Pharmacovigilance (PhV) databases were screened from 1986 until 2013 without revealing signals – though as highlighted above there are doubts about as to the use of such a database in uncovering relationships between SCIT and e.g., neurodegenerative diseases having a latency period of many years. A perceived positive benefit–risk-ratio is reiterated in their statement. However, since the potential of accumulation of aluminium in the body is clearly significant in the course of SCIT, companies learn more themselves indicate in relevant sections of their SmPCs as follows: “During therapy with AVANZ®preparations, taking

aluminium-containing drugs (e.g. antacids) should be restricted.” [67]. Additionally, “This product contains aluminium (4 mg). The risk of aluminium accumulation in tissues (CNS, bones) must be taken into account, in particular in case of renal insufficiency. The effects on the immune system of long-term administration of aluminium are unknown. As this preparation contains a considerable amount of aluminium, it is recommended to avoid taking other aluminium-containing medications (e.g. antacids) concomitantly.” [68]. Furthermore, PD0332991 molecular weight “Patients with Alzheimer’s

disease, Down’s syndrome and renal insufficiency are theoretically at risk from aluminium intake, including alum precipitated allergenic extracts” [69]. While so far it has not yet been definitely clarified which form of aluminium acts as an antigen [70], immune reactions to antigenic aluminium as a consequence of SCIT is plausible. Such immune reactions would target aluminium deposits in the human body, which has the potential to contribute to the onset and progression of aluminium-induced

autoimmune diseases [59]. The amount of aluminium in SCIT is a significant addition to the lifelong exposure to the metal in children and adults. Taking this into account the toxicological considerations, it is not unreasonable to question the long-term impact this has on human health. Long-term aluminium adjuvant-based immunotherapy treatment unquestionably predisposes an individual to a likely set of circumstances that could lead to accumulation, Tryptophan synthase toxicity and disease. According to Good Pharmacovigilance Practices, assessment of a benefit–risk relation must take into account the severity of the treated disease (e.g. hay fever), the presence of therapy alternatives, and to the type of risk assessed. In Germany, licensed and comprehensively documented alternative products with other depot mediators are commercially available for example use of l-tyrosine, a non-essential amino acid physiologically generated from phenylalanine and fully metabolised with a half-time of 48 h, has been well-documented as a commercial alternative for over 40 years [71], [72] and [73].