carnosine as a 5% solution has also been shown to be beneficial in slowing cataract development in cattle and humans.12 I first became aware of this in 1998 via an English abstract of a Russian article that I cajoled Ganady Raskin, MD, ND, to give me a cursory translation of for clinical purposes; I have since used carnosine eye drops as a 1% solution of N-acetylcarnosine with benefit to some patients. Key to clinical success with carnosine in most trials is the use of a form resistant to carnosinase enzyme degradation, such as N-acetylcarnosine, acetyl-L-carnosine, and homocarnosine.3
In the current trial the authors provide a cursory review of carnosine, and the reference given for their 1-sentence review of Hibiscus sabdariffa (HS), of the Malvaceae family, is actually for carnosine, not HS. This plant is probably from India or Saudi Arabia with domestication going back to before 4000 BC in western Sudan.12 HS sepals or calyces that encase the flowers contain at least 4 organic acids, 2 anthocyanins, and at least 33 flavonoids and phenolic acids.12 HS has been shown in humans to be an antioxidant, hepatoprotective, nephroprotective, and antihypertensive in type 2 diabetics; to increase corticosterone during pregnancy and lactation; and to have a good safety profile.13 It may be in this formula for its anti-inflammatory effect. Clinically I find HS useful for hypertension and the effects of stress-induced anxiety.
Saliva pH is a critical factor in the formation of dental caries. A consistent pH of less than 5.5 can lead to tooth demineralization. Saliva pH range is normally 6.2 to 7.6, with an average of 6.7.14 In a recent study of saliva pH and type 2 diabetes, the non-diabetic control group had a saliva pH of 7.88, while the diabetic patients had a saliva pH of 6.51.14
The article is well written. The researchers do not state the rationale behind the combination of carnosine and HS, nor do they describe the amount of each ingredient or how the HS was extracted. The trial was in patients with multiple causes of xerostomia, but in the final analysis, there was no indication if 1 or more conditions had a better outcome compared to other causes, nor was the distribution of diagnoses across the 2 treatment groups stated. Six treatment days is a very short trial, and the extent of lasting benefit after the trial is unclear. Whether a longer treatment time would yield better results is also unknown.
During a 6-day trial with AqualiefTM, the treatment group had a significant improvement in saliva pH, saliva production, and stimulated saliva production compared to the placebo group. Nearly half of the subjects had xerostomia due to side effects of chemotherapy and/or radiation treatments, suggesting this supplement may benefit patients with those causes for their xerostomia.